Cancers

14 pages, 1475 KiB

Open AccessEditor’s ChoiceReview

Fatty Acid Metabolism in Myeloid-Derived Suppressor Cells and Tumor-Associated Macrophages: Key Factor in Cancer Immune Evasion

by Sophiya Siddiqui and Rainer Glauben

Cancers 2022, 14(1), 250; https://doi.org/10.3390/cancers14010250 - 4 Jan 2022

Cited by 18 | Viewed by 4102

Abstract

The tumor microenvironment (TME) comprises various cell types, soluble factors, viz, metabolites or cytokines, which together play in promoting tumor metastasis. Tumor infiltrating immune cells play an important role against cancer, and metabolic switching in immune cells has been shown to affect activation, [...] Read more.

The tumor microenvironment (TME) comprises various cell types, soluble factors, viz, metabolites or cytokines, which together play in promoting tumor metastasis. Tumor infiltrating immune cells play an important role against cancer, and metabolic switching in immune cells has been shown to affect activation, differentiation, and polarization from tumor suppressive into immune suppressive phenotypes. Macrophages represent one of the major immune infiltrates into TME. Blood monocyte-derived macrophages and myeloid derived suppressor cells (MDSCs) infiltrating into the TME potentiate hostile tumor progression by polarizing into immunosuppressive tumor-associated macrophages (TAMs). Recent studies in the field of immunometabolism focus on metabolic reprogramming at the TME in polarizing tumor-associated macrophages (TAMs). Lipid droplets (LD), detected in almost every eukaryotic cell type, represent the major source for intra-cellular fatty acids. Previously, LDs were mainly described as storage sites for fatty acids. However, LDs are now recognized to play an integral role in cellular signaling and consequently in inflammation and metabolism-mediated phenotypical changes in immune cells. In recent years, the role of LD dependent metabolism in macrophage functionality and phenotype has been being investigated. In this review article, we discuss fatty acids stored in LDs, their role in modulating metabolism of tumor-infiltrating immune cells and, therefore, in shaping the cancer progression. Full article

(This article belongs to the Special Issue Epigenetic and Metabolic Alterations in the Tumor Microenvironment)

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13 pages, 2379 KiB

Open AccessEditor’s ChoiceArticle

Delta-Radiomics Predicts Response to First-Line Oxaliplatin-Based Chemotherapy in Colorectal Cancer Patients with Liver Metastases

by Valentina Giannini, Laura Pusceddu, Arianna Defeudis, Giulia Nicoletti, Giovanni Cappello, Simone Mazzetti, Andrea Sartore-Bianchi, Salvatore Siena, Angelo Vanzulli, Francesco Rizzetto, Elisabetta Fenocchio, Luca Lazzari, Alberto Bardelli, Silvia Marsoni and Daniele Regge

Cancers 2022, 14(1), 241; https://doi.org/10.3390/cancers14010241 - 4 Jan 2022

Cited by 18 | Viewed by 6148

Abstract

The purpose of this paper is to develop and validate a delta-radiomics score to predict the response of individual colorectal cancer liver metastases (lmCRC) to first-line FOLFOX chemotherapy. Three hundred one lmCRC were manually segmented on both CT performed at baseline and after [...] Read more.

The purpose of this paper is to develop and validate a delta-radiomics score to predict the response of individual colorectal cancer liver metastases (lmCRC) to first-line FOLFOX chemotherapy. Three hundred one lmCRC were manually segmented on both CT performed at baseline and after the first cycle of first-line FOLFOX, and 107 radiomics features were computed by subtracting textural features of CT at baseline from those at timepoint 1 (TP1). LmCRC were classified as nonresponders (R−) if they showed progression of disease (PD), according to RECIST1.1, before 8 months, and as responders (R+), otherwise. After feature selection, we developed a decision tree statistical model trained using all lmCRC coming from one hospital. The final output was a delta-radiomics signature subsequently validated on an external dataset. Sensitivity, specificity, positive (PPV), and negative (NPV) predictive values in correctly classifying individual lesions were assessed on both datasets. Per-lesion sensitivity, specificity, PPV, and NPV were 99%, 94%, 95%, 99%, 85%, 92%, 90%, and 87%, respectively, in the training and validation datasets. The delta-radiomics signature was able to reliably predict R− lmCRC, which were wrongly classified by lesion RECIST as R+ at TP1, (93%, averaging training and validation set, versus 67% of RECIST). The delta-radiomics signature developed in this study can reliably predict the response of individual lmCRC to oxaliplatin-based chemotherapy. Lesions forecasted as poor or nonresponders by the signature could be further investigated, potentially paving the way to lesion-specific therapies. Full article

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

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16 pages, 524 KiB

Open AccessEditor’s ChoiceReview

The Impact of Biomarkers in Pancreatic Ductal Adenocarcinoma on Diagnosis, Surveillance and Therapy

by Niklas Sturm, Thomas J. Ettrich and Lukas Perkhofer

Cancers 2022, 14(1), 217; https://doi.org/10.3390/cancers14010217 - 3 Jan 2022

Cited by 24 | Viewed by 3602

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is still difficult to treat due to insufficient methods for early diagnosis and prediction of therapy response. Furthermore, surveillance after curatively intended surgery lacks adequate methods for timely detection of recurrence. Therefore, several molecules have been analyzed as predictors [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is still difficult to treat due to insufficient methods for early diagnosis and prediction of therapy response. Furthermore, surveillance after curatively intended surgery lacks adequate methods for timely detection of recurrence. Therefore, several molecules have been analyzed as predictors of recurrence or early detection of PDAC. Enhanced understanding of molecular tumorigenesis and treatment response triggered the identification of novel biomarkers as predictors for response to conventional chemotherapy or targeted therapy. In conclusion, progress has been made especially in the prediction of therapy response with biomarkers. The use of molecules for early detection and recurrence of PDAC is still at an early stage, but there are promising approaches in noninvasive biomarkers, composite panels and scores that can already ameliorate the current clinical practice. The present review summarizes the current state of research on biomarkers for diagnosis and therapy of pancreatic cancer. Full article

(This article belongs to the Special Issue Hepatobiliary and Pancreatic Neoplasms: Biomarkers and Targeted Therapy)

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15 pages, 3727 KiB

Open AccessEditor’s ChoiceArticle

Phototheranostics of Cervical Neoplasms with Chlorin e6 Photosensitizer

by Aida Gilyadova, Anton Ishchenko, Artem Shiryaev, Polina Alekseeva, Kanamat Efendiev, Radmila Karpova, Maxim Loshchenov, Victor Loschenov and Igor Reshetov

Cancers 2022, 14(1), 211; https://doi.org/10.3390/cancers14010211 - 2 Jan 2022

Cited by 12 | Viewed by 3430

Abstract

(1) Purpose: Improving the treatment effectiveness of intraepithelial neoplasia of the cervix associated with human papillomavirus infection, based on the application of the method of photodynamic therapy with simultaneous laser excitation of fluorescence to clarify the boundaries of cervical neoplasms. (2) Methods: Examination [...] Read more.

