Cancers

16 pages, 1272 KiB

Open AccessEditor’s ChoiceArticle

CT-Based Radiomics Analysis to Predict Histopathological Outcomes Following Liver Resection in Colorectal Liver Metastases

by Vincenza Granata, Roberta Fusco, Sergio Venanzio Setola, Federica De Muzio, Federica Dell’ Aversana, Carmen Cutolo, Lorenzo Faggioni, Vittorio Miele, Francesco Izzo and Antonella Petrillo

Cancers 2022, 14(7), 1648; https://doi.org/10.3390/cancers14071648 - 24 Mar 2022

Cited by 32 | Viewed by 5280

Abstract

Purpose: We aimed to assess the efficacy of radiomic features extracted by computed tomography (CT) in predicting histopathological outcomes following liver resection in colorectal liver metastases patients, evaluating recurrence, mutational status, histopathological characteristics (mucinous), and surgical resection margin. Methods: This retrospectively approved study [...] Read more.

Purpose: We aimed to assess the efficacy of radiomic features extracted by computed tomography (CT) in predicting histopathological outcomes following liver resection in colorectal liver metastases patients, evaluating recurrence, mutational status, histopathological characteristics (mucinous), and surgical resection margin. Methods: This retrospectively approved study included a training set and an external validation set. The internal training set included 49 patients with a median age of 60 years and 119 liver colorectal metastases. The validation cohort consisted of 28 patients with single liver colorectal metastasis and a median age of 61 years. Radiomic features were extracted using PyRadiomics on CT portal phase. Nonparametric Kruskal–Wallis tests, intraclass correlation, receiver operating characteristic (ROC) analyses, linear regression modeling, and pattern recognition methods (support vector machine (SVM), k-nearest neighbors (KNN), artificial neural network (NNET), and decision tree (DT)) were considered. Results: The median value of intraclass correlation coefficients for the features was 0.92 (range 0.87–0.96). The best performance in discriminating expansive versus infiltrative front of tumor growth was wavelet_HHL_glcm_Imc2, with an accuracy of 79%, a sensitivity of 84%, and a specificity of 67%. The best performance in discriminating expansive versus tumor budding was wavelet_LLL_firstorder_Mean, with an accuracy of 86%, a sensitivity of 91%, and a specificity of 65%. The best performance in differentiating the mucinous type of tumor was original_firstorder_RobustMeanAbsoluteDeviation, with an accuracy of 88%, a sensitivity of 42%, and a specificity of 100%. The best performance in identifying tumor recurrence was the wavelet_HLH_glcm_Idmn, with an accuracy of 85%, a sensitivity of 81%, and a specificity of 88%. The best linear regression model was obtained with the identification of recurrence considering the linear combination of the 16 significant textural metrics (accuracy of 97%, sensitivity of 94%, and specificity of 98%). The best performance for each outcome was reached using KNN as a classifier with an accuracy greater than 86% in the training and validation sets for each classification problem; the best results were obtained with the identification of tumor front growth considering the seven significant textural features (accuracy of 97%, sensitivity of 90%, and specificity of 100%). Conclusions: This study confirmed the capacity of radiomics data to identify several prognostic features that may affect the treatment choice in patients with liver metastases, in order to obtain a more personalized approach. Full article

(This article belongs to the Special Issue Radiology and Imaging of Cancer)

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33 pages, 1563 KiB

Open AccessEditor’s ChoiceReview

Using Quantitative Imaging for Personalized Medicine in Pancreatic Cancer: A Review of Radiomics and Deep Learning Applications

by Kiersten Preuss, Nate Thach, Xiaoying Liang, Michael Baine, Justin Chen, Chi Zhang, Huijing Du, Hongfeng Yu, Chi Lin, Michael A. Hollingsworth and Dandan Zheng

Cancers 2022, 14(7), 1654; https://doi.org/10.3390/cancers14071654 - 24 Mar 2022

Cited by 34 | Viewed by 7292

Abstract

As the most lethal major cancer, pancreatic cancer is a global healthcare challenge. Personalized medicine utilizing cutting-edge multi-omics data holds potential for major breakthroughs in tackling this critical problem. Radiomics and deep learning, two trendy quantitative imaging methods that take advantage of data [...] Read more.

As the most lethal major cancer, pancreatic cancer is a global healthcare challenge. Personalized medicine utilizing cutting-edge multi-omics data holds potential for major breakthroughs in tackling this critical problem. Radiomics and deep learning, two trendy quantitative imaging methods that take advantage of data science and modern medical imaging, have shown increasing promise in advancing the precision management of pancreatic cancer via diagnosing of precursor diseases, early detection, accurate diagnosis, and treatment personalization and optimization. Radiomics employs manually-crafted features, while deep learning applies computer-generated automatic features. These two methods aim to mine hidden information in medical images that is missed by conventional radiology and gain insights by systematically comparing the quantitative image information across different patients in order to characterize unique imaging phenotypes. Both methods have been studied and applied in various pancreatic cancer clinical applications. In this review, we begin with an introduction to the clinical problems and the technology. After providing technical overviews of the two methods, this review focuses on the current progress of clinical applications in precancerous lesion diagnosis, pancreatic cancer detection and diagnosis, prognosis prediction, treatment stratification, and radiogenomics. The limitations of current studies and methods are discussed, along with future directions. With better standardization and optimization of the workflow from image acquisition to analysis and with larger and especially prospective high-quality datasets, radiomics and deep learning methods could show real hope in the battle against pancreatic cancer through big data-based high-precision personalization. Full article

(This article belongs to the Special Issue Radiomics and Cancers)

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22 pages, 1333 KiB

Open AccessEditor’s ChoiceReview

Advances in Immunotherapy for the Treatment of Adult Glioblastoma: Overcoming Chemical and Physical Barriers

by Mirna Lechpammer, Rohan Rao, Sanjit Shah, Mona Mirheydari, Debanjan Bhattacharya, Abigail Koehler, Donatien Kamdem Toukam, Kevin J. Haworth, Daniel Pomeranz Krummel and Soma Sengupta

Cancers 2022, 14(7), 1627; https://doi.org/10.3390/cancers14071627 - 23 Mar 2022

Cited by 8 | Viewed by 4737

Abstract

Glioblastoma, or glioblastoma multiforme (GBM, WHO Grade IV), is a highly aggressive adult glioma. Despite extensive efforts to improve treatment, the current standard-of-care (SOC) regimen, which consists of maximal resection, radiotherapy, and temozolomide (TMZ), achieves only a 12–15 month survival. The clinical improvements [...] Read more.

Glioblastoma, or glioblastoma multiforme (GBM, WHO Grade IV), is a highly aggressive adult glioma. Despite extensive efforts to improve treatment, the current standard-of-care (SOC) regimen, which consists of maximal resection, radiotherapy, and temozolomide (TMZ), achieves only a 12–15 month survival. The clinical improvements achieved through immunotherapy in several extracranial solid tumors, including non-small-cell lung cancer, melanoma, and non-Hodgkin lymphoma, inspired investigations to pursue various immunotherapeutic interventions in adult glioblastoma patients. Despite some encouraging reports from preclinical and early-stage clinical trials, none of the tested agents have been convincing in Phase III clinical trials. One, but not the only, factor that is accountable for the slow progress is the blood–brain barrier, which prevents most antitumor drugs from reaching the target in appreciable amounts. Herein, we review the current state of immunotherapy in glioblastoma and discuss the significant challenges that prevent advancement. We also provide thoughts on steps that may be taken to remediate these challenges, including the application of ultrasound technologies. Full article

(This article belongs to the Special Issue Response, Toxicity and Resistance to Immune Checkpoint Inhibitor Cancer Therapy: Biological Mechanisms and Promising Solutions to Improve Future Outcomes)

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24 pages, 1677 KiB

Open AccessEditor’s ChoiceReview

Clinical Applications of Short Non-Coding RNA-Based Therapies in the Era of Precision Medicine

by Ellen S. Smith, Eric Whitty, Byunghee Yoo, Anna Moore, Lorenzo F. Sempere and Zdravka Medarova

Cancers 2022, 14(6), 1588; https://doi.org/10.3390/cancers14061588 - 21 Mar 2022

Cited by 34 | Viewed by 4896

Abstract

Traditional targeted therapeutic agents have relied on small synthetic molecules or large proteins, such as monoclonal antibodies. These agents leave a lot of therapeutic targets undruggable because of the lack or inaccessibility of active sites and/or pockets in their three-dimensional structure that can [...] Read more.

Traditional targeted therapeutic agents have relied on small synthetic molecules or large proteins, such as monoclonal antibodies. These agents leave a lot of therapeutic targets undruggable because of the lack or inaccessibility of active sites and/or pockets in their three-dimensional structure that can be chemically engaged. RNA presents an attractive, transformative opportunity to reach any genetic target with therapeutic intent. RNA therapeutic design is amenable to modularity and tunability and is based on a computational blueprint presented by the genetic code. Here, we will focus on short non-coding RNAs (sncRNAs) as a promising therapeutic modality because of their potency and versatility. We review recent progress towards clinical application of small interfering RNAs (siRNAs) for single-target therapy and microRNA (miRNA) activity modulators for multi-target therapy. siRNAs derive their potency from the fact that the underlying RNA interference (RNAi) mechanism is catalytic and reliant on post-transcriptional mRNA degradation. Therapeutic siRNAs can be designed against virtually any mRNA sequence in the transcriptome and specifically target a disease-causing mRNA variant. Two main classes of microRNA activity modulators exist to increase (miRNA mimics) or decrease (anti-miRNA inhibitors) the function of a specific microRNA. Since a single microRNA regulates the expression of multiple target genes, a miRNA activity modulator can have a more profound effect on global gene expression and protein output than siRNAs do. Both types of sncRNA-based drugs have been investigated in clinical trials and some siRNAs have already been granted FDA approval for the treatment of genetic, cardiometabolic, and infectious diseases. Here, we detail clinical results using siRNA and miRNA therapeutics and present an outlook for the potential of these sncRNAs in medicine. Full article

(This article belongs to the Special Issue Molecular Function and Clinical Value of Non-coding RNAs (ncRNAs) in Cancer Regulation)

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18 pages, 1147 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Mesothelin: An Immunotherapeutic Target beyond Solid Tumors

by Joshua R. Faust, Darcy Hamill, Edward Anders Kolb, Anilkumar Gopalakrishnapillai and Sonali P. Barwe

Cancers 2022, 14(6), 1550; https://doi.org/10.3390/cancers14061550 - 18 Mar 2022

Cited by 27 | Viewed by 8607

Abstract

Modern targeted cancer therapies rely on the overexpression of tumor associated antigens with very little to no expression in normal cell types. Mesothelin is a glycosylphosphatidylinositol-anchored cell surface protein that has been identified in many different tumor types, including lung adenocarcinomas, ovarian carcinomas, [...] Read more.

Modern targeted cancer therapies rely on the overexpression of tumor associated antigens with very little to no expression in normal cell types. Mesothelin is a glycosylphosphatidylinositol-anchored cell surface protein that has been identified in many different tumor types, including lung adenocarcinomas, ovarian carcinomas, and most recently in hematological malignancies, including acute myeloid leukemia (AML). Although the function of mesothelin is widely unknown, interactions with MUC16/CA125 indicate that mesothelin plays a role in the regulation of proliferation, growth, and adhesion signaling. Most research on mesothelin currently focuses on utilizing mesothelin to design targeted cancer therapies such as monoclonal antibodies, antibody–drug conjugates, chimeric antigen receptor T and NK cells, bispecific T cell engaging molecules, and targeted alpha therapies, amongst others. Both in vitro and in vivo studies using different immunotherapeutic modalities in mesothelin-positive AML models highlight the potential impact of this approach as a unique opportunity to treat hard-to-cure AML. Full article

(This article belongs to the Special Issue Advances in Immunotherapy for Hematological Malignancies)

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20 pages, 2006 KiB

Open AccessEditor’s ChoiceReview

The Role of Artificial Intelligence in Early Cancer Diagnosis

by Benjamin Hunter, Sumeet Hindocha and Richard W. Lee

Cancers 2022, 14(6), 1524; https://doi.org/10.3390/cancers14061524 - 16 Mar 2022

Cited by 84 | Viewed by 17348

Abstract

Improving the proportion of patients diagnosed with early-stage cancer is a key priority of the World Health Organisation. In many tumour groups, screening programmes have led to improvements in survival, but patient selection and risk stratification are key challenges. In addition, there are [...] Read more.