(1) Purpose: Improving the treatment effectiveness of intraepithelial neoplasia of the cervix associated with human papillomavirus infection, based on the application of the method of photodynamic therapy with simultaneous laser excitation of fluorescence to clarify the boundaries of cervical neoplasms. (2) Methods: Examination and treatment of 52 patients aged 22 to 53 years with morphologically and cytologically confirmed mild to severe intraepithelial cervix neoplasia, preinvasive, micro-invasive, and squamous cell cervix carcinoma. All patients were carriers of human papillomavirus infection. The patients underwent photodynamic therapy with simultaneous laser excitation of fluorescence. The combined use of video and spectral fluorescence diagnostics for cervical neoplasms made it possible to control the photodynamic therapy process at all stages of the procedure. Evaluation of the photodynamic therapy of intraepithelial cervical neoplasms was carried out with colposcopic examination, cytological conclusion, and morphological verification of the biopsy material after the photodynamic therapy course. The success of human papillomavirus therapy was assessed based on the results of the polymerase chain reaction. (3) Results. The possibility of simultaneous spectral fluorescence diagnostics and photodynamic therapy using a laser source with a wavelength of 660 nm has been established, making it possible to assess the fluorescence index in real-time and control the photobleaching of photosensitizers in the irradiated area. The treatment of all 52 patients was successful after the first photodynamic therapy procedure. According to the PCR test of the discharge from the cervical canal, the previously identified HPV types were not observed in 48 patients. Previously identified HPV types were absent after repeated PDT in four patients (CIN III (n = 2), CIS (n = 2)). In 80.8% of patients, regression of the lesion was noted. (4) Conclusions. The high efficiency of photodynamic therapy with intravenous photosensitizer administration of chlorin e6 has been demonstrated both in relation to eradication therapy of human papillomavirus and in relation to the treatment of intraepithelial lesions of the cervix. Full article

(This article belongs to the Special Issue Innovative Cancer Treatments and Photodynamic Therapy)

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18 pages, 3590 KiB

Open AccessEditor’s ChoiceArticle

Combining an Autophagy Inhibitor, MPT0L145, with Abemaciclib Is a New Therapeutic Strategy in GBM Treatment

by Tsung-Han Hsieh, Muh-Lii Liang, Jia-Huei Zheng, Yu-Chen Lin, Yu-Chen Yang, Thanh-Hoa Vo, Jing-Ping Liou, Yun Yen and Chun-Han Chen

Cancers 2021, 13(23), 6117; https://doi.org/10.3390/cancers13236117 - 4 Dec 2021

Cited by 4 | Viewed by 3092

Abstract

Glioblastoma multiforme (GBM) is the most malignant brain tumor in the world, only 25% of GBM patients were alive one year after diagnosis. Although Temozolamide combined with radiation therapy more effectively prolonged the survival rate than radiation alone, the overall survival rate is [...] Read more.

Glioblastoma multiforme (GBM) is the most malignant brain tumor in the world, only 25% of GBM patients were alive one year after diagnosis. Although Temozolamide combined with radiation therapy more effectively prolonged the survival rate than radiation alone, the overall survival rate is still dismal. Therefore, a new therapeutic strategy is urgently needed. CDK4/6 inhibitors are newly FDA-approved agents to treat HR-positive, HER2-negative advanced, and metastatic breast cancers, and preclinical results showed that CDK4/6 inhibitors significantly reduced cell proliferation and tumor growth. However, several studies have suggested that CDK4/6 inhibitor-induced non-genetic changes caused treatment failure, including autophagy activation. Therefore, this study aimed to combine an autophagy inhibitor, MPT0L145, with abemaciclib to improve therapeutic efficiency. The use of abemaciclib effectively inhibited cell proliferation via suppression of RB phosphorylation and induced autophagy activation in GBM cancer cells. MPT0L145 treatment alone not only blocked autophagy activation, but also induced generation of ROS and DNA damage in a concentration-dependent manner. Importantly, MPT0L145 had a comparable penetration ability to TMZ in our blood brain barrier permeability assay. Combined MPT0L145 with abemaciclib significantly reduced cell proliferation, suppressed RB phosphorylation, and increased ROS production. In conclusion, the data suggested that blocking autophagy by MPT0L145 synergistically sensitized GBM cancer cells to abemaciclib and represents a potential therapeutic strategy for treating GBM in the future. Full article

(This article belongs to the Special Issue Brain Tumors: Molecular and Cell Biology for Target Therapy)

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16 pages, 3828 KiB

Open AccessEditor’s ChoiceArticle

Brain-Derived Neurotrophic Factor, Neutrophils and Cysteinyl Leukotriene Receptor 1 as Potential Prognostic Biomarkers for Patients with Colon Cancer

by Syrina F. Mehrabi, Souvik Ghatak, Lubna M. Mehdawi, Geriolda Topi, Shakti Ranjan Satapathy and Anita Sjölander

Cancers 2021, 13(21), 5520; https://doi.org/10.3390/cancers13215520 - 3 Nov 2021

Cited by 4 | Viewed by 2673

Abstract

The tumor microenvironment has been recognized as a complex network in which immune cells play an important role in cancer progression. We found significantly higher CD66b neutrophil expression in tumor tissue than in matched normal mucosa in the Malmö colon cancer (CC) cohort [...] Read more.

The tumor microenvironment has been recognized as a complex network in which immune cells play an important role in cancer progression. We found significantly higher CD66b neutrophil expression in tumor tissue than in matched normal mucosa in the Malmö colon cancer (CC) cohort and poorer survival of stage I-III patients with high CD66b expression. Additionally, mice lacking CysLT₁R expression (cysltr1^−/−) produce less brain-derived neurotrophic factor (BDNF) compared to WT mice and Montelukast (a CysLT₁R antagonist)-treated mice also reduced BDNF expression in a mouse xenograft model with human SW480 CC cells. CD66b and BDNF expression was significantly higher in patient tumor tissues than in the matched normal mucosa. The univariate Cox PH analysis yielded CD66b and BDNF as an independent predictor of overall survival, which was also found in the public TCGA-COAD dataset. We also discovered a strong positive correlation between CD66b, BDNF and CysLT₁R expression in the Malmö CC cohort and in the TCGA-COAD dataset. Our data suggest that CD66b/BDNF/CysLT₁R expression as a prognostic combined biomarker signature for CC patients. Full article

(This article belongs to the Section Cancer Biomarkers)

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25 pages, 1192 KiB

Open AccessEditor’s ChoiceReview

Genetic Landscape and Emerging Therapies in Uveal Melanoma

by Rino S. Seedor, Marlana Orloff and Takami Sato

Cancers 2021, 13(21), 5503; https://doi.org/10.3390/cancers13215503 - 2 Nov 2021

Cited by 21 | Viewed by 4755

Abstract

Despite successful treatment of primary uveal melanoma, up to 50% of patients will develop systemic metastasis. Metastatic disease portends a poor outcome, and no adjuvant or metastatic therapy has been FDA approved. The genetic landscape of uveal melanoma is unique, providing prognostic and [...] Read more.

Despite successful treatment of primary uveal melanoma, up to 50% of patients will develop systemic metastasis. Metastatic disease portends a poor outcome, and no adjuvant or metastatic therapy has been FDA approved. The genetic landscape of uveal melanoma is unique, providing prognostic and potentially therapeutic insight. In this review, we discuss our current understanding of the molecular and cytogenetic mutations in uveal melanoma, and the importance of obtaining such information. Most of our knowledge is based on primary uveal melanoma and a better understanding of the mutational landscape in metastatic uveal melanoma is needed. Clinical trials targeting certain mutations such as GNAQ/GNA11, BAP1, and SF3B1 are ongoing and promising. We also discuss the role of liquid biopsies in uveal melanoma in this review. Full article

(This article belongs to the Special Issue Metastatic Uveal Melanoma)

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14 pages, 8959 KiB

Open AccessEditor’s ChoiceReview

Tumor Heterogeneity and Consequences for Bladder Cancer Treatment

by Etienne Lavallee, John P. Sfakianos and David J. Mulholland

Cancers 2021, 13(21), 5297; https://doi.org/10.3390/cancers13215297 - 22 Oct 2021

Cited by 15 | Viewed by 3641

Abstract

Acquired therapeutic resistance remains a major challenge in cancer management and associates with poor oncological outcomes in most solid tumor types. A major contributor is tumor heterogeneity (TH) which can be influenced by the stromal; immune and epithelial tumor compartments. We hypothesize that [...] Read more.

Acquired therapeutic resistance remains a major challenge in cancer management and associates with poor oncological outcomes in most solid tumor types. A major contributor is tumor heterogeneity (TH) which can be influenced by the stromal; immune and epithelial tumor compartments. We hypothesize that heterogeneity in tumor epithelial subpopulations—whether de novo or newly acquired—closely regulate the clinical course of bladder cancer. Changes in these subpopulations impact the tumor microenvironment including the extent of immune cell infiltration and response to immunotherapeutics. Mechanisms driving epithelial tumor heterogeneity (EpTH) can be broadly categorized as mutational and non-mutational. Mechanisms regulating lineage plasticity; acquired cellular mutations and changes in lineage-defined subpopulations regulate stress responses to clinical therapies. If tumor heterogeneity is a dynamic process; an increased understanding of how EpTH is regulated is critical in order for clinical therapies to be more sustained and durable. In this review and analysis, we assess the importance and regulatory mechanisms governing EpTH in bladder cancer and the impact on treatment response. Full article

(This article belongs to the Special Issue Systemic Treatment of Advanced Bladder Cancer – Status Update)

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25 pages, 6772 KiB

Open AccessEditor’s ChoiceReview

Cancer-Associated Fibroblast Functions as a Road-Block in Cancer Therapy

by Pradip De, Jennifer Aske and Nandini Dey

Cancers 2021, 13(20), 5246; https://doi.org/10.3390/cancers13205246 - 19 Oct 2021

Cited by 25 | Viewed by 4595

Abstract

The journey of a normal resident fibroblast belonging to the tumor microenvironment (TME) from being a tumor pacifier to a tumor patron is fascinating. We introduce cancer-associated fibroblast (CAF) as a crucial component of the TME. Activated-CAF partners with tumor cells and all [...] Read more.

The journey of a normal resident fibroblast belonging to the tumor microenvironment (TME) from being a tumor pacifier to a tumor patron is fascinating. We introduce cancer-associated fibroblast (CAF) as a crucial component of the TME. Activated-CAF partners with tumor cells and all components of TME in an established solid tumor. We briefly overview the origin, activation, markers, and overall functions of CAF with a particular reference to how different functions of CAF in an established tumor are functionally connected to the development of resistance to cancer therapy in solid tumors. We interrogate the role of CAF in mediating resistance to different modes of therapies. Functional diversity of CAF in orchestrating treatment resistance in solid tumors portrays CAF as a common orchestrator of treatment resistance; a roadblock in cancer therapy Full article

(This article belongs to the Special Issue Targeted Cancer Therapy: Targeting Tyrosine/Serine Kinases by Small Molecule Inhibitors, Immune Modulators, and Monoclonal Antibodies)

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15 pages, 1359 KiB

Open AccessEditor’s ChoiceReview

MSC-Derived Extracellular Vesicles in Tumors and Therapy

by Tianjiao Luo, Juliane von der Ohe and Ralf Hass

Cancers 2021, 13(20), 5212; https://doi.org/10.3390/cancers13205212 - 18 Oct 2021

Cited by 37 | Viewed by 3126

Abstract

Exosomes derived from mesenchymal stroma-/stem-like cells (MSCs) as part of extracellular vesicles are considered cell-free biocompatible nanovesicles that promote repair activities of damaged tissues or organs by exhibiting low immunogenic and cytotoxic effects. Contributions to regenerative activities include wound healing, maintenance of stem [...] Read more.