Improving the proportion of patients diagnosed with early-stage cancer is a key priority of the World Health Organisation. In many tumour groups, screening programmes have led to improvements in survival, but patient selection and risk stratification are key challenges. In addition, there are concerns about limited diagnostic workforces, particularly in light of the COVID-19 pandemic, placing a strain on pathology and radiology services. In this review, we discuss how artificial intelligence algorithms could assist clinicians in (1) screening asymptomatic patients at risk of cancer, (2) investigating and triaging symptomatic patients, and (3) more effectively diagnosing cancer recurrence. We provide an overview of the main artificial intelligence approaches, including historical models such as logistic regression, as well as deep learning and neural networks, and highlight their early diagnosis applications. Many data types are suitable for computational analysis, including electronic healthcare records, diagnostic images, pathology slides and peripheral blood, and we provide examples of how these data can be utilised to diagnose cancer. We also discuss the potential clinical implications for artificial intelligence algorithms, including an overview of models currently used in clinical practice. Finally, we discuss the potential limitations and pitfalls, including ethical concerns, resource demands, data security and reporting standards. Full article

(This article belongs to the Special Issue Early Diagnosis of Cancer)

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17 pages, 2808 KiB

Open AccessEditor’s ChoiceArticle

A Randomised, Comparative, Effectiveness Trial Evaluating Low- versus High-Level Supervision of an Exercise Intervention for Women with Breast Cancer: The SAFE Trial

by Rosalind R. Spence, Carolina X. Sandler, Benjamin Singh, Jodie Tanner, Christopher Pyke, Elizabeth Eakin, Dimitrios Vagenas and Sandra C. Hayes

Cancers 2022, 14(6), 1528; https://doi.org/10.3390/cancers14061528 - 16 Mar 2022

Cited by 6 | Viewed by 2973

Abstract

The aim of this comparative, effectiveness trial was to evaluate the safety, feasibility and effect of an exercise intervention delivered via low-level versus high-level supervision. The target population were women who were diagnosed with ≥stage II breast cancer, had ≥ one comorbidity and/or [...] Read more.

The aim of this comparative, effectiveness trial was to evaluate the safety, feasibility and effect of an exercise intervention delivered via low-level versus high-level supervision. The target population were women who were diagnosed with ≥stage II breast cancer, had ≥ one comorbidity and/or persistent treatment-related side-effects, and were insufficiently physically active. Sixty women (50 ± 9 years) were randomized to the low-supervision group (n = 30) or high-supervision group (n = 30). The low-supervision group participated in a 12-week, individually-tailored exercise intervention supported by five supervised sessions with an exercise professional. The high-supervision group participated in the same exercise intervention but received 20 supervised sessions across the 12-week period. The target weekly dosage of 600 metabolic equivalent minutes of exercise per week (MET-mins/wk) and the session content, such as safety and behaviour change topics, were standardized between the groups. The primary outcomes were intervention safety, defined as the number, type, and severity of exercise-related adverse events (e.g., musculoskeletal injury or exacerbated treatment-related side effects), and feasibility, which was defined as compliance to target exercise dosage. The effect of the intervention on quality of life, physical activity, self-efficacy, fitness, and strength was also assessed (pre- and post-intervention, and at 12-week follow-up). The intervention was safe, with no exercise-related adverse events of grade 3 or above in either group. Both groups reported high compliance to the target exercise dosage (median MET-mins/wk: High = 817; Low = 663), suggesting the exercise intervention was feasible, irrespective of supervision level. Improvements in quality of life, physical activity and fitness were observed post-intervention and maintained at follow-up for both groups (p < 0.05). Only the high-supervision group showed clinically-relevant improvements in strength and self-efficacy at post-intervention (p < 0.05). Individually-targeted exercise delivered under high- or low-levels of supervision is safe, feasible and beneficial for women with stage II+ breast cancer. Future research needs to assess whether the greater gains observed in the group who received higher supervision may contribute to longer term maintenance of physical activity levels and overall health benefits. Australian and New Zealand Clinical Trials Registry: ACTRN12616000547448. Full article

(This article belongs to the Special Issue Physical Activity and Cancer Care)

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20 pages, 3124 KiB

Open AccessEditor’s ChoiceArticle

MitoQ Inhibits Human Breast Cancer Cell Migration, Invasion and Clonogenicity

by Tania Capeloa, Joanna Krzystyniak, Donatienne d’Hose, Amanda Canas Rodriguez, Valery L. Payen, Luca X. Zampieri, Justine A. Van de Velde, Zohra Benyahia, Erica Pranzini, Thibaut Vazeille, Maude Fransolet, Caroline Bouzin, Davide Brusa, Carine Michiels, Bernard Gallez, Michael P. Murphy, Paolo E. Porporato and Pierre Sonveaux

Cancers 2022, 14(6), 1516; https://doi.org/10.3390/cancers14061516 - 16 Mar 2022

Cited by 16 | Viewed by 5153

Abstract

To successfully generate distant metastases, metastatic progenitor cells must simultaneously possess mesenchymal characteristics, resist to anoïkis, migrate and invade directionally, resist to redox and shear stresses in the systemic circulation, and possess stem cell characteristics. These cells primarily originate from metabolically hostile areas [...] Read more.

To successfully generate distant metastases, metastatic progenitor cells must simultaneously possess mesenchymal characteristics, resist to anoïkis, migrate and invade directionally, resist to redox and shear stresses in the systemic circulation, and possess stem cell characteristics. These cells primarily originate from metabolically hostile areas of the primary tumor, where oxygen and nutrient deprivation, together with metabolic waste accumulation, exert a strong selection pressure promoting evasion. Here, we followed the hypothesis according to which metastasis as a whole implies the existence of metabolic sensors. Among others, mitochondria are singled out as a major source of superoxide that supports the metastatic phenotype. Molecularly, stressed cancer cells increase mitochondrial superoxide production, which activates the transforming growth factor-β pathway through src directly within mitochondria, ultimately activating focal adhesion kinase Pyk2. The existence of mitochondria-targeted antioxidants constitutes an opportunity to interfere with the metastatic process. Here, using aggressive triple-negative and HER2-positive human breast cancer cell lines as models, we report that MitoQ inhibits all the metastatic traits that we tested in vitro. Compared to other mitochondria-targeted antioxidants, MitoQ already successfully passed Phase I safety clinical trials, which provides an important incentive for future preclinical and clinical evaluations of this drug for the prevention of breast cancer metastasis. Full article

(This article belongs to the Topic Targeting Tumor Metabolism for Cancer Therapy)

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28 pages, 1969 KiB

Open AccessEditor’s ChoiceReview

NRF2 and Key Transcriptional Targets in Melanoma Redox Manipulation

by Evan L. Carpenter, Alyssa L. Becker and Arup K. Indra

Cancers 2022, 14(6), 1531; https://doi.org/10.3390/cancers14061531 - 16 Mar 2022

Cited by 19 | Viewed by 5486

Abstract

Melanocytes are dendritic, pigment-producing cells located in the skin and are responsible for its protection against the deleterious effects of solar ultraviolet radiation (UVR), which include DNA damage and elevated reactive oxygen species (ROS). They do so by synthesizing photoprotective melanin pigments and [...] Read more.

Melanocytes are dendritic, pigment-producing cells located in the skin and are responsible for its protection against the deleterious effects of solar ultraviolet radiation (UVR), which include DNA damage and elevated reactive oxygen species (ROS). They do so by synthesizing photoprotective melanin pigments and distributing them to adjacent skin cells (e.g., keratinocytes). However, melanocytes encounter a large burden of oxidative stress during this process, due to both exogenous and endogenous sources. Therefore, melanocytes employ numerous antioxidant defenses to protect themselves; these are largely regulated by the master stress response transcription factor, nuclear factor erythroid 2-related factor 2 (NRF2). Key effector transcriptional targets of NRF2 include the components of the glutathione and thioredoxin antioxidant systems. Despite these defenses, melanocyte DNA often is subject to mutations that result in the dysregulation of the proliferative mitogen-activated protein kinase (MAPK) pathway and the cell cycle. Following tumor initiation, endogenous antioxidant systems are co-opted, a consequence of elevated oxidative stress caused by metabolic reprogramming, to establish an altered redox homeostasis. This altered redox homeostasis contributes to tumor progression and metastasis, while also complicating the application of exogenous antioxidant treatments. Further understanding of melanocyte redox homeostasis, in the presence or absence of disease, would contribute to the development of novel therapies to aid in the prevention and treatment of melanomas and other skin diseases Full article

(This article belongs to the Special Issue Study on the Complex Melanoma)

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22 pages, 1450 KiB

Open AccessEditor’s ChoiceReview

Biomarkers and Genetic Markers of Hepatocellular Carcinoma and Cholangiocarcinoma—What Do We Already Know

by Jacek Baj, Łukasz Bryliński, Filip Woliński, Michał Granat, Katarzyna Kostelecka, Piotr Duda, Jolanta Flieger, Grzegorz Teresiński, Grzegorz Buszewicz, Marzena Furtak-Niczyporuk and Piero Portincasa

Cancers 2022, 14(6), 1493; https://doi.org/10.3390/cancers14061493 - 15 Mar 2022

Cited by 15 | Viewed by 6895

Abstract

Hepatocellular carcinoma (HCC) is the most common primary liver cancer with an increasing worldwide mortality rate. Cholangiocarcinoma (CCA) is the second most common primary liver cancer. In both types of cancers, early detection is very important. Biomarkers are a relevant part of diagnosis, [...] Read more.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer with an increasing worldwide mortality rate. Cholangiocarcinoma (CCA) is the second most common primary liver cancer. In both types of cancers, early detection is very important. Biomarkers are a relevant part of diagnosis, enabling non-invasive detection and control of cancer recurrence, as well as in the application of screening tests in high-risk groups. Furthermore, some of these biomarkers are useful in controlling therapy and treatment selection. Detection of some markers presents higher sensitivity and specificity in combination with other markers when compared with a single detection. Some gene aberrations are also prognostic markers in the two types of cancers. In the following review, we discuss the most common biomarkers and genetic markers currently being used in the diagnosis of hepatocellular carcinoma and cholangiocarcinoma. Full article

(This article belongs to the Special Issue Chronic Liver Disease and Hepatocellular Carcinoma Biomarkers)

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15 pages, 1299 KiB

Open AccessEditor’s ChoiceArticle

Tumor Infiltration Levels of CD3, Foxp3 (+) Lymphocytes and CD68 Macrophages at Diagnosis Predict 5-Year Disease-Specific Survival in Patients with Oropharynx Squamous Cell Carcinoma

by Borghild Ljokjel, Hilde Haave, Stein Lybak, Olav Karsten Vintermyr, Lars Helgeland and Hans Jørgen Aarstad

Cancers 2022, 14(6), 1508; https://doi.org/10.3390/cancers14061508 - 15 Mar 2022

Cited by 11 | Viewed by 2372

Abstract

Head and neck cancer (HNC) is the sixth most common cancer worldwide. Oropharyngeal (OP) cancers are of special interest because of possible underlying HPV infection which is tied to prognosis. Influxes of inflammatory cells into tumors may vary with prognoses. We wanted to [...] Read more.

Head and neck cancer (HNC) is the sixth most common cancer worldwide. Oropharyngeal (OP) cancers are of special interest because of possible underlying HPV infection which is tied to prognosis. Influxes of inflammatory cells into tumors may vary with prognoses. We wanted to study whether the number of tumor-infiltrating lymphocytes (TIL) and tumor-associated macrophages (TAM) in tumors correlated to HPV status and predicted 5-year disease-specific survival (DSS). Formalin-fixed paraffin-embedded (FFPE) biopsies cut sections from 170 patients treated for OP cancer were stained by immunohistochemistry and evaluated for the number of CD68 (+) TAMs, CD3 (+), and Foxp3 (+) (T regulatory) TILs. From FFPE slides HPV by PCR and p16 by immunohistochemistry were established. From FFPE Hematoxylin-Eosin slides, levels of tumor nuclear polymorphism, tumor invasion, desmoplasia, and inflammation were determined as previously published. Levels of TIL CD3 (+) and TIL Foxp3 (+) were increased among the HPV (+) compared to the HPV (−) patients. High levels of TIL Foxp3 (+) and CD68 (+) macrophages predicted better 5-year DSS. TIL Foxp3 (+) levels predicted independent of age, gender, TNM stage, and HPV infection as well as level of stromal desmoplasia, tumor invasion, and nuclear polymorphism, but more pronounced among tumor HPV (+) than HPV (−) patients. Full article

(This article belongs to the Topic Anti-Tumor Immune Responses)

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13 pages, 1406 KiB

Open AccessEditor’s ChoiceArticle

MitoQ Prevents Human Breast Cancer Recurrence and Lung Metastasis in Mice

by Tania Capeloa, Joanna Krzystyniak, Amanda Canas Rodriguez, Valéry L. Payen, Luca X. Zampieri, Erica Pranzini, Françoise Derouane, Thibaut Vazeille, Caroline Bouzin, François P. Duhoux, Michael P. Murphy, Paolo E. Porporato and Pierre Sonveaux

Cancers 2022, 14(6), 1488; https://doi.org/10.3390/cancers14061488 - 15 Mar 2022

Cited by 13 | Viewed by 9844

Abstract

In oncology, the occurrence of distant metastases often marks the transition from curative to palliative care. Such outcome is highly predictable for breast cancer patients, even if tumors are detected early, and there is no specific treatment to prevent metastasis. Previous observations indicated [...] Read more.