Exosomes derived from mesenchymal stroma-/stem-like cells (MSCs) as part of extracellular vesicles are considered cell-free biocompatible nanovesicles that promote repair activities of damaged tissues or organs by exhibiting low immunogenic and cytotoxic effects. Contributions to regenerative activities include wound healing, maintenance of stem cell niches, beneficial regenerative effects in various diseases, and reduction of senescence. However, the mode of action in MSC-derived exosomes strongly depends on the biological content like different regulatory microRNAs that are determined by the tissue origin of MSCs. In tumors, MSCs use indirect and direct pathways in a communication network to interact with cancer cells. This leads to mutual functional changes with the acquisition of an aberrant tumor-associated MSC phenotype accompanied by altered cargo in the exosomes. Consequently, MSC-derived exosomes either from normal tissue-originating MSCs or from aberrant tumor-associated MSCs can confer different actions on tumor development. These processes exhibiting tumor-inhibitory and tumor-supportive effects with a focus on exosome microRNA content will be discriminated and discussed within this review. Full article

(This article belongs to the Special Issue Exosome Biology for Nucleic Acid Medicine—From Bench to Bed)

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22 pages, 553 KiB

Open AccessEditor’s ChoiceReview

Molecular Targets for Gastric Cancer Treatment and Future Perspectives from a Clinical and Translational Point of View

by Justus Körfer, Florian Lordick and Ulrich T. Hacker

Cancers 2021, 13(20), 5216; https://doi.org/10.3390/cancers13205216 - 18 Oct 2021

Cited by 17 | Viewed by 4439

Abstract

Gastric cancer is a leading cause of cancer death worldwide. Systemic treatment comprising chemotherapy and targeted therapy is the standard of care in advanced/metastatic gastric cancer. Comprehensive molecular characterization of gastric adenocarcinomas by the TCGA Consortium and ACRG has resulted in the definition [...] Read more.

Gastric cancer is a leading cause of cancer death worldwide. Systemic treatment comprising chemotherapy and targeted therapy is the standard of care in advanced/metastatic gastric cancer. Comprehensive molecular characterization of gastric adenocarcinomas by the TCGA Consortium and ACRG has resulted in the definition of distinct molecular subtypes. These efforts have in parallel built a basis for the development of novel molecularly stratified treatment approaches. Based on this molecular characterization, an increasing number of specific genomic alterations can potentially serve as treatment targets. Consequently, the development of promising compounds is ongoing. In this review, key molecular alterations in gastric and gastroesophageal junction cancers will be addressed. Finally, the current status of the translation of targeted therapy towards clinical applications will be reviewed. Full article

(This article belongs to the Special Issue New Molecular Insights for GC Characterization and Treatment)

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16 pages, 3674 KiB

Open AccessEditor’s ChoiceReview

Could Photodynamic Therapy Be a Promising Therapeutic Modality in Hepatocellular Carcinoma Patients? A Critical Review of Experimental and Clinical Studies

by Abhishek Kumar, Olivier Moralès, Serge Mordon, Nadira Delhem and Emmanuel Boleslawski

Cancers 2021, 13(20), 5176; https://doi.org/10.3390/cancers13205176 - 15 Oct 2021

Cited by 22 | Viewed by 3336

Abstract

Photodynamic Therapy (PDT) relies on local or systemic administration of a light-sensitive dye, called photosensitizer, to accumulate into the target site followed by excitation with light of appropriate wavelength and fluence. This photo-activated molecule reacts with the intracellular oxygen to induce selective cytotoxicity [...] Read more.

Photodynamic Therapy (PDT) relies on local or systemic administration of a light-sensitive dye, called photosensitizer, to accumulate into the target site followed by excitation with light of appropriate wavelength and fluence. This photo-activated molecule reacts with the intracellular oxygen to induce selective cytotoxicity of targeted cells by the generation of reactive oxygen species. Hepatocellular carcinoma (HCC), one of the leading causes of cancer-associated mortality worldwide, has insufficient treatment options available. In this review, we discuss the mechanism and merits of PDT along with its recent developments as an anti-cancerous therapy. We also highlight the application of this novel therapy for diagnosis, visualization, and treatment of HCC. We examine the underlying challenges, some pre-clinical and clinical studies, and possibilities of future studies associated with PDT. Finally, we discuss the mechanism of an active immune response by PDT and thereafter explored the role of PDT in the generation of anti-tumor immune response in the context of HCC, with an emphasis on checkpoint inhibitor-based immunotherapy. The objective of this review is to propose PDT as a plausible adjuvant to existing therapies for HCC, highlighting a feasible combinatorial approach for HCC treatment. Full article

(This article belongs to the Special Issue Innovative Cancer Treatments and Photodynamic Therapy)

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18 pages, 1333 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Genetic Drivers of Ileal Neuroendocrine Tumors

by Darren R. Carpizo and Chris R. Harris

Cancers 2021, 13(20), 5070; https://doi.org/10.3390/cancers13205070 - 10 Oct 2021

Cited by 5 | Viewed by 3280

Abstract

The genetic causes of ileal neuroendocrine tumors (ileal NETs, or I-NETs) have been a mystery. For most types of tumors, key genes were revealed by large scale genomic sequencing that demonstrated recurrent mutations of specific oncogenes or tumor suppressors. In contrast, genomic sequencing [...] Read more.

The genetic causes of ileal neuroendocrine tumors (ileal NETs, or I-NETs) have been a mystery. For most types of tumors, key genes were revealed by large scale genomic sequencing that demonstrated recurrent mutations of specific oncogenes or tumor suppressors. In contrast, genomic sequencing of ileal NETs demonstrated a distinct lack of recurrently mutated genes, suggesting that the mechanisms that drive the formation of I-NETs may be quite different than the cell-intrinsic mutations that drive the formation of other tumor types. However, recent mouse studies have identified the IGF2 and RB1 pathways in the formation of ileal NETs, which is supported by the subsequent analysis of patient samples. Thus, ileal NETs no longer appear to be a cancer without genetic causes. Full article

(This article belongs to the Special Issue Advances in Neuroendocrine Neoplasms Research)

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26 pages, 3827 KiB

Open AccessEditor’s ChoiceReview

Vimentin Is at the Heart of Epithelial Mesenchymal Transition (EMT) Mediated Metastasis

by Saima Usman, Naushin H. Waseem, Thuan Khanh Ngoc Nguyen, Sahar Mohsin, Ahmad Jamal, Muy-Teck Teh and Ahmad Waseem

Cancers 2021, 13(19), 4985; https://doi.org/10.3390/cancers13194985 - 5 Oct 2021

Cited by 158 | Viewed by 12649

Abstract

Epithelial-mesenchymal transition (EMT) is a reversible plethora of molecular events where epithelial cells gain the phenotype of mesenchymal cells to invade the surrounding tissues. EMT is a physiological event during embryogenesis (type I) but also happens during fibrosis (type II) and cancer metastasis [...] Read more.

Epithelial-mesenchymal transition (EMT) is a reversible plethora of molecular events where epithelial cells gain the phenotype of mesenchymal cells to invade the surrounding tissues. EMT is a physiological event during embryogenesis (type I) but also happens during fibrosis (type II) and cancer metastasis (type III). It is a multifaceted phenomenon governed by the activation of genes associated with cell migration, extracellular matrix degradation, DNA repair, and angiogenesis. The cancer cells employ EMT to acquire the ability to migrate, resist therapeutic agents and escape immunity. One of the key biomarkers of EMT is vimentin, a type III intermediate filament that is normally expressed in mesenchymal cells but is upregulated during cancer metastasis. This review highlights the pivotal role of vimentin in the key events during EMT and explains its role as a downstream as well as an upstream regulator in this highly complex process. This review also highlights the areas that require further research in exploring the role of vimentin in EMT. As a cytoskeletal protein, vimentin filaments support mechanical integrity of the migratory machinery, generation of directional force, focal adhesion modulation and extracellular attachment. As a viscoelastic scaffold, it gives stress-bearing ability and flexible support to the cell and its organelles. However, during EMT it modulates genes for EMT inducers such as Snail, Slug, Twist and ZEB1/2, as well as the key epigenetic factors. In addition, it suppresses cellular differentiation and upregulates their pluripotent potential by inducing genes associated with self-renewability, thus increasing the stemness of cancer stem cells, facilitating the tumour spread and making them more resistant to treatments. Several missense and frameshift mutations reported in vimentin in human cancers may also contribute towards the metastatic spread. Therefore, we propose that vimentin should be a therapeutic target using molecular technologies that will curb cancer growth and spread with reduced mortality and morbidity. Full article

(This article belongs to the Section Systematic Review or Meta-Analysis in Cancer Research)

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20 pages, 1514 KiB

Open AccessEditor’s ChoiceReview

Heterogeneity in Pancreatic Cancer Fibroblasts—TGFβ as a Master Regulator?

by Dale M. Watt and Jennifer P. Morton

Cancers 2021, 13(19), 4984; https://doi.org/10.3390/cancers13194984 - 4 Oct 2021

Cited by 9 | Viewed by 4115

Abstract

Pancreatic ductal adenocarcinoma is an aggressive disease for which there are very few available therapies. It is notable for its high degree of tumour complexity, with the tumour microenvironment often accounting for the majority of the tumour volume. Until recently, the biology of [...] Read more.

Pancreatic ductal adenocarcinoma is an aggressive disease for which there are very few available therapies. It is notable for its high degree of tumour complexity, with the tumour microenvironment often accounting for the majority of the tumour volume. Until recently, the biology of the stroma was poorly understood, particularly in terms of heterogeneity. Recent research, however, has shed light on the intricacy of signalling within the stroma and particularly the molecular and functional heterogeneity of the cancer associated fibroblasts. In this review, we summarise the recent improvements in our understanding of the different fibroblast populations within PDAC, with a focus on the role TGFβ plays to dictate their formation and function. These studies have highlighted some of the reasons for the failure of trials targeting the tumour stroma, however, there are still considerable gaps in our knowledge, and more work is needed to make effective fibroblast targeting a reality in the clinic. Full article

(This article belongs to the Special Issue Tumor Heterogeneity in Pancreatic Cancer)

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27 pages, 1198 KiB

Open AccessEditor’s ChoiceReview

Keeping Myeloma in Check: The Past, Present and Future of Immunotherapy in Multiple Myeloma

by James Ackley, Miguel Armenta Ochoa, Delta Ghoshal, Krishnendu Roy, Sagar Lonial and Lawrence H. Boise

Cancers 2021, 13(19), 4787; https://doi.org/10.3390/cancers13194787 - 24 Sep 2021

Cited by 14 | Viewed by 3928

Abstract

Multiple myeloma is an incurable disease of malignant plasma cells and an ideal target for modern immune therapy. The unique plasma cell biology maintained in multiple myeloma, coupled with its hematological nature and unique bone marrow microenvironment, provide an opportunity to design specifically [...] Read more.

Multiple myeloma is an incurable disease of malignant plasma cells and an ideal target for modern immune therapy. The unique plasma cell biology maintained in multiple myeloma, coupled with its hematological nature and unique bone marrow microenvironment, provide an opportunity to design specifically targeted immunotherapies that selectively kill transformed cells with limited on-target off-tumor effects. Broadly defined, immune therapy is the utilization of the immune system and immune agents to treat a disease. In the context of multiple myeloma, immune therapy can be subdivided into four main categories: immune modulatory imide drugs, targeted antibodies, adoptive cell transfer therapies, and vaccines. In recent years, advances in all four of these categories have led to improved therapies with enhanced antitumor activity and specificity. In IMiDs, modified chemical structures have been developed that improve drug potency while reducing dose limiting side effects. Targeted antibody therapies have resulted from the development of new selectively expressed targets as well as the development of antibody drug conjugates and bispecific antibodies. Adoptive cell therapies, particularly CAR-T therapies, have been enhanced through improvements in the manufacturing process, as well as through the development of CAR constructs that enhance CAR-T activation and provide protection from a suppressive immune microenvironment. This review will first cover in-class breakthrough therapies for each of these categories, as well as therapies currently utilized in the clinic. Additionally, this review will explore up and coming therapeutics in the preclinical and clinical trial stage. Full article

(This article belongs to the Special Issue Multiple Myeloma: Targeted Therapy and Immunotherapy)

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33 pages, 1692 KiB

Open AccessEditor’s ChoiceReview

Current Landscape of Non-Small Cell Lung Cancer: Epidemiology, Histological Classification, Targeted Therapies, and Immunotherapy

by Olga Rodak, Manuel David Peris-Díaz, Mateusz Olbromski, Marzenna Podhorska-Okołów and Piotr Dzięgiel

Cancers 2021, 13(18), 4705; https://doi.org/10.3390/cancers13184705 - 20 Sep 2021

Cited by 95 | Viewed by 12690

Abstract

Non-small cell lung cancer (NSCLC) is a subtype of the most frequently diagnosed cancer in the world. Its epidemiology depends not only on tobacco exposition but also air quality. While the global trends in NSCLC incidence have started to decline, we can observe [...] Read more.