In oncology, the occurrence of distant metastases often marks the transition from curative to palliative care. Such outcome is highly predictable for breast cancer patients, even if tumors are detected early, and there is no specific treatment to prevent metastasis. Previous observations indicated that cancer cell mitochondria are bioenergetic sensors of the tumor microenvironment that produce superoxide to promote evasion. Here, we tested whether mitochondria-targeted antioxidant MitoQ is capable to prevent metastasis in the MDA-MB-231 model of triple-negative human breast cancer in mice and in the MMTV-PyMT model of spontaneously metastatic mouse breast cancer. At clinically relevant doses, we report that MitoQ not only prevented metastatic take and dissemination, but also local recurrence after surgery. We further provide in vitro evidence that MitoQ does not interfere with conventional chemotherapies used to treat breast cancer patients. Since MitoQ already successfully passed Phase I safety clinical trials, our preclinical data collectively provide a strong incentive to test this drug for the prevention of cancer dissemination and relapse in clinical trials with breast cancer patients. Full article

(This article belongs to the Topic Targeting Tumor Metabolism for Cancer Therapy)

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23 pages, 2069 KiB

Open AccessEditor’s ChoiceReview

Radiolabeled Antibodies for Cancer Imaging and Therapy

by Sagun Parakh, Sze Ting Lee, Hui K. Gan and Andrew M. Scott

Cancers 2022, 14(6), 1454; https://doi.org/10.3390/cancers14061454 - 11 Mar 2022

Cited by 38 | Viewed by 6824

Abstract

Radioimmunoconjugates consist of a monoclonal antibody (mAb) linked to a radionuclide. Radioimmunoconjugates as theranostics tools have been in development with success, particularly in hematological malignancies, leading to approval by the US Food and Drug Administration (FDA) for the treatment of non-Hodgkin’s lymphoma. Radioimmunotherapy [...] Read more.

Radioimmunoconjugates consist of a monoclonal antibody (mAb) linked to a radionuclide. Radioimmunoconjugates as theranostics tools have been in development with success, particularly in hematological malignancies, leading to approval by the US Food and Drug Administration (FDA) for the treatment of non-Hodgkin’s lymphoma. Radioimmunotherapy (RIT) allows for reduced toxicity compared to conventional radiation therapy and enhances the efficacy of mAbs. In addition, using radiolabeled mAbs with imaging methods provides critical information on the pharmacokinetics and pharmacodynamics of therapeutic agents with direct relevance to the optimization of the dose and dosing schedule, real-time antigen quantitation, antigen heterogeneity, and dynamic antigen changes. All of these parameters are critical in predicting treatment responses and identifying patients who are most likely to benefit from treatment. Historically, RITs have been less effective in solid tumors; however, several strategies are being investigated to improve their therapeutic index, including targeting patients with minimal disease burden; using pre-targeting strategies, newer radionuclides, and improved labeling techniques; and using combined modalities and locoregional application. This review provides an overview of the radiolabeled intact antibodies currently in clinical use and those in development. Full article

(This article belongs to the Special Issue Recent Developments of Nuclear Medicine in Cancer Diagnosis and Theranostics)

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27 pages, 4349 KiB

Open AccessEditor’s ChoiceReview

Exosomes as Emerging Drug Delivery and Diagnostic Modality for Breast Cancer: Recent Advances in Isolation and Application

by Dulla Naveen Kumar, Aiswarya Chaudhuri, Farrukh Aqil, Deepa Dehari, Radha Munagala, Sanjay Singh, Ramesh C. Gupta and Ashish Kumar Agrawal

Cancers 2022, 14(6), 1435; https://doi.org/10.3390/cancers14061435 - 10 Mar 2022

Cited by 47 | Viewed by 7234

Abstract

Breast cancer (BC) is the most common type of malignancy which covers almost one-fourth of all the cancers diagnosed in women. Conventionally, chemo-, hormonal-, immune-, surgery, and radiotherapy are the clinically available therapies for BC. However, toxicity and other related adverse effects are [...] Read more.

Breast cancer (BC) is the most common type of malignancy which covers almost one-fourth of all the cancers diagnosed in women. Conventionally, chemo-, hormonal-, immune-, surgery, and radiotherapy are the clinically available therapies for BC. However, toxicity and other related adverse effects are still the major challenges. A variety of nano platforms have been reported to overcome these limitations, among them, exosomes provide a versatile platform not only for the diagnosis but also as a delivery vehicle for drugs. Exosomes are biological nanovesicles made up of a lipidic bilayer and known for cell-to-cell communication. Exosomes have been reported to be present in almost all bodily fluids, viz., blood, milk, urine, saliva, pancreatic juice, bile, peritoneal, and cerebrospinal fluid. Such characteristics of exosomes have attracted immense interest in cancer diagnosis and therapy. They can deliver bioactive moieties such as protein, lipids, hydrophilic as well as hydrophobic drugs, various RNAs to both distant and nearby recipient cells as well as have specific biological markers. By considering the growing interest of the scientific community in this field, we comprehensively compiled the information about the biogenesis of exosomes, various isolation methods, the drug loading techniques, and their diverse applications in breast cancer diagnosis and therapy along with ongoing clinical trials which will assist future scientific endeavors in a more organized direction. Full article

(This article belongs to the Special Issue Nanotherapeutics in Cancer Management)

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13 pages, 3562 KiB

Open AccessEditor’s ChoiceArticle

The Matrisome Is Associated with Metabolic Reprograming in Stem-like Phenotypes of Gastric Cancer

by Ji-Yong Sung and Jae-Ho Cheong

Cancers 2022, 14(6), 1438; https://doi.org/10.3390/cancers14061438 - 10 Mar 2022

Cited by 8 | Viewed by 2812

Abstract

The extracellular matrix (ECM) is an important regulator of all cellular functions, and the matrisome represents a major component of the tumor microenvironment. The matrisome is an essential component comprising genes encoding ECM glycoproteins, collagens, and proteoglycans; however, its role in cancer progression [...] Read more.

The extracellular matrix (ECM) is an important regulator of all cellular functions, and the matrisome represents a major component of the tumor microenvironment. The matrisome is an essential component comprising genes encoding ECM glycoproteins, collagens, and proteoglycans; however, its role in cancer progression and the development of stem-like molecular subtypes in gastric cancer is unknown. We analyzed gastric cancer data from five molecular subtypes (n = 497) and found that metabolic reprograming differs based on the state of the matrisome. Approximately 95% of stem-like cancer type samples of gastric cancer were in the high-matrisome category, and energy metabolism was considerably increased in the high-matrisome group. Particularly, high glycosaminoglycan biosynthesis-chondroitin sulfate metabolic reprograming was associated with an unfavorable prognosis. Glycosaminoglycan biosynthesis-chondroitin sulfate metabolic reprograming may occur according to the matrisome status and contribute to the development of stem-like phenotypes. Our analysis suggests the possibility of precision medicine for anticancer therapies. Full article

(This article belongs to the Special Issue Matrix Glycans as Multifunctional Pathogenesis Factors and Therapeutic Targets in Cancer)

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15 pages, 1098 KiB

Open AccessEditor’s ChoiceReview

PARP Inhibitors Resistance: Mechanisms and Perspectives

by Elena Giudice, Marica Gentile, Vanda Salutari, Caterina Ricci, Lucia Musacchio, Maria Vittoria Carbone, Viola Ghizzoni, Floriana Camarda, Francesca Tronconi, Camilla Nero, Francesca Ciccarone, Giovanni Scambia and Domenica Lorusso

Cancers 2022, 14(6), 1420; https://doi.org/10.3390/cancers14061420 - 10 Mar 2022

Cited by 27 | Viewed by 6641

Abstract

PolyADP-ribose polymerase (PARP) inhibitors (PARPis) represent the first clinically approved drugs able to provoke “synthetic lethality” in patients with homologous recombination-deficient (HRD) tumors. Four PARPis have just received approval for the treatment of several types of cancer. Besides, another three additional PARPis underlying [...] Read more.

PolyADP-ribose polymerase (PARP) inhibitors (PARPis) represent the first clinically approved drugs able to provoke “synthetic lethality” in patients with homologous recombination-deficient (HRD) tumors. Four PARPis have just received approval for the treatment of several types of cancer. Besides, another three additional PARPis underlying the same mechanism of action are currently under investigation. Despite the success of these targeted agents, the increasing use of PARPis in clinical practice for the treatment of different tumors raised the issue of PARPis resistance, and the consequent disease relapse and dismal prognosis for patients. Several mechanisms of resistance have been investigated, and ongoing studies are currently focusing on strategies to address this challenge and overcome PARPis resistance. This review aims to analyze the mechanisms underlying PARPis resistance known today and discuss potential therapeutic strategies to overcome these processes of resistance in the future. Full article

(This article belongs to the Special Issue Clinical Use of PARP Inhibitors in Cancer – From Bench to Bedside and Back Again)

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20 pages, 825 KiB

Open AccessEditor’s ChoiceReview

Updated Prognostic Factors in Localized NSCLC

by Simon Garinet, Pascal Wang, Audrey Mansuet-Lupo, Ludovic Fournel, Marie Wislez and Hélène Blons

Cancers 2022, 14(6), 1400; https://doi.org/10.3390/cancers14061400 - 9 Mar 2022

Cited by 42 | Viewed by 4986

Abstract

Lung cancer is the most common cause of cancer mortality worldwide, and non-small cell lung cancer (NSCLC) represents 80% of lung cancer subtypes. Patients with localized non-small cell lung cancer may be considered for upfront surgical treatment. However, the overall 5-year survival rate [...] Read more.

Lung cancer is the most common cause of cancer mortality worldwide, and non-small cell lung cancer (NSCLC) represents 80% of lung cancer subtypes. Patients with localized non-small cell lung cancer may be considered for upfront surgical treatment. However, the overall 5-year survival rate is 59%. To improve survival, adjuvant chemotherapy (ACT) was largely explored and showed an overall benefit of survival at 5 years < 7%. The evaluation of recurrence risk and subsequent need for ACT is only based on tumor stage (TNM classification); however, more than 25% of patients with stage IA/B tumors will relapse. Recently, adjuvant targeted therapy has been approved for EGFR-mutated resected NSCLC and trials are evaluating other targeted therapies and immunotherapies in adjuvant settings. Costs, treatment duration, emergence of resistant clones and side effects stress the need for a better selection of patients. The identification and validation of prognostic and theranostic markers to better stratify patients who could benefit from adjuvant therapies are needed. In this review, we report current validated clinical, pathological and molecular prognosis biomarkers that influence outcome in resected NSCLC, and we also describe molecular biomarkers under evaluation that could be available in daily practice to drive ACT in resected NSCLC. Full article

(This article belongs to the Special Issue Advances in Prognosis and Theranostics of Lung Cancer)

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12 pages, 1540 KiB

Open AccessEditor’s ChoiceSystematic Review

Impact of Proton Pump Inhibitors and Histamine-2-Receptor Antagonists on Non-Small Cell Lung Cancer Immunotherapy: A Systematic Review and Meta-Analysis

by Alessandro Rizzo, Antonio Cusmai, Francesco Giovannelli, Silvana Acquafredda, Lucia Rinaldi, Andrea Misino, Elisabetta Sara Montagna, Valentina Ungaro, Mariagrazia Lorusso and Gennaro Palmiotti

Cancers 2022, 14(6), 1404; https://doi.org/10.3390/cancers14061404 - 9 Mar 2022

Cited by 83 | Viewed by 3562

Abstract

(1) Background: In recent years, immunotherapy has revolutionized the treatment landscape of non-small cell lung cancer (NSCLC), representing a therapeutic breakthrough in this field. Antacid agents such as proton pump inhibitors (PPIs) and histamine-2-receptor antagonists (H2RAs) are commonly prescribed for extended periods in [...] Read more.

(1) Background: In recent years, immunotherapy has revolutionized the treatment landscape of non-small cell lung cancer (NSCLC), representing a therapeutic breakthrough in this field. Antacid agents such as proton pump inhibitors (PPIs) and histamine-2-receptor antagonists (H2RAs) are commonly prescribed for extended periods in NSCLC patients, and these drugs have the potential to modify the efficacy of immune checkpoint inhibitors (ICIs). (2) Materials and Methods: Herein, we conducted a systematic review and meta-analysis to investigate the impact of PPIs and H2RAs on progression-free survival (PFS) and overall survival (OS) among patients receiving immunotherapy for metastatic NSCLC. Effect measures for OS were Hazard Ratios (HRs) and 95% Confidence Intervals (CIs), which were extracted from available studies. Forest plots were used to assess HRs to describe the relationship between treatment and OS in the specified cohorts of patients. (3) Results: Six studies were included in the analysis, involving 2267 patients. The pooled HRs for OS and PFS were 1.4 (95% CI, 1.25–1.58) and 1.29 (95% CI, 1.17–1.43), respectively, suggesting that PPIs and H2RAs administration was negatively associated with PFS and OS. (4) Conclusion: Concomitant antacid use could modify the activity of ICIs in NSCLC patients. Full article

(This article belongs to the Special Issue Immunotherapy for Solid Tumors)

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14 pages, 2090 KiB

Open AccessEditor’s ChoiceArticle

Rintatolimod (Ampligen^®) Enhances Numbers of Peripheral B Cells and Is Associated with Longer Survival in Patients with Locally Advanced and Metastasized Pancreatic Cancer Pre-Treated with FOLFIRINOX: A Single-Center Named Patient Program

by Hassana el Haddaoui, Rianne Brood, Diba Latifi, Astrid A. Oostvogels, Yarne Klaver, Miranda Moskie, Dana A. Mustafa, Reno Debets and Casper H. J. van Eijck

Cancers 2022, 14(6), 1377; https://doi.org/10.3390/cancers14061377 - 8 Mar 2022

Cited by 4 | Viewed by 5727

Abstract

Background: Treatment with the TLR-3 agonist rintatolimod may improve pancreatic cancer patients’ survival via immunomodulation, but the effect is unproven. Methods: In this single-center named patient program, patients with locally advanced pancreatic cancer (LAPC) or metastatic disease were treated with rintatolimod (six weeks [...] Read more.