Non-small cell lung cancer (NSCLC) is a subtype of the most frequently diagnosed cancer in the world. Its epidemiology depends not only on tobacco exposition but also air quality. While the global trends in NSCLC incidence have started to decline, we can observe region-dependent differences related to the education and the economic level of the patients. Due to an increasing understanding of NSCLC biology, new diagnostic and therapeutic strategies have been developed, such as the reorganization of histopathological classification or tumor genotyping. Precision medicine is focused on the recognition of a genetic mutation in lung cancer cells called “driver mutation” to provide a variety of specific inhibitors of improperly functioning proteins. A rapidly growing group of approved drugs for targeted therapy in NSCLC currently allows the following mutated proteins to be treated: EGFR family (ERBB-1, ERBB-2), ALK, ROS1, MET, RET, NTRK, and RAF. Nevertheless, one of the most frequent NSCLC molecular sub-types remains without successful treatment: the K-Ras protein. In this review, we discuss the current NSCLC landscape treatment focusing on targeted therapy and immunotherapy, including first- and second-line monotherapies, immune checkpoint inhibitors with chemotherapy treatment, and approved predictive biomarkers. Full article

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

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49 pages, 2362 KiB

Open AccessEditor’s ChoiceReview

3D Cancer Models: Depicting Cellular Crosstalk within the Tumour Microenvironment

by Teresa Franchi-Mendes, Rodrigo Eduardo, Giacomo Domenici and Catarina Brito

Cancers 2021, 13(18), 4610; https://doi.org/10.3390/cancers13184610 - 14 Sep 2021

Cited by 27 | Viewed by 5940

Abstract

The tumour microenvironment plays a critical role in tumour progression and drug resistance processes. Non-malignant cell players, such as fibroblasts, endothelial cells, immune cells and others, interact with each other and with the tumour cells, shaping the disease. Though the role of each [...] Read more.

The tumour microenvironment plays a critical role in tumour progression and drug resistance processes. Non-malignant cell players, such as fibroblasts, endothelial cells, immune cells and others, interact with each other and with the tumour cells, shaping the disease. Though the role of each cell type and cell communication mechanisms have been progressively studied, the complexity of this cellular network and its role in disease mechanism and therapeutic response are still being unveiled. Animal models have been mainly used, as they can represent systemic interactions and conditions, though they face recognized limitations in translational potential due to interspecies differences. In vitro 3D cancer models can surpass these limitations, by incorporating human cells, including patient-derived ones, and allowing a range of experimental designs with precise control of each tumour microenvironment element. We summarize the role of each tumour microenvironment component and review studies proposing 3D co-culture strategies of tumour cells and non-malignant cell components. Moreover, we discuss the potential of these modelling approaches to uncover potential therapeutic targets in the tumour microenvironment and assess therapeutic efficacy, current bottlenecks and perspectives. Full article

(This article belongs to the Special Issue Organotypic 3D In Vitro Tumor Models: Bioengineering and Applications)

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31 pages, 3058 KiB

Open AccessEditor’s ChoiceReview

Understanding MNPs Behaviour in Response to AMF in Biological Milieus and the Effects at the Cellular Level: Implications for a Rational Design That Drives Magnetic Hyperthermia Therapy toward Clinical Implementation

by David Egea-Benavente, Jesús G. Ovejero, María del Puerto Morales and Domingo F. Barber

Cancers 2021, 13(18), 4583; https://doi.org/10.3390/cancers13184583 - 12 Sep 2021

Cited by 33 | Viewed by 4977

Abstract

Hyperthermia has emerged as a promising alternative to conventional cancer therapies and in fact, traditional hyperthermia is now commonly used in combination with chemotherapy or surgery during cancer treatment. Nevertheless, non-specific application of hyperthermia generates various undesirable side-effects, such that nano-magnetic hyperthermia has [...] Read more.

Hyperthermia has emerged as a promising alternative to conventional cancer therapies and in fact, traditional hyperthermia is now commonly used in combination with chemotherapy or surgery during cancer treatment. Nevertheless, non-specific application of hyperthermia generates various undesirable side-effects, such that nano-magnetic hyperthermia has arisen a possible solution to this problem. This technique to induce hyperthermia is based on the intrinsic capacity of magnetic nanoparticles to accumulate in a given target area and to respond to alternating magnetic fields (AMFs) by releasing heat, based on different principles of physics. Unfortunately, the clinical implementation of nano-magnetic hyperthermia has not been fluid and few clinical trials have been carried out. In this review, we want to demonstrate the need for more systematic and basic research in this area, as many of the sub-cellular and molecular mechanisms associated with this approach remain unclear. As such, we shall consider here the biological effects that occur and why this theoretically well-designed nano-system fails in physiological conditions. Moreover, we will offer some guidelines that may help establish successful strategies through the rational design of magnetic nanoparticles for magnetic hyperthermia. Full article

(This article belongs to the Special Issue Prospects from Diagnosis to Treatment in Cancer Using Magnetic Methods)

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24 pages, 2060 KiB

Open AccessEditor’s ChoiceReview

Immune Checkpoints in Cancers: From Signaling to the Clinic

by Céline Pisibon, Amira Ouertani, Corine Bertolotto, Robert Ballotti and Yann Cheli

Cancers 2021, 13(18), 4573; https://doi.org/10.3390/cancers13184573 - 12 Sep 2021

Cited by 33 | Viewed by 3742

Abstract

The immune system is known to help fight cancers. Ten years ago, the first immune checkpoint inhibitor targeting CTLA4 was approved by the FDA to treat patients with metastatic melanoma. Since then, immune checkpoint therapies have revolutionized the field of oncology and the [...] Read more.

The immune system is known to help fight cancers. Ten years ago, the first immune checkpoint inhibitor targeting CTLA4 was approved by the FDA to treat patients with metastatic melanoma. Since then, immune checkpoint therapies have revolutionized the field of oncology and the treatment of cancer patients. Numerous immune checkpoint inhibitors have been developed and tested, alone or in combination with other treatments, in melanoma and other cancers, with overall clear benefits to patient outcomes. However, many patients fail to respond or develop resistance to these treatments. It is therefore essential to decipher the mechanisms of action of immune checkpoints and to understand how immune cells are affected by signaling to be able to understand and overcome resistance. In this review, we discuss the signaling and effects of each immune checkpoint on different immune cells and their biological and clinical relevance. Restoring the functionality of T cells and their coordination with other immune cells is necessary to overcome resistance and help design new clinical immunotherapy strategies. In this respect, NK cells have recently been implicated in the resistance to anti-PD1 evoked by a protein secreted by melanoma, ITGBL1. The complexity of this network will have to be considered to improve the efficiency of future immunotherapies and may lead to the discovery of new immune checkpoints. Full article

(This article belongs to the Special Issue Latest Development in Melanoma Research)

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14 pages, 982 KiB

Open AccessEditor’s ChoiceArticle

Poor Neutralizing Antibody Responses in 132 Patients with CLL, NHL and HL after Vaccination against SARS-CoV-2: A Prospective Study

by Evangelos Terpos, Maria Gavriatopoulou, Despina Fotiou, Chara Giatra, Ioannis Asimakopoulos, Maria Dimou, Aimilia D. Sklirou, Ioannis Ntanasis-Stathopoulos, Ismini Darmani, Alexandros Briasoulis, Efstathios Kastritis, Maria Angelopoulou, Ioannis Baltadakis, Panayiotis Panayiotidis, Ioannis P. Trougakos, Theodoros P. Vassilakopoulos, Maria Pagoni and Meletios A. Dimopoulos

Cancers 2021, 13(17), 4480; https://doi.org/10.3390/cancers13174480 - 6 Sep 2021

Cited by 43 | Viewed by 3753

Abstract

Emerging data suggest suboptimal antibody responses to COVID-19 vaccination in patients with hematological malignancies. We evaluated the humoral response following the BNT162b2 vaccine in patients with chronic lymphocytic leukemia (CLL), non-Hodgkin’s lymphoma (NHL), and Hodgkin’s lymphoma (HL). An FDA-approved, ELISA-based methodology was implemented [...] Read more.

Emerging data suggest suboptimal antibody responses to COVID-19 vaccination in patients with hematological malignancies. We evaluated the humoral response following the BNT162b2 vaccine in patients with chronic lymphocytic leukemia (CLL), non-Hodgkin’s lymphoma (NHL), and Hodgkin’s lymphoma (HL). An FDA-approved, ELISA-based methodology was implemented to evaluate the titers of neutralizing antibodies (NAbs) against SARS-CoV-2 on day 1 of the first vaccine, and afterwards on day 22 and 50. One hundred and thirty-two patients with CLL/lymphomas and 214 healthy matched controls vaccinated during the same period, at the same center were enrolled in the study (NCT04743388). Vaccination with two doses of the BNT162b2 vaccine led to lower production of NAbs against SARS-CoV-2 in patients with CLL/lymphomas compared with controls both on day 22 and on day 50 (p < 0.001 for all comparisons). Disease-related immune dysregulation and therapy-related immunosuppression are involved in the low humoral response. Importantly, active treatment with Rituximab, Bruton’s tyrosine kinase inhibitors, or chemotherapy was an independent prognostic factor for suboptimal antibody response. Patients with HL showed superior humoral responses to the NHL/CLL subgroups. In conclusion, patients with CLL/lymphomas have low humoral response following COVID-19 vaccination, underlining the need for timely vaccination ideally during a treatment-free period and for continuous vigilance on infection control measures. Full article

(This article belongs to the Special Issue Preclinical and Clinical Studies of Novel Therapies in Leukemia and Lymphoma)

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21 pages, 945 KiB

Open AccessEditor’s ChoiceReview

In Vitro Magnetic Techniques for Investigating Cancer Progression

by Sarah Libring, Ángel Enríquez, Hyowon Lee and Luis Solorio

Cancers 2021, 13(17), 4440; https://doi.org/10.3390/cancers13174440 - 3 Sep 2021

Cited by 5 | Viewed by 2996

Abstract

Worldwide, there are currently around 18.1 million new cancer cases and 9.6 million cancer deaths yearly. Although cancer diagnosis and treatment has improved greatly in the past several decades, a complete understanding of the complex interactions between cancer cells and the tumor microenvironment [...] Read more.

Worldwide, there are currently around 18.1 million new cancer cases and 9.6 million cancer deaths yearly. Although cancer diagnosis and treatment has improved greatly in the past several decades, a complete understanding of the complex interactions between cancer cells and the tumor microenvironment during primary tumor growth and metastatic expansion is still lacking. Several aspects of the metastatic cascade require in vitro investigation. This is because in vitro work allows for a reduced number of variables and an ability to gather real-time data of cell responses to precise stimuli, decoupling the complex environment surrounding in vivo experimentation. Breakthroughs in our understanding of cancer biology and mechanics through in vitro assays can lead to better-designed ex vivo precision medicine platforms and clinical therapeutics. Multiple techniques have been developed to imitate cancer cells in their primary or metastatic environments, such as spheroids in suspension, microfluidic systems, 3D bioprinting, and hydrogel embedding. Recently, magnetic-based in vitro platforms have been developed to improve the reproducibility of the cell geometries created, precisely move magnetized cell aggregates or fabricated scaffolding, and incorporate static or dynamic loading into the cell or its culture environment. Here, we will review the latest magnetic techniques utilized in these in vitro environments to improve our understanding of cancer cell interactions throughout the various stages of the metastatic cascade. Full article

(This article belongs to the Special Issue Prospects from Diagnosis to Treatment in Cancer Using Magnetic Methods)

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19 pages, 1329 KiB

Open AccessEditor’s ChoiceReview

Normalizing Tumor Vasculature to Reduce Hypoxia, Enhance Perfusion, and Optimize Therapy Uptake

by Kathy Matuszewska, Madison Pereira, Duncan Petrik, Jack Lawler and Jim Petrik

Cancers 2021, 13(17), 4444; https://doi.org/10.3390/cancers13174444 - 3 Sep 2021

Cited by 44 | Viewed by 6031

Abstract

A basic requirement of tumorigenesis is the development of a vascular network to support the metabolic requirements of tumor growth and metastasis. Tumor vascular formation is regulated by a balance between promoters and inhibitors of angiogenesis. Typically, the pro-angiogenic environment created by the [...] Read more.