Background: Treatment with the TLR-3 agonist rintatolimod may improve pancreatic cancer patients’ survival via immunomodulation, but the effect is unproven. Methods: In this single-center named patient program, patients with locally advanced pancreatic cancer (LAPC) or metastatic disease were treated with rintatolimod (six weeks total, twice per week, with a maximum of 400 mg per infusion). The primary endpoints were the systemic immune-inflammation index (SIII), the neutrophil to lymphocyte ratio (NLR), and the absolute counts of 18 different populations of circulating immune cells as measured by flow cytometry. Secondary endpoints were progression-free survival (PFS) and overall survival (OS). Subgroup analyses were performed in long-term survivors (>1-year overall survival after starting rintatolimod) and compared to short-term survivors (≤1 year). Results: Between January 2017 and February 2019, twenty-seven patients with stable LAPC or metastatic disease were pre-treated with FOLFIRINOX and treated with rintatolimod. Rintatolimod treatment was well-tolerated. The SIII and NLR values were significantly lower in the 11 long-term survivors, versus 16 short-term survivors. The numbers of B-cells were significantly increased in long-term survivors. Numbers of T cells and myeloid cells were not significantly increased after treatment with rintatolimod. Median PFS was 13 months with rintatolimod, versus 8.6 months in a subset of matched controls (n = 27, hazard ratio = 0.52, 95% CI = 0.28–0.90, p = 0.007). The median OS was 19 months with rintatolimod, versus 12.5 months in the matched control (hazard ratio = 0.51, 95% CI = 0.28–0.90, p = 0.016). Conclusions: Treatment with rintatolimod showed a favorable effect on the numbers of peripheral B cells in patients with pancreatic cancer and improved survival in pancreatic cancer, but additional evidence is required. Full article

(This article belongs to the Special Issue Combination and Innovative Therapies for Pancreatic Cancer)

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20 pages, 5118 KiB

Open AccessEditor’s ChoiceArticle

Assessing the Acceptability of Home-Based HPV Self-Sampling: A Qualitative Study on Cervical Cancer Screening Conducted in Reunion Island Prior to the RESISTE Trial

by Dolorès Pourette, Amber Cripps, Margaux Guerrien, Caroline Desprès, Eric Opigez, Marc Bardou and Alexandre Dumont

Cancers 2022, 14(6), 1380; https://doi.org/10.3390/cancers14061380 - 8 Mar 2022

Cited by 7 | Viewed by 2560

Abstract

Cervical cancer incidence and mortality rates are 2 to 3 times higher in the overseas department of Reunion compared with mainland France. RESISTE’s cluster-randomized controlled trial aims to test the effectiveness of home-based self-sampling (HBSS) through a high-risk oncogenic papillomavirus test sent out [...] Read more.

Cervical cancer incidence and mortality rates are 2 to 3 times higher in the overseas department of Reunion compared with mainland France. RESISTE’s cluster-randomized controlled trial aims to test the effectiveness of home-based self-sampling (HBSS) through a high-risk oncogenic papillomavirus test sent out by post to women who have not been screened in the past 3 years, despite having been invited to do so through a reminder letter. Prior to the trial, qualitative research was carried out to understand screening barriers and assess anticipated acceptability. Semi-structured interviews were conducted with 35 women and 20 healthcare providers. Providers consider HBSS a viable method in reaching women who tend not to visit a doctor regularly, or who are reluctant to undergo a smear pap, as well as those who are geographically isolated. They considered, however, that women would require support, and that outreach was necessary to ensure more socially isolated women participate. The majority of the women surveyed were in favour of HBSS. However, two-thirds voiced concerns regarding the test’s efficiency and their ability to perform the test correctly, without harming themselves. Based on these findings, recommendations were formulated to reassure women on usage and quality, and to help reach socially isolated women. Full article

(This article belongs to the Special Issue Successes and Barriers of HPV Vaccination and Cervical Screening on Cervical Cancer Elimination)

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23 pages, 1321 KiB

Open AccessEditor’s ChoiceReview

Deciphering Tumour Heterogeneity: From Tissue to Liquid Biopsy

by Pauline Gilson, Jean-Louis Merlin and Alexandre Harlé

Cancers 2022, 14(6), 1384; https://doi.org/10.3390/cancers14061384 - 8 Mar 2022

Cited by 39 | Viewed by 6170

Abstract

Human solid malignancies harbour a heterogeneous set of cells with distinct genotypes and phenotypes. This heterogeneity is installed at multiple levels. A biological diversity is commonly observed between tumours from different patients (inter-tumour heterogeneity) and cannot be fully captured by the current consensus [...] Read more.

Human solid malignancies harbour a heterogeneous set of cells with distinct genotypes and phenotypes. This heterogeneity is installed at multiple levels. A biological diversity is commonly observed between tumours from different patients (inter-tumour heterogeneity) and cannot be fully captured by the current consensus molecular classifications for specific cancers. To extend the complexity in cancer, there are substantial differences from cell to cell within an individual tumour (intra-tumour heterogeneity, ITH) and the features of cancer cells evolve in space and time. Currently, treatment-decision making usually relies on the molecular characteristics of a limited tumour tissue sample at the time of diagnosis or disease progression but does not take into account the complexity of the bulk tumours and their constant evolution over time. In this review, we explore the extent of tumour heterogeneity with an emphasis on ITH and report the mechanisms that promote and sustain this diversity in cancers. We summarise the clinical strikes of ITH in the management of patients with cancer. Finally, we discuss the current material and technological approaches that are relevant to adequately appreciate ITH. Full article

(This article belongs to the Special Issue Liquid Nucleic Acid-Based Biomarkers in Solid Tumors)

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21 pages, 7075 KiB

Open AccessEditor’s ChoiceArticle

Discovery of a New CaMKII-Targeted Synthetic Lethal Therapy against Glioblastoma Stem-like Cells

by Jang Mi Han, Yu Jin Kim and Hye Jin Jung

Cancers 2022, 14(5), 1315; https://doi.org/10.3390/cancers14051315 - 4 Mar 2022

Cited by 13 | Viewed by 4797

Abstract

Glioblastoma stem-like cells (GSCs) drive tumor initiation, cancer invasion, immune evasion, and therapeutic resistance and are thus a key therapeutic target for improving treatment for glioblastoma multiforme (GBM). We previously identified calcium/calmodulin-dependent protein kinase II (CaMKII) as an emerging molecular target for eliminating [...] Read more.

Glioblastoma stem-like cells (GSCs) drive tumor initiation, cancer invasion, immune evasion, and therapeutic resistance and are thus a key therapeutic target for improving treatment for glioblastoma multiforme (GBM). We previously identified calcium/calmodulin-dependent protein kinase II (CaMKII) as an emerging molecular target for eliminating GSCs. In this study, we aim to explore a new CaMKII-targeted synthetic lethal therapy for GSCs. Through high-throughput drug combination screening using CaMKII inhibitors and a bioactive compound library in GSCs, neurokinin 1 receptor (NK1R) inhibitors such as SR 140333 and aprepitant are found to be potential anticancer agents that exhibit chemical synthetic lethal interactions with CaMKII inhibitors, including hydrazinobenzoylcurcumin (HBC), berbamine, and KN93. Combined treatment with NK1R and CaMKII inhibitors markedly suppresses the viability and neurosphere formation of U87MG- and U373MG-derived GSCs. In addition, the combination of HBC and NK1R inhibitors significantly inhibits U87MG GSC tumor growth in a chick embryo chorioallantoic membrane (CAM) model. Furthermore, the synthetic lethal interaction is validated using RNA interference of CaMKIIγ and NK1R. Notably, the synthetic lethal effects in GSCs are associated with the activation of caspase-mediated apoptosis by inducing p53 expression and reactive oxygen species generation, as well as the suppression of stemness marker expression by reducing nuclear factor-kappa B (NF-κB) activity. This follows the downregulation of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling and a decrease in intracellular calcium concentration. Moreover, NK1R affects CaMKIIγ activation. These findings demonstrate that NK1R is a potential synthetic lethal partner of CaMKII that is involved in eradicating GSCs, and they suggest a new CaMKII-targeted combination therapy for treating GBM. Full article

(This article belongs to the Special Issue Recent Advances in Drug Therapy for Glioblastoma)

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19 pages, 2320 KiB

Open AccessEditor’s ChoiceReview

Direct Targeting KRAS Mutation in Non-Small Cell Lung Cancer: Focus on Resistance

by Damien Reita, Lucile Pabst, Erwan Pencreach, Eric Guérin, Laurent Dano, Valérie Rimelen, Anne-Claire Voegeli, Laurent Vallat, Céline Mascaux and Michèle Beau-Faller

Cancers 2022, 14(5), 1321; https://doi.org/10.3390/cancers14051321 - 4 Mar 2022

Cited by 37 | Viewed by 9982

Abstract

KRAS is the most frequently mutated oncogene in non-small cell lung cancers (NSCLC), with a frequency of around 30%, and encoding a GTPAse that cycles between active form (GTP-bound) to inactive form (GDP-bound). The KRAS mutations favor the active form with inhibition of [...] Read more.

KRAS is the most frequently mutated oncogene in non-small cell lung cancers (NSCLC), with a frequency of around 30%, and encoding a GTPAse that cycles between active form (GTP-bound) to inactive form (GDP-bound). The KRAS mutations favor the active form with inhibition of GTPAse activity. KRAS mutations are often with poor response of EGFR targeted therapies. KRAS mutations are good predictive factor for immunotherapy. The lack of success with direct targeting of KRAS proteins, downstream inhibition of KRAS effector pathways, and other strategies contributed to a focus on developing mutation-specific KRAS inhibitors. KRAS p.G12C mutation is one of the most frequent KRAS mutation in NSCLC, especially in current and former smokers (over 40%), which occurs among approximately 12–14% of NSCLC tumors. The mutated cysteine resides next to a pocket (P2) of the switch II region, and P2 is present only in the inactive GDP-bound KRAS. Small molecules such as sotorasib are now the first targeted drugs for KRAS G12C mutation, preventing conversion of the mutant protein to GTP-bound active state. Little is known about primary or acquired resistance. Acquired resistance does occur and may be due to genetic alterations in the nucleotide exchange function or adaptative mechanisms in either downstream pathways or in newly expressed KRAS G12C mutation. Full article

(This article belongs to the Special Issue Targeting KRAS: Elucidating Mechanisms of Sensitivity and Resistance)

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32 pages, 461 KiB

Open AccessEditor’s ChoiceReview

The Minimal Residual Disease Using Liquid Biopsies in Hematological Malignancies

by Rafael Colmenares, Noemí Álvarez, Santiago Barrio, Joaquín Martínez-López and Rosa Ayala

Cancers 2022, 14(5), 1310; https://doi.org/10.3390/cancers14051310 - 3 Mar 2022

Cited by 21 | Viewed by 4883

Abstract

The study of cell-free DNA (cfDNA) and other peripheral blood components (known as “liquid biopsies”) is promising, and has been investigated especially in solid tumors. Nevertheless, it is increasingly showing a greater utility in the diagnosis, prognosis, and response to treatment of hematological [...] Read more.

The study of cell-free DNA (cfDNA) and other peripheral blood components (known as “liquid biopsies”) is promising, and has been investigated especially in solid tumors. Nevertheless, it is increasingly showing a greater utility in the diagnosis, prognosis, and response to treatment of hematological malignancies; in the future, it could prevent invasive techniques, such as bone marrow (BM) biopsies. Most of the studies about this topic have focused on B-cell lymphoid malignancies; some of them have shown that cfDNA can be used as a novel way for the diagnosis and minimal residual monitoring of B-cell lymphomas, using techniques such as next-generation sequencing (NGS). In myelodysplastic syndromes, multiple myeloma, or chronic lymphocytic leukemia, liquid biopsies may allow for an interesting genomic representation of the tumor clones affecting different lesions (spatial heterogeneity). In acute leukemias, it can be helpful in the monitoring of the early treatment response and the prediction of treatment failure. In chronic lymphocytic leukemia, the evaluation of cfDNA permits the definition of clonal evolution and drug resistance in real time. However, there are limitations, such as the difficulty in obtaining sufficient circulating tumor DNA for achieving a high sensitivity to assess the minimal residual disease, or the lack of standardization of the method, and clinical studies, to confirm its prognostic impact. This review focuses on the clinical applications of cfDNA on the minimal residual disease in hematological malignancies. Full article

(This article belongs to the Special Issue Latest Development in B Cell Malignancies)

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25 pages, 23552 KiB

Open AccessEditor’s ChoiceArticle

Comprehensive Metabolic Profiling of MYC-Amplified Medulloblastoma Tumors Reveals Key Dependencies on Amino Acid, Tricarboxylic Acid and Hexosamine Pathways

by Khoa Pham, Allison R. Hanaford, Brad A. Poore, Micah J. Maxwell, Heather Sweeney, Akhila Parthasarathy, Jesse Alt, Rana Rais, Barbara S. Slusher, Charles G. Eberhart and Eric H. Raabe

Cancers 2022, 14(5), 1311; https://doi.org/10.3390/cancers14051311 - 3 Mar 2022

Cited by 10 | Viewed by 4455

Abstract

Reprograming of cellular metabolism is a hallmark of cancer. Altering metabolism allows cancer cells to overcome unfavorable microenvironment conditions and to proliferate and invade. Medulloblastoma is the most common malignant brain tumor of children. Genomic amplification of MYC defines a subset of poor-prognosis [...] Read more.

Reprograming of cellular metabolism is a hallmark of cancer. Altering metabolism allows cancer cells to overcome unfavorable microenvironment conditions and to proliferate and invade. Medulloblastoma is the most common malignant brain tumor of children. Genomic amplification of MYC defines a subset of poor-prognosis medulloblastoma. We performed comprehensive metabolic studies of human MYC-amplified medulloblastoma by comparing the metabolic profiles of tumor cells in three different conditions—in vitro, in flank xenografts and in orthotopic xenografts in the cerebellum. Principal component analysis showed that the metabolic profiles of brain and flank high-MYC medulloblastoma tumors clustered closely together and separated away from normal brain and in vitro MYC-amplified cells. Compared to normal brain, MYC-amplified medulloblastoma orthotopic xenograft tumors showed upregulation of the TCA cycle as well as the synthesis of nucleotides, hexosamines, amino acids and glutathione. There was significantly higher glucose uptake and usage in orthotopic xenograft tumors compared to flank xenograft tumors and cells in culture. In orthotopic tumors, glucose was the main carbon source for the de novo synthesis of glutamate, glutamine and glutathione through the TCA cycle. In vivo, the glutaminase II pathway was the main pathway utilizing glutamine. Glutathione was the most abundant upregulated metabolite in orthotopic tumors compared to normal brain. Glutamine-derived glutathione was synthesized through the glutamine transaminase K (GTK) enzyme in vivo. In conclusion, high MYC medulloblastoma cells have different metabolic profiles in vitro compared to in vivo, and key vulnerabilities may be missed by not performing in vivo metabolic analyses. Full article

(This article belongs to the Special Issue Updates on Molecular Targeted Therapies for CNS Tumors)

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22 pages, 1566 KiB

Open AccessEditor’s ChoiceReview

Understanding Retinoblastoma Post-Translational Regulation for the Design of Targeted Cancer Therapies

by Radoslav Janostiak, Ariadna Torres-Sanchez, Francesc Posas and Eulàlia de Nadal

Cancers 2022, 14(5), 1265; https://doi.org/10.3390/cancers14051265 - 28 Feb 2022

Cited by 10 | Viewed by 3672

Abstract

The retinoblastoma protein (Rb1) is a prototypical tumor suppressor protein whose role was described more than 40 years ago. Together with p107 (also known as RBL1) and p130 (also known as RBL2), the Rb1 belongs to a family of structurally and functionally similar [...] Read more.

The retinoblastoma protein (Rb1) is a prototypical tumor suppressor protein whose role was described more than 40 years ago. Together with p107 (also known as RBL1) and p130 (also known as RBL2), the Rb1 belongs to a family of structurally and functionally similar proteins that inhibits cell cycle progression. Given the central role of Rb1 in regulating proliferation, its expression or function is altered in most types of cancer. One of the mechanisms underlying Rb-mediated cell cycle inhibition is the binding and repression of E2F transcription factors, and these processes are dependent on Rb1 phosphorylation status. However, recent work shows that Rb1 is a convergent point of many pathways and thus the regulation of its function through post-translational modifications is more complex than initially expected. Moreover, depending on the context, downstream signaling can be both E2F-dependent and -independent. This review seeks to summarize the most recent research on Rb1 function and regulation and discuss potential avenues for the design of novel cancer therapies. Full article

(This article belongs to the Special Issue Multiple Roles of the RB Family of Tumor Suppressors and Implications for Cancer Therapy)

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28 pages, 2895 KiB

Open AccessEditor’s ChoiceReview

Innate and Adaptive Immunopathogeneses in Viral Hepatitis; Crucial Determinants of Hepatocellular Carcinoma

by Marco Y. W. Zaki, Ahmed M. Fathi, Samara Samir, Nardeen Eldafashi, Kerolis Y. William, Maiiada Hassan Nazmy, Moustafa Fathy, Upkar S. Gill and Shishir Shetty

Cancers 2022, 14(5), 1255; https://doi.org/10.3390/cancers14051255 - 28 Feb 2022

Cited by 26 | Viewed by 4742

Abstract

Viral hepatitis B (HBV) and hepatitis C (HCV) infections remain the most common risk factors for the development of hepatocellular carcinoma (HCC), and their heterogeneous distribution influences the global prevalence of this common type of liver cancer. Typical hepatitis infection elicits various immune [...] Read more.

Viral hepatitis B (HBV) and hepatitis C (HCV) infections remain the most common risk factors for the development of hepatocellular carcinoma (HCC), and their heterogeneous distribution influences the global prevalence of this common type of liver cancer. Typical hepatitis infection elicits various immune responses within the liver microenvironment, and viral persistence induces chronic liver inflammation and carcinogenesis. HBV is directly mutagenic but can also cause low-grade liver inflammation characterized by episodes of intermittent high-grade liver inflammation, liver fibrosis, and cirrhosis, which can progress to decompensated liver disease and HCC. Equally, the absence of key innate and adaptive immune responses in chronic HCV infection dampens viral eradication and induces an exhausted and immunosuppressive liver niche that favors HCC development and progression. The objectives of this review are to (i) discuss the epidemiological pattern of HBV and HCV infections, (ii) understand the host immune response to acute and chronic viral hepatitis, and (iii) explore the link between this diseased immune environment and the development and progression of HCC in preclinical models and HCC patients. Full article

(This article belongs to the Special Issue Molecular Mechanisms Involved in Hepatocarcinogenesis)

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29 pages, 1267 KiB

Open AccessEditor’s ChoiceReview

Targeting HIF-2α in the Tumor Microenvironment: Redefining the Role of HIF-2α for Solid Cancer Therapy

by Leah Davis, Matthias Recktenwald, Evan Hutt, Schuyler Fuller, Madison Briggs, Arnav Goel and Nichole Daringer

Cancers 2022, 14(5), 1259; https://doi.org/10.3390/cancers14051259 - 28 Feb 2022

Cited by 32 | Viewed by 7071

Abstract

Inadequate oxygen supply, or hypoxia, is characteristic of the tumor microenvironment and correlates with poor prognosis and therapeutic resistance. Hypoxia leads to the activation of the hypoxia-inducible factor (HIF) signaling pathway and stabilization of the HIF-α subunit, driving tumor progression. The homologous alpha [...] Read more.

Inadequate oxygen supply, or hypoxia, is characteristic of the tumor microenvironment and correlates with poor prognosis and therapeutic resistance. Hypoxia leads to the activation of the hypoxia-inducible factor (HIF) signaling pathway and stabilization of the HIF-α subunit, driving tumor progression. The homologous alpha subunits, HIF-1α and HIF-2α, are responsible for mediating the transcription of a multitude of critical proteins that control proliferation, angiogenic signaling, metastasis, and other oncogenic factors, both differentially and sequentially regulating the hypoxic response. Post-translational modifications of HIF play a central role in its behavior as a mediator of transcription, as well as the temporal transition from HIF-1α to HIF-2α that occurs in response to chronic hypoxia. While it is evident that HIF-α is highly dynamic, HIF-2α remains vastly under-considered. HIF-2α can intensify the behaviors of the most aggressive tumors by adapting the cell to oxidative stress, thereby promoting metastasis, tissue remodeling, angiogenesis, and upregulating cancer stem cell factors. The structure, function, hypoxic response, spatiotemporal dynamics, and roles in the progression and persistence of cancer of this HIF-2α molecule and its EPAS1 gene are highlighted in this review, alongside a discussion of current therapeutics and future directions. Full article

(This article belongs to the Special Issue Hypoxia and Cancer: From Bench to Bedside)

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29 pages, 2394 KiB

Open AccessEditor’s ChoiceReview

Cancer-Associated Fibroblasts: Mechanisms of Tumor Progression and Novel Therapeutic Targets

by Ralf-Peter Czekay, Dong-Joo Cheon, Rohan Samarakoon, Stacie M. Kutz and Paul J. Higgins

Cancers 2022, 14(5), 1231; https://doi.org/10.3390/cancers14051231 - 27 Feb 2022

Cited by 45 | Viewed by 6235

Abstract

Cancer-associated fibroblasts (CAFs) are a heterogenous population of stromal cells found in solid malignancies that coexist with the growing tumor mass and other immune/nonimmune cellular elements. In certain neoplasms (e.g., desmoplastic tumors), CAFs are the prominent mesenchymal cell type in the tumor microenvironment, [...] Read more.

Cancer-associated fibroblasts (CAFs) are a heterogenous population of stromal cells found in solid malignancies that coexist with the growing tumor mass and other immune/nonimmune cellular elements. In certain neoplasms (e.g., desmoplastic tumors), CAFs are the prominent mesenchymal cell type in the tumor microenvironment, where their presence and abundance signal a poor prognosis in multiple cancers. CAFs play a major role in the progression of various malignancies by remodeling the supporting stromal matrix into a dense, fibrotic structure while secreting factors that lead to the acquisition of cancer stem-like characteristics and promoting tumor cell survival, reduced sensitivity to chemotherapeutics, aggressive growth and metastasis. Tumors with high stromal fibrotic signatures are more likely to be associated with drug resistance and eventual relapse. Clarifying the molecular basis for such multidirectional crosstalk among the various normal and neoplastic cell types present in the tumor microenvironment may yield novel targets and new opportunities for therapeutic intervention. This review highlights the most recent concepts regarding the complexity of CAF biology including CAF heterogeneity, functionality in drug resistance, contribution to a progressively fibrotic tumor stroma, the involved signaling pathways and the participating genes. Full article

(This article belongs to the Special Issue Cancer-Associated Fibroblasts: Mechanisms of Tumor Progression and Novel Therapeutic Targets)

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26 pages, 3662 KiB

Open AccessEditor’s ChoiceReview

Emerging CAR T Cell Strategies for the Treatment of AML

by Paresh Vishwasrao, Gongbo Li, Justin C. Boucher, D. Lynne Smith and Susanta K. Hui

Cancers 2022, 14(5), 1241; https://doi.org/10.3390/cancers14051241 - 27 Feb 2022

Cited by 26 | Viewed by 7344

Abstract

Engineered T cells expressing chimeric antigen receptors (CARs) on their cell surface can redirect antigen specificity. This ability makes CARs one of the most promising cancer therapeutic agents. CAR-T cells for treating patients with B cell hematological malignancies have shown impressive results. Clinical [...] Read more.

Engineered T cells expressing chimeric antigen receptors (CARs) on their cell surface can redirect antigen specificity. This ability makes CARs one of the most promising cancer therapeutic agents. CAR-T cells for treating patients with B cell hematological malignancies have shown impressive results. Clinical manifestation has yielded several trials, so far five CAR-T cell therapies have received US Food and Drug Administration (FDA) approval. However, emerging clinical data and recent findings have identified some immune-related toxicities due to CAR-T cell therapy. Given the outcome and utilization of the same proof of concept, further investigation in other hematological malignancies, such as leukemias, is warranted. This review discusses the previous findings from the pre-clinical and human experience with CAR-T cell therapy. Additionally, we describe recent developments of novel targets for adoptive immunotherapy. Here we present some of the early findings from the pre-clinical studies of CAR-T cell modification through advances in genetic engineering, gene editing, cellular programming, and formats of synthetic biology, along with the ongoing efforts to restore the function of exhausted CAR-T cells through epigenetic remodeling. We aim to shed light on the new targets focusing on acute myeloid leukemia (AML). Full article

(This article belongs to the Special Issue Immune Therapies for Hematologic Malignancies)

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11 pages, 10534 KiB

Open AccessEditor’s ChoiceReview

Diverse Roles and Targets of miRNA in the Pathogenesis of Testicular Germ Cell Tumour

by Mrinal K. Das, Øyvind P. Haugen and Trine B. Haugen

Cancers 2022, 14(5), 1190; https://doi.org/10.3390/cancers14051190 - 25 Feb 2022

Cited by 10 | Viewed by 2645

Abstract

Testicular germ cell tumour (TGCT) is the most common cancer type among young adults in many parts of the world. Although the pathogenesis of TGCT is not well understood, the involvement of heritable components is evident, and the risk is polygenic. Genome-wide association [...] Read more.

Testicular germ cell tumour (TGCT) is the most common cancer type among young adults in many parts of the world. Although the pathogenesis of TGCT is not well understood, the involvement of heritable components is evident, and the risk is polygenic. Genome-wide association studies have so far found 78 susceptibility loci for TGCT, and many of the loci are in non-coding regions indicating the involvement of non-coding RNAs in TGCT pathogenesis. MicroRNAs (miRNAs), a class of non-coding RNAs, have emerged as important gene regulators at the post-transcriptional level. They are crucial in controlling many cellular processes, such as proliferation, differentiation, and apoptosis, and an aberrant miRNA expression may contribute to the pathogenesis of several cancers, including TGCT. In support of this notion, several studies reported differential expression of miRNAs in TGCTs. We previously demonstrated that miRNAs were the most common group of small non-coding RNAs in TGCTs, and several functional studies of miRNAs in TGCTs suggest that they may act as either oncogene or tumour suppressors. Moreover, individual miRNA targets and downstream pathways in the context of TGCT development have been explored. In this review, we will focus on the diverse roles and targets of miRNAs in TGCT pathogenesis. Full article

(This article belongs to the Special Issue Non-coding RNA in Cancer: A Focus on Mechanisms of Action, Biomarker Properties, and Treatment Options)

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33 pages, 2754 KiB

Open AccessEditor’s ChoiceReview

Actively Targeted Nanomedicines in Breast Cancer: From Pre-Clinal Investigation to Clinic

by Ana Isabel Fraguas-Sánchez, Irene Lozza and Ana Isabel Torres-Suárez

Cancers 2022, 14(5), 1198; https://doi.org/10.3390/cancers14051198 - 25 Feb 2022

Cited by 37 | Viewed by 5794

Abstract

Breast cancer is one of the most frequently diagnosed tumors and the second leading cause of cancer death in women worldwide. The use of nanosystems specifically targeted to tumor cells (active targeting) can be an excellent therapeutic tool to improve and optimize current [...] Read more.

Breast cancer is one of the most frequently diagnosed tumors and the second leading cause of cancer death in women worldwide. The use of nanosystems specifically targeted to tumor cells (active targeting) can be an excellent therapeutic tool to improve and optimize current chemotherapy for this type of neoplasm, since they make it possible to reduce the toxicity and, in some cases, increase the efficacy of antineoplastic drugs. Currently, there are 14 nanomedicines that have reached the clinic for the treatment of breast cancer, 4 of which are already approved (Kadcyla^®, Enhertu^®, Trodelvy^®, and Abraxane^®). Most of these nanomedicines are antibody–drug conjugates. In the case of HER-2-positive breast cancer, these conjugates (Kadcyla^®, Enhertu^®, Trastuzumab-duocarmycin, RC48, and HT19-MMAF) target HER-2 receptors, and incorporate maytansinoid, deruxtecan, duocarmicyn, or auristatins as antineoplastics. In TNBC these conjugates (Trodelvy^®, Glembatumumab-Vedotin, Ladiratuzumab-vedotin, Cofetuzumab-pelidotin, and PF-06647263) are directed against various targets, in particular Trop-2 glycoprotein, NMB glycoprotein, Zinc transporter LIV-1, and Ephrin receptor-4, to achieve this selective accumulation, and include campthotecins, calicheamins, or auristatins as drugs. Apart from the antibody–drug conjugates, there are other active targeted nanosystems that have reached the clinic for the treatment of these tumors such as Abraxane^® and Nab-rapamicyn (albumin nanoparticles entrapping placlitaxel and rapamycin respectively) and various liposomes (MM-302, C225-ILS-Dox, and MM-310) loaded with doxorubicin or docetaxel and coated with ligands targeted to Ephrin A2, EPGF, or HER-2 receptors. In this work, all these active targeted nanomedicines are discussed, analyzing their advantages and disadvantages over conventional chemotherapy as well as the challenges involved in their lab to clinical translation. In addition, examples of formulations developed and evaluated at the preclinical level are also discussed. Full article

(This article belongs to the Special Issue Development of Innovative Formulations for Breast Cancer Chemotherapy)

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15 pages, 12400 KiB

Open AccessEditor’s ChoiceArticle

A Deep Learning Model for Cervical Cancer Screening on Liquid-Based Cytology Specimens in Whole Slide Images

by Fahdi Kanavati, Naoki Hirose, Takahiro Ishii, Ayaka Fukuda, Shin Ichihara and Masayuki Tsuneki

Cancers 2022, 14(5), 1159; https://doi.org/10.3390/cancers14051159 - 24 Feb 2022

Cited by 30 | Viewed by 7557

Abstract

Liquid-based cytology (LBC) for cervical cancer screening is now more common than the conventional smears, which when digitised from glass slides into whole-slide images (WSIs), opens up the possibility of artificial intelligence (AI)-based automated image analysis. Since conventional screening processes by cytoscreeners and [...] Read more.

Liquid-based cytology (LBC) for cervical cancer screening is now more common than the conventional smears, which when digitised from glass slides into whole-slide images (WSIs), opens up the possibility of artificial intelligence (AI)-based automated image analysis. Since conventional screening processes by cytoscreeners and cytopathologists using microscopes is limited in terms of human resources, it is important to develop new computational techniques that can automatically and rapidly diagnose a large amount of specimens without delay, which would be of great benefit for clinical laboratories and hospitals. The goal of this study was to investigate the use of a deep learning model for the classification of WSIs of LBC specimens into neoplastic and non-neoplastic. To do so, we used a dataset of 1605 cervical WSIs. We evaluated the model on three test sets with a combined total of 1468 WSIs, achieving ROC AUCs for WSI diagnosis in the range of 0.89–0.96, demonstrating the promising potential use of such models for aiding screening processes. Full article

(This article belongs to the Collection Artificial Intelligence in Oncology)

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15 pages, 5789 KiB

Open AccessEditor’s ChoiceArticle

Cannabidiol Inhibits Tumorigenesis in Cisplatin-Resistant Non-Small Cell Lung Cancer via TRPV2

by Swati Misri, Kirti Kaul, Sanjay Mishra, Manish Charan, Ajeet Kumar Verma, Martin P. Barr, Dinesh K. Ahirwar and Ramesh K. Ganju

Cancers 2022, 14(5), 1181; https://doi.org/10.3390/cancers14051181 - 24 Feb 2022

Cited by 26 | Viewed by 3918

Abstract

Chemotherapy forms the backbone of current treatments for many patients with advanced non-small-cell lung cancer (NSCLC). However, the survival rate is low in these patients due to the development of drug resistance, including cisplatin resistance. In this study, we developed a novel strategy [...] Read more.

Chemotherapy forms the backbone of current treatments for many patients with advanced non-small-cell lung cancer (NSCLC). However, the survival rate is low in these patients due to the development of drug resistance, including cisplatin resistance. In this study, we developed a novel strategy to combat the growth of cisplatin-resistant (CR) NSCLC cells. We have shown that treatment with the plant-derived, non-psychotropic small molecular weight molecule, cannabidiol (CBD), significantly induced apoptosis of CR NSCLC cells. In addition, CBD treatment significantly reduced tumor progression and metastasis in a mouse xenograft model and suppressed cancer stem cell properties. Further mechanistic studies demonstrated the ability of CBD to inhibit the growth of CR cell lines by reducing NRF-2 and enhancing the generation of reactive oxygen species (ROS). Moreover, we show that CBD acts through Transient Receptor Potential Vanilloid-2 (TRPV2) to induce apoptosis, where TRPV2 is expressed on human lung adenocarcinoma tumors. High expression of TRPV2 correlates with better overall survival of lung cancer patients. Our findings identify CBD as a novel therapeutic agent targeting TRPV2 to inhibit the growth and metastasis of this aggressive cisplatin-resistant phenotype in NSCLC. Full article

(This article belongs to the Special Issue Advances in Lung Cancer Therapy)

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22 pages, 1555 KiB

Open AccessEditor’s ChoiceArticle

Immune Checkpoint Inhibitors—Associated Cardiotoxicity

by Chenghui Li, Sajjad A. Bhatti and Jun Ying

Cancers 2022, 14(5), 1145; https://doi.org/10.3390/cancers14051145 - 23 Feb 2022

Cited by 27 | Viewed by 4235

Abstract

Large population-based studies examining differences in ICI-associated cardiotoxicity across cancer types and agents are limited. Data of 5518 cancer patients who received at least one cycle of ICIs were extracted from a large network of health care organizations. ICI treatment groups were classified [...] Read more.

Large population-based studies examining differences in ICI-associated cardiotoxicity across cancer types and agents are limited. Data of 5518 cancer patients who received at least one cycle of ICIs were extracted from a large network of health care organizations. ICI treatment groups were classified by the first ICI agent(s) (ipilimumab, nivolumab, pembrolizumab, cemiplimab, avelumab, atezolizumab, or durvalumab) or its class (PD-1 inhibitors, PD-L1 inhibitors, CTLA4-inhibitors, or their combination (ipilimumab + nivolumab)). Time to first cardiac adverse event (CAE) (arrhythmia, acute myocardial infarction, myocarditis, cardiomyopathy, or pericarditis) developed within one year after ICI initiation was analyzed using a competing-risks regression model adjusting for ICI treatment groups, patient demographic and clinical characteristics, and cancer sites. By month 12, 12.5% developed cardiotoxicity. The most common cardiotoxicity was arrhythmia (9.3%) and 2.1% developed myocarditis. After adjusting for patient characteristics and cancer sites, patients who initiated on monotherapy with ipilimumab (adjusted Hazard Ratio (aHR): 2.00; 95% CI: 1.49–2.70; p < 0.001) or pembrolizumab (aHR: 1.21; 95% CI: 1.01–1.46; p = 0.040) had a higher risk of developing CAEs within one year compared to nivolumab monotherapy. Ipilimumab and pembrolizumab use may increase the risk of cardiotoxicity compared to other agents. Avelumab also estimated a highly elevated risk (aHR: 1.92; 95% CI: 0.85–4.34; p = 0.117) compared to nivolumab and other PD-L1 agents, although the estimate did not reach statistical significance, warranting future studies. Full article

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21 pages, 803 KiB

Open AccessEditor’s ChoiceReview

The Role of TP53 Mutations in EGFR-Mutated Non-Small-Cell Lung Cancer: Clinical Significance and Implications for Therapy

by Matteo Canale, Kalliopi Andrikou, Ilaria Priano, Paola Cravero, Luigi Pasini, Milena Urbini, Angelo Delmonte, Lucio Crinò, Giuseppe Bronte and Paola Ulivi

Cancers 2022, 14(5), 1143; https://doi.org/10.3390/cancers14051143 - 23 Feb 2022

Cited by 26 | Viewed by 5298

Abstract

Non-Small-Cell Lung Cancer (NSCLC) is the primary cause of cancer-related death worldwide. Oncogene-addicted patients usually benefit from targeted therapy, but primary and acquired resistance mechanisms inevitably occur. Tumor protein 53 (TP53) gene is the most frequently mutated gene in cancer, including [...] Read more.

Non-Small-Cell Lung Cancer (NSCLC) is the primary cause of cancer-related death worldwide. Oncogene-addicted patients usually benefit from targeted therapy, but primary and acquired resistance mechanisms inevitably occur. Tumor protein 53 (TP53) gene is the most frequently mutated gene in cancer, including NSCLC. TP53 mutations are able to induce carcinogenesis, tumor development and resistance to therapy, influencing patient prognosis and responsiveness to therapy. TP53 mutants present in different forms, suggesting that different gene alterations confer specific acquired protein functions. In recent years, many associations between different TP53 mutations and responses to Epidermal Growth Factor Receptor (EGFR) targeted therapy in NSCLC patients have been found. In this review, we discuss the current landscape concerning the role of TP53 mutants to guide primary and acquired resistance to Tyrosine-Kinase Inhibitors (TKIs) EGFR-directed, investigating the possible mechanisms of TP53 mutants within the cellular compartments. We also discuss the role of the TP53 mutations in predicting the response to targeted therapy with EGFR-TKIs, as a possible biomarker to guide patient stratification for treatment. Full article

(This article belongs to the Special Issue Mechanisms of Resistance in EGFR-Mutated Non-Small Cell Lung Cancer)

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21 pages, 790 KiB

Open AccessEditor’s ChoiceReview

The Role of Purinergic P2X7 Receptor in Inflammation and Cancer: Novel Molecular Insights and Clinical Applications

by John Charles Rotondo, Chiara Mazziotta, Carmen Lanzillotti, Chiara Stefani, Giada Badiale, Giulia Campione, Fernanda Martini and Mauro Tognon

Cancers 2022, 14(5), 1116; https://doi.org/10.3390/cancers14051116 - 22 Feb 2022

Cited by 45 | Viewed by 6851

Abstract

The purinergic P2X7 receptor (P2X7R) is a transmembrane protein whose expression has been related to a variety of cellular processes, while its dysregulation has been linked to inflammation and cancer. P2X7R is expressed in cancer and immune system cell surfaces. ATP plays a [...] Read more.

The purinergic P2X7 receptor (P2X7R) is a transmembrane protein whose expression has been related to a variety of cellular processes, while its dysregulation has been linked to inflammation and cancer. P2X7R is expressed in cancer and immune system cell surfaces. ATP plays a key role in numerous metabolic processes due to its abundance in the tumour microenvironment. P2X7R plays an important role in cancer by interacting with ATP. The unusual property of P2X7R is that stimulation with low doses of ATP causes the opening of a permeable channel for sodium, potassium, and calcium ions, whereas sustained stimulation with high doses of ATP favours the formation of a non-selective pore. The latter effect induces a change in intracellular homeostasis that leads to cell death. This evidence suggests that P2X7R has both pro- and anti-tumour proprieties. P2X7R is increasingly recognised as a regulator of inflammation. In this review, we aimed to describe the most relevant characteristics of P2X7R function, activation, and its ligands, while also summarising the role of P2X7R activation in the context of inflammation and cancer. The currently used therapeutic approaches and clinical trials of P2X7R modulators are also described. Full article

(This article belongs to the Special Issue Crosstalk between Inflammation and Carcinogenesis)

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13 pages, 2514 KiB

Open AccessEditor’s ChoiceReview

Update on Epidemiology, Diagnosis, and Biomarkers in Gastroenteropancreatic Neuroendocrine Neoplasms

by Daisuke Takayanagi, Hourin Cho, Erika Machida, Atsushi Kawamura, Atsuo Takashima, Satoshi Wada, Takuya Tsunoda, Takashi Kohno and Kouya Shiraishi

Cancers 2022, 14(5), 1119; https://doi.org/10.3390/cancers14051119 - 22 Feb 2022

Cited by 29 | Viewed by 3778

Abstract

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a heterogeneous group of malignancies that originate from the diffuse neuroendocrine cell system of the pancreas and gastrointestinal tract and have increasingly increased in number over the decades. GEP-NENs are roughly classified into well-differentiated neuroendocrine tumors and poorly [...] Read more.

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a heterogeneous group of malignancies that originate from the diffuse neuroendocrine cell system of the pancreas and gastrointestinal tract and have increasingly increased in number over the decades. GEP-NENs are roughly classified into well-differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas; it is essential to understand the pathological classification according to the mitotic count and Ki67 proliferation index. In addition, with the advent of molecular-targeted drugs and somatostatin analogs and advances in endoscopic and surgical treatments, the multidisciplinary treatment of GEP-NENs has made great progress. In the management of GEP-NENs, accurate diagnosis is key for the proper selection among these diversified treatment methods. The evaluation of hormone-producing ability, diagnostic imaging, and histological diagnosis is central. Advances in the study of the genetic landscape have led to deeper understanding of tumor biology; it has also become possible to identify druggable mutations and predict therapeutic effects. Liquid biopsy, based on blood mRNA expression for GEP-NENs, has been developed, and is useful not only for early detection but also for assessing minimal residual disease after surgery and prediction of therapeutic effects. This review outlines the updates and future prospects of the epidemiology, diagnosis, and management of GEP-NENs. Full article

(This article belongs to the Collection Neuroendocrine Tumors: Treatment and Management)

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16 pages, 4091 KiB

Open AccessEditor’s ChoiceReview

Targeting Protein Kinase C for Cancer Therapy

by Sijia He, Qi Li, Qian Huang and Jin Cheng

Cancers 2022, 14(5), 1104; https://doi.org/10.3390/cancers14051104 - 22 Feb 2022

Cited by 29 | Viewed by 4652

Abstract

Protein kinase C (PKC) isoforms, a group of serine-threonine kinases, are important regulators in carcinogenesis. Numerous studies have demonstrated that PKC isoforms exert both positive and negative effects on cancer cell demise. In this review, we systematically summarize the current findings on the [...] Read more.

Protein kinase C (PKC) isoforms, a group of serine-threonine kinases, are important regulators in carcinogenesis. Numerous studies have demonstrated that PKC isoforms exert both positive and negative effects on cancer cell demise. In this review, we systematically summarize the current findings on the architecture, activity regulation and biological functions of PKCs, especially their relationship with anti-cancer therapy-induced cell death. Additionally, we elaborate on current knowledge of the effects of PKCs on tumor metabolism and microenvironment, which have gained increasing attention in oncology-related areas. Furthermore, we underscore the basic experimental and clinical implications of PKCs as a target for cancer therapy to evaluate their therapeutic benefits and potential applications. Full article

(This article belongs to the Special Issue AGC Kinases and Cancer)

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24 pages, 1557 KiB

Open AccessEditor’s ChoiceReview

The Roles of microRNAs in Cancer Multidrug Resistance

by Lucia Pavlíková, Mário Šereš, Albert Breier and Zdena Sulová

Cancers 2022, 14(4), 1090; https://doi.org/10.3390/cancers14041090 - 21 Feb 2022

Cited by 20 | Viewed by 3769

Abstract

Cancer chemotherapy may induce a multidrug resistance (MDR) phenotype. The development of MDR is based on various molecular causes, of which the following are very common: induction of ABC transporter expression; induction/activation of drug-metabolizing enzymes; alteration of the expression/function of apoptosis-related proteins; changes [...] Read more.

Cancer chemotherapy may induce a multidrug resistance (MDR) phenotype. The development of MDR is based on various molecular causes, of which the following are very common: induction of ABC transporter expression; induction/activation of drug-metabolizing enzymes; alteration of the expression/function of apoptosis-related proteins; changes in cell cycle checkpoints; elevated DNA repair mechanisms. Although these mechanisms of MDR are well described, information on their molecular interaction in overall multidrug resistance is still lacking. MicroRNA (miRNA) expression and subsequent RNA interference are candidates that could be important players in the interplay of MDR mechanisms. The regulation of post-transcriptional processes in the proteosynthetic pathway is considered to be a major function of miRNAs. Due to their complementarity, they are able to bind to target mRNAs, which prevents the mRNAs from interacting effectively with the ribosome, and subsequent degradation of the mRNAs can occur. The aim of this paper is to provide an overview of the possible role of miRNAs in the molecular mechanisms that lead to MDR. The possibility of considering miRNAs as either specific effectors or interesting targets for cancer therapy is also analyzed. Full article

(This article belongs to the Special Issue The Roles of microRNAs in Cancer Aggressiveness and Drug Resistance)

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24 pages, 1132 KiB

Open AccessEditor’s ChoiceReview

Knowns and Unknowns about CAR-T Cell Dysfunction

by Aleksei Titov, Yaroslav Kaminskiy, Irina Ganeeva, Ekaterina Zmievskaya, Aygul Valiullina, Aygul Rakhmatullina, Alexey Petukhov, Regina Miftakhova, Albert Rizvanov and Emil Bulatov

Cancers 2022, 14(4), 1078; https://doi.org/10.3390/cancers14041078 - 21 Feb 2022

Cited by 31 | Viewed by 6308

Abstract

Immunotherapy using chimeric antigen receptor (CAR) T cells is a promising option for cancer treatment. However, T cells and CAR-T cells frequently become dysfunctional in cancer, where numerous evasion mechanisms impair antitumor immunity. Cancer frequently exploits intrinsic T cell dysfunction mechanisms that evolved [...] Read more.

Immunotherapy using chimeric antigen receptor (CAR) T cells is a promising option for cancer treatment. However, T cells and CAR-T cells frequently become dysfunctional in cancer, where numerous evasion mechanisms impair antitumor immunity. Cancer frequently exploits intrinsic T cell dysfunction mechanisms that evolved for the purpose of defending against autoimmunity. T cell exhaustion is the most studied type of T cell dysfunction. It is characterized by impaired proliferation and cytokine secretion and is often misdefined solely by the expression of the inhibitory receptors. Another type of dysfunction is T cell senescence, which occurs when T cells permanently arrest their cell cycle and proliferation while retaining cytotoxic capability. The first section of this review provides a broad overview of T cell dysfunctional states, including exhaustion and senescence; the second section is focused on the impact of T cell dysfunction on the CAR-T therapeutic potential. Finally, we discuss the recent efforts to mitigate CAR-T cell exhaustion, with an emphasis on epigenetic and transcriptional modulation. Full article

(This article belongs to the Special Issue Current Advances in Chimeric Antigen Receptor Technology)

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15 pages, 589 KiB

Open AccessEditor’s ChoiceReview

The New Era of Immunotherapy in Gastric Cancer

by Shogo Takei, Akihito Kawazoe and Kohei Shitara

Cancers 2022, 14(4), 1054; https://doi.org/10.3390/cancers14041054 - 18 Feb 2022

Cited by 77 | Viewed by 11205

Abstract

Immune checkpoint inhibitors (ICIs) such as anti-programmed cell death-1 (PD-1) or programmed cell death ligand-1 (PD-L1) monoclonal antibodies have prolonged survival in various types of malignancies, including advanced gastric cancer (AGC). Nivolumab, a monoclonal anti-PD-1 antibody, showed an improvement in overall survival at [...] Read more.

Immune checkpoint inhibitors (ICIs) such as anti-programmed cell death-1 (PD-1) or programmed cell death ligand-1 (PD-L1) monoclonal antibodies have prolonged survival in various types of malignancies, including advanced gastric cancer (AGC). Nivolumab, a monoclonal anti-PD-1 antibody, showed an improvement in overall survival at a later-line therapy in unselected AGC patients in the ATTRACTION-2 study or in combination with chemotherapy as first-line therapy in the global CheckMate-649 study. Another monoclonal anti-PD-1 antibody, pembrolizumab, showed single agent activity in tumors with high microsatellite instability or high tumor mutational burden. Furthermore, a recent KEYNOTE-811 study demonstrated significant improvement in response rate with pembrolizumab combined with trastuzumab and chemotherapy for HER2-positive AGC. Based on these results, ICIs are now incorporated into standard treatment for AGC patients. As a result of pivotal clinical trials, three anti-PD-1 antibodies were approved for AGC: nivolumab combined with chemotherapy as first-line treatment or nivolumab monotherapy as third- or later-line treatment in Asian countries; pembrolizumab for previously treated microsatellite instability-high (MSI-H) or tumor mutational burden-high AGC, or pembrolizumab combined with trastuzumab and chemotherapy for HER2-positive AGC in the United States; and dostarlimab for previously treated MSI-H AGC in the United States. However, a substantial number of patients have showed resistance to ICIs, highlighting the importance of the better selection of patients or further combined immunotherapy. This review focused on molecular and immunological profiles, pivotal clinical trials of ICIs with related biomarkers, and investigational immunotherapy for AGC. Full article

(This article belongs to the Special Issue Contemporary Perspectives and Emerging Trends in the Management of Gastric Cancer)

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17 pages, 6811 KiB

Open AccessEditor’s ChoiceReview

Matrix Stiffness Contributes to Cancer Progression by Regulating Transcription Factors

by Seiichiro Ishihara and Hisashi Haga

Cancers 2022, 14(4), 1049; https://doi.org/10.3390/cancers14041049 - 18 Feb 2022

Cited by 60 | Viewed by 8423

Abstract

Matrix stiffness is critical for the progression of various types of cancers. In solid cancers such as mammary and pancreatic cancers, tumors often contain abnormally stiff tissues, mainly caused by stiff extracellular matrices due to accumulation, contraction, and crosslinking. Stiff extracellular matrices trigger [...] Read more.

Matrix stiffness is critical for the progression of various types of cancers. In solid cancers such as mammary and pancreatic cancers, tumors often contain abnormally stiff tissues, mainly caused by stiff extracellular matrices due to accumulation, contraction, and crosslinking. Stiff extracellular matrices trigger mechanotransduction, the conversion of mechanical cues such as stiffness of the matrix to biochemical signaling in the cells, and as a result determine the cellular phenotypes of cancer and stromal cells in tumors. Transcription factors are key molecules for these processes, as they respond to matrix stiffness and are crucial for cellular behaviors. The Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) is one of the most studied transcription factors that is regulated by matrix stiffness. The YAP/TAZ are activated by a stiff matrix and promotes malignant phenotypes in cancer and stromal cells, including cancer-associated fibroblasts. In addition, other transcription factors such as β-catenin and nuclear factor kappa B (NF-κB) also play key roles in mechanotransduction in cancer tissues. In this review, the mechanisms of stiffening cancer tissues are introduced, and the transcription factors regulated by matrix stiffness in cancer and stromal cells and their roles in cancer progression are shown. Full article

(This article belongs to the Special Issue Molecular Mechanism of the Interaction Between Cells and Extracellular Matrix in Cancer Progression)

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21 pages, 1236 KiB

Open AccessEditor’s ChoiceReview

Current Limitations and Novel Perspectives in Pancreatic Cancer Treatment

by Steve Robatel and Mirjam Schenk

Cancers 2022, 14(4), 985; https://doi.org/10.3390/cancers14040985 - 16 Feb 2022

Cited by 28 | Viewed by 4656

Abstract

Pancreatic cancer is one of the deadliest cancers worldwide, largely due to its aggressive development. Consequently, treatment options are often palliative, as only one-fifth of patients present with potentially curable tumors. The only available treatment with curative intent is surgery followed by adjuvant [...] Read more.

Pancreatic cancer is one of the deadliest cancers worldwide, largely due to its aggressive development. Consequently, treatment options are often palliative, as only one-fifth of patients present with potentially curable tumors. The only available treatment with curative intent is surgery followed by adjuvant chemotherapy. However, even for patients that are eligible for surgery, the 5-year OS remains below 10%. Hence, there is an urgent need to find new therapeutic regimens. In the first part of this review, we discuss the tumor staging method and its impact on the corresponding current standard-of-care treatments for PDAC. We also consider the key clinical trials over the last 20 years that have improved patient survival. In the second part, we provide an overview of the major components and cell types involved in PDAC, as well as their respective roles and interactions with each other. A deeper knowledge of the interactions taking place in the TME may lead to the discovery of potential new therapeutic targets. Finally, we discuss promising treatment strategies targeting specific components of the TME and potential combinations thereof. Overall, this review provides an overview of the current challenges and future perspectives in the treatment of pancreatic cancer. Full article

(This article belongs to the Special Issue Molecular Mechanisms Underlying Resistance and New Therapeutic Approaches in Pancreatic Cancer)

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16 pages, 1034 KiB

Open AccessEditor’s ChoiceReview

PARP Inhibitors in Glioma: A Review of Therapeutic Opportunities

by Hao-Wen Sim, Evanthia Galanis and Mustafa Khasraw

Cancers 2022, 14(4), 1003; https://doi.org/10.3390/cancers14041003 - 16 Feb 2022

Cited by 22 | Viewed by 7134

Abstract

Gliomas are the most common malignant primary brain tumor in adults. Despite advances in multimodality therapy, incorporating surgery, radiotherapy, systemic therapy, tumor treating fields and supportive care, patient outcomes remain poor, especially in glioblastoma where median survival has remained static at around 15 [...] Read more.

Gliomas are the most common malignant primary brain tumor in adults. Despite advances in multimodality therapy, incorporating surgery, radiotherapy, systemic therapy, tumor treating fields and supportive care, patient outcomes remain poor, especially in glioblastoma where median survival has remained static at around 15 months, for decades. Low-grade gliomas typically harbor isocitrate dehydrogenase (IDH) mutations, grow more slowly and confer a better prognosis than glioblastoma. However, nearly all gliomas eventually recur and progress in a way similar to glioblastoma. One of the novel therapies being developed in this area are poly(ADP-Ribose) polymerase (PARP) inhibitors. PARP inhibitors belong to a class of drugs that target DNA damage repair pathways. This leads to synthetic lethality of cancer cells with coexisting homologous recombination deficiency. PARP inhibitors may also potentiate the cytotoxic effects of radiotherapy and chemotherapy, and prime the tumor microenvironment for immunotherapy. In this review, we examine the rationale and clinical evidence for PARP inhibitors in glioma and suggest therapeutic opportunities. Full article

(This article belongs to the Special Issue Clinical Use of PARP Inhibitors in Cancer – From Bench to Bedside and Back Again)

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16 pages, 2548 KiB

Open AccessEditor’s ChoiceArticle

Risk Stratification Using a Novel Nomogram for 2190 EGFR-Mutant NSCLC Patients Receiving the First or Second Generation EGFR-TKI

by John Wen-Cheng Chang, Chen-Yang Huang, Yueh-Fu Fang, Ching-Fu Chang, Cheng-Ta Yang, Chih-Hsi Scott Kuo, Ping-Chih Hsu and Chiao-En Wu

Cancers 2022, 14(4), 977; https://doi.org/10.3390/cancers14040977 - 15 Feb 2022

Cited by 15 | Viewed by 2469

Abstract

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the standard treatment for EGFR mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC). This study aimed to create a novel nomogram to help physicians suggest the optimal treatment for patients with EGFRm+ NSCLC. Records of [...] Read more.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the standard treatment for EGFR mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC). This study aimed to create a novel nomogram to help physicians suggest the optimal treatment for patients with EGFRm+ NSCLC. Records of 2190 patients with EGFRm+ NSCLC cancer who were treated with EGFR-TKIs (including gefitinib, erlotinib, and afatinib) at the branches of a hospital group between 2011 and 2018 were retrospectively reviewed. Their clinicopathological characteristics, clinical tumor response, progression-free survival (PFS), and overall survival (OS) data were collected. Univariate and multivariate analyses were performed to identify potential prognostic factors to create a nomogram for risk stratification. Univariate analysis identified 14 prognostic factors, and multivariate analysis confirmed the pretreatment independent factors, including Eastern Cooperative Oncology Group performance status, morphology, mutation, stage, EGFR-TKIs (gefitinib, erlotinib, or afatinib), and metastasis to liver, brain, bone, pleura, adrenal gland, and distant lymph nodes. Based on these factors, a novel nomogram was created and used to stratify the patients into five different risk groups for PFS and OS using recursive partitioning analysis. This risk stratification can provide additional information to clinicians and patients when determining the optimal therapeutic options for EGFRm+ NSCLC. Full article

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28 pages, 15719 KiB

Open AccessEditor’s ChoiceReview

Dissecting Tumor Growth: The Role of Cancer Stem Cells in Drug Resistance and Recurrence

by Beatrice Aramini, Valentina Masciale, Giulia Grisendi, Federica Bertolini, Michela Maur, Giorgia Guaitoli, Isca Chrystel, Uliano Morandi, Franco Stella, Massimo Dominici and Khawaja Husnain Haider

Cancers 2022, 14(4), 976; https://doi.org/10.3390/cancers14040976 - 15 Feb 2022

Cited by 45 | Viewed by 9317

Abstract

Emerging evidence suggests that a small subpopulation of cancer stem cells (CSCs) is responsible for initiation, progression, and metastasis cascade in tumors. CSCs share characteristics with normal stem cells, i.e., self-renewal and differentiation potential, suggesting that they can drive cancer progression. Consequently, targeting [...] Read more.

Emerging evidence suggests that a small subpopulation of cancer stem cells (CSCs) is responsible for initiation, progression, and metastasis cascade in tumors. CSCs share characteristics with normal stem cells, i.e., self-renewal and differentiation potential, suggesting that they can drive cancer progression. Consequently, targeting CSCs to prevent tumor growth or regrowth might offer a chance to lead the fight against cancer. CSCs create their niche, a specific area within tissue with a unique microenvironment that sustains their vital functions. Interactions between CSCs and their niches play a critical role in regulating CSCs’ self-renewal and tumorigenesis. Differences observed in the frequency of CSCs, due to the phenotypic plasticity of many cancer cells, remain a challenge in cancer therapeutics, since CSCs can modulate their transcriptional activities into a more stem-like state to protect themselves from destruction. This plasticity represents an essential step for future therapeutic approaches. Regarding self-renewal, CSCs are modulated by the same molecular pathways found in normal stem cells, such as Wnt/β-catenin signaling, Notch signaling, and Hedgehog signaling. Another key characteristic of CSCs is their resistance to standard chemotherapy and radiotherapy treatments, due to their capacity to rest in a quiescent state. This review will analyze the primary mechanisms involved in CSC tumorigenesis, with particular attention to the roles of CSCs in tumor progression in benign and malignant diseases; and will examine future perspectives on the identification of new markers to better control tumorigenesis, as well as dissecting the metastasis process. Full article

(This article belongs to the Special Issue Understanding Molecular Regulation of Cancer Progression and Metastasis)

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20 pages, 8036 KiB

Open AccessEditor’s ChoiceArticle

Patient-Derived Ovarian Cancer Spheroids Rely on PI3K-AKT Signaling Addiction for Cancer Stemness and Chemoresistance

by Deepak Parashar, Anjali Geethadevi, Sonam Mittal, Lindsey A. McAlarnen, Jasmine George, Ishaque P. Kadamberi, Prachi Gupta, Denise S. Uyar, Elizabeth E. Hopp, Holli Drendel, Erin A. Bishop, William H. Bradley, Kathleen M. Bone, Janet S. Rader, Sunila Pradeep and Pradeep Chaluvally-Raghavan

Cancers 2022, 14(4), 958; https://doi.org/10.3390/cancers14040958 - 15 Feb 2022

Cited by 14 | Viewed by 3220

Abstract

Ovarian cancer is the most lethal gynecological malignancy among women worldwide and is characterized by aggressiveness, cancer stemness, and frequent relapse due to resistance to platinum-based therapy. Ovarian cancer cells metastasize through ascites fluid as 3D spheroids which are more resistant to apoptosis [...] Read more.

Ovarian cancer is the most lethal gynecological malignancy among women worldwide and is characterized by aggressiveness, cancer stemness, and frequent relapse due to resistance to platinum-based therapy. Ovarian cancer cells metastasize through ascites fluid as 3D spheroids which are more resistant to apoptosis and chemotherapeutic agents. However, the precise mechanism as an oncogenic addiction that makes 3D spheroids resistant to apoptosis and chemotherapeutic agents is not understood. To study the signaling addiction mechanism that occurs during cancer progression in patients, we developed an endometrioid subtype ovarian cancer cell line named ‘MCW-OV-SL-3’ from the ovary of a 70-year-old patient with stage 1A endometrioid adenocarcinoma of the ovary. We found that the cell line MCW-OV-SL-3 exhibits interstitial duplication of 1q (q21–q42), where this duplication resulted in high expression of the PIK3C2B gene and aberrant activation of PI3K-AKT-ERK signaling. Using short tandem repeat (STR) analysis, we demonstrated that the cell line exhibits a unique genetic identity compared to existing ovarian cancer cell lines. Notably, the MCW-OV-SL-3 cell line was able to form 3D spheroids spontaneously, which is an inherent property of tumor cells when plated on cell culture dishes. Importantly, the tumor spheroids derived from the MCW-OV-SL-3 cell line expressed high levels of c-Kit, PROM1, ZEB1, SNAI, VIM, and Twist1 compared to 2D monolayer cells. We also observed that the hyperactivation of ERK and PI3K/AKT signaling in these cancer cells resulted in resistance to cisplatin. In summary, the MCW-OV-SL3 endometrioid cell line is an excellent model to study the mechanism of cancer stemness and chemoresistance in endometrioid ovarian cancer. Full article

(This article belongs to the Topic Advances in Ovarian Cancer Research: From Biology to Therapeutics)

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17 pages, 867 KiB

Open AccessEditor’s ChoiceReview

Intrinsic and Extrinsic Factors Impacting Cancer Stemness and Tumor Progression

by Alexey Ponomarev, Zarema Gilazieva, Valeriya Solovyeva, Cinzia Allegrucci and Albert Rizvanov

Cancers 2022, 14(4), 970; https://doi.org/10.3390/cancers14040970 - 15 Feb 2022

Cited by 19 | Viewed by 5564

Abstract

Tumor heterogeneity represents an important limitation to the development of effective cancer therapies. The presence of cancer stem cells (CSCs) and their differentiation hierarchies contribute to cancer complexity and confer tumors the ability to grow, resist treatment, survive unfavorable conditions, and invade neighboring [...] Read more.

Tumor heterogeneity represents an important limitation to the development of effective cancer therapies. The presence of cancer stem cells (CSCs) and their differentiation hierarchies contribute to cancer complexity and confer tumors the ability to grow, resist treatment, survive unfavorable conditions, and invade neighboring and distant tissues. A large body of research is currently focusing on understanding the properties of CSCs, including their cellular and molecular origin, as well as their biological behavior in different tumor types. In turn, this knowledge informs strategies for targeting these tumor initiating cells and related cancer stemness. Cancer stemness is modulated by the tumor microenvironment, which influences CSC function and survival. Several advanced in vitro models are currently being developed to study cancer stemness in order to advance new knowledge of the key molecular pathways involved in CSC self-renewal and dormancy, as well as to mimic the complexity of patients’ tumors in pre-clinical drug testing. In this review, we discuss CSCs and the modulation of cancer stemness by the tumor microenvironment, stemness factors and signaling pathways. In addition, we introduce current models that allow the study of CSCs for the development of new targeted therapies. Full article

(This article belongs to the Special Issue Cancer Stem Cells (CSCs) in Drug Resistance and Their Therapeutic Implications in Cancer Treatment)

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22 pages, 894 KiB

Open AccessEditor’s ChoiceReview

Everything Comes with a Price: The Toxicity Profile of DNA-Damage Response Targeting Agents

by Federica Martorana, Leandro Apolinario Da Silva, Cristiana Sessa and Ilaria Colombo

Cancers 2022, 14(4), 953; https://doi.org/10.3390/cancers14040953 - 14 Feb 2022

Cited by 20 | Viewed by 4699

Abstract

Targeting the inherent vulnerability of cancer cells with an impaired DNA Damage Repair (DDR) machinery, Poly-ADP-Ribose-Polymerase (PARP) inhibitors have yielded significant results in several tumor types, eventually entering clinical practice for the treatment of ovarian, breast, pancreatic and prostate cancer. More recently, inhibitors [...] Read more.

Targeting the inherent vulnerability of cancer cells with an impaired DNA Damage Repair (DDR) machinery, Poly-ADP-Ribose-Polymerase (PARP) inhibitors have yielded significant results in several tumor types, eventually entering clinical practice for the treatment of ovarian, breast, pancreatic and prostate cancer. More recently, inhibitors of other key components of DNA repair, such as ATR, CHK1 and WEE1, have been developed and are currently under investigation in clinical trials. The inhibition of DDR inevitably induces on-target and off-target adverse events. Hematological and gastrointestinal toxicities as well as fatigue are common with all DDR-targeting agents, while other adverse events are drug specific, such as hypertension with niraparib and transaminase elevation with rucaparib. Cases of pneumonitis and secondary hematological malignancies have been reported with PARP inhibitors and, despite being overly rare, they deserve particular attention due to their severity. Safety also represents a crucial issue for the development of combination regimens incorporating DDR-targeting agents with other treatments, such as chemotherapy, anti-angiogenics or immunotherapy. As such, overlapping and cumulative toxicities should be considered, especially when more than two classes of drugs are combined. Here, we review the safety profile of DDR-targeting agents when used as single agents or in combination and we provide principles of toxicity management. Full article

(This article belongs to the Special Issue DNA Damage Response Targeting: Challenges and Opportunities)

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