A basic requirement of tumorigenesis is the development of a vascular network to support the metabolic requirements of tumor growth and metastasis. Tumor vascular formation is regulated by a balance between promoters and inhibitors of angiogenesis. Typically, the pro-angiogenic environment created by the tumor is extremely aggressive, resulting in the rapid vessel formation with abnormal, dysfunctional morphology. The altered morphology and function of tumor blood and lymphatic vessels has numerous implications including poor perfusion, tissue hypoxia, and reduced therapy uptake. Targeting tumor angiogenesis as a therapeutic approach has been pursued in a host of different cancers. Although some preclinical success was seen, there has been a general lack of clinical success with traditional anti-angiogenic therapeutics as single agents. Typically, following anti-angiogenic therapy, there is remodeling of the tumor microenvironment and widespread tumor hypoxia, which is associated with development of therapy resistance. A more comprehensive understanding of the biology of tumor angiogenesis and insights into new clinical approaches, including combinations with immunotherapy, are needed to advance vascular targeting as a therapeutic area. Full article

(This article belongs to the Special Issue Tumor Vasculature – Biological Insights and Therapeutic Opportunities)

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29 pages, 3048 KiB

Open AccessEditor’s ChoiceReview

Photodynamic Therapy: A Compendium of Latest Reviews

by José Francisco Algorri, Mario Ochoa, Pablo Roldán-Varona, Luís Rodríguez-Cobo and José Miguel López-Higuera

Cancers 2021, 13(17), 4447; https://doi.org/10.3390/cancers13174447 - 3 Sep 2021

Cited by 145 | Viewed by 8436

Abstract

Photodynamic therapy (PDT) is a promising therapy against cancer. Even though it has been investigated for more than 100 years, scientific publications have grown exponentially in the last two decades. For this reason, we present a brief compendium of reviews of the last [...] Read more.

Photodynamic therapy (PDT) is a promising therapy against cancer. Even though it has been investigated for more than 100 years, scientific publications have grown exponentially in the last two decades. For this reason, we present a brief compendium of reviews of the last two decades classified under different topics, namely, overviews, reviews about specific cancers, and meta-analyses of photosensitisers, PDT mechanisms, dosimetry, and light sources. The key issues and main conclusions are summarized, including ways and means to improve therapy and outcomes. Due to the broad scope of this work and it being the first time that a compendium of the latest reviews has been performed for PDT, it may be of interest to a wide audience. Full article

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15 pages, 1056 KiB

Open AccessEditor’s ChoiceReview

Urological Melanoma: A Comprehensive Review of a Rare Subclass of Mucosal Melanoma with Emphasis on Differential Diagnosis and Therapeutic Approaches

by Gerardo Cazzato, Anna Colagrande, Antonietta Cimmino, Concetta Caporusso, Pragnell Mary Victoria Candance, Senia Maria Rosaria Trabucco, Marcello Zingarelli, Alfonso Lorusso, Maricla Marrone, Alessandra Stellacci, Francesca Arezzo, Andrea Marzullo, Gabriella Serio, Angela Filoni, Domenico Bonamonte, Paolo Romita, Caterina Foti, Teresa Lettini, Vera Loizzi, Gennaro Cormio, Leonardo Resta, Roberta Rossi and Giuseppe Ingravallo Show full author list Hide full author list

Cancers 2021, 13(17), 4424; https://doi.org/10.3390/cancers13174424 - 2 Sep 2021

Cited by 10 | Viewed by 3248

Abstract

Melanoma is reported as the 19th most common cancer worldwide, with estimated age-standardized incidence rates of 2.8–3.1 per 100,000. Although the origin is most frequently cutaneous, mucosal melanoma has been described several times in literature, and despite its rarity (only 1% of all [...] Read more.

Melanoma is reported as the 19th most common cancer worldwide, with estimated age-standardized incidence rates of 2.8–3.1 per 100,000. Although the origin is most frequently cutaneous, mucosal melanoma has been described several times in literature, and despite its rarity (only 1% of all melanomas), increasing attention is being paid to this disease form. Within this subgroup, melanomas of the uropoetic apparatus are a rarity among rarities. Indeed, less than 50 cases of primary melanoma originating from the urinary bladder have been described, and even less originating from the kidney, renal pelvis and urethra. In this work, we present a detailed review of the literature related to this subclass of mucosal melanoma, delve into the biological landscape of this neoplasm and discuss current approaches, future perspectives and potential therapeutic approaches. Full article

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

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26 pages, 1144 KiB

Open AccessEditor’s ChoiceReview

Apoptosis Deregulation and the Development of Cancer Multi-Drug Resistance

by Christiana M. Neophytou, Ioannis P. Trougakos, Nuray Erin and Panagiotis Papageorgis

Cancers 2021, 13(17), 4363; https://doi.org/10.3390/cancers13174363 - 28 Aug 2021

Cited by 135 | Viewed by 12282

Abstract

The ability of tumor cells to evade apoptosis is established as one of the hallmarks of cancer. The deregulation of apoptotic pathways conveys a survival advantage enabling cancer cells to develop multi-drug resistance (MDR), a complex tumor phenotype referring to concurrent resistance toward [...] Read more.

The ability of tumor cells to evade apoptosis is established as one of the hallmarks of cancer. The deregulation of apoptotic pathways conveys a survival advantage enabling cancer cells to develop multi-drug resistance (MDR), a complex tumor phenotype referring to concurrent resistance toward agents with different function and/or structure. Proteins implicated in the intrinsic pathway of apoptosis, including the Bcl-2 superfamily and Inhibitors of Apoptosis (IAP) family members, as well as their regulator, tumor suppressor p53, have been implicated in the development of MDR in many cancer types. The PI₃K/AKT pathway is pivotal in promoting survival and proliferation and is often overactive in MDR tumors. In addition, the tumor microenvironment, particularly factors secreted by cancer-associated fibroblasts, can inhibit apoptosis in cancer cells and reduce the effectiveness of different anti-cancer drugs. In this review, we describe the main alterations that occur in apoptosis-and related pathways to promote MDR. We also summarize the main therapeutic approaches against resistant tumors, including agents targeting Bcl-2 family members, small molecule inhibitors against IAPs or AKT and agents of natural origin that may be used as monotherapy or in combination with conventional therapeutics. Finally, we highlight the potential of therapeutic exploitation of epigenetic modifications to reverse the MDR phenotype. Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Tools Against Multidrug Resistant Tumors (STRATAGEM Special Issue, EU-COST CA17104))

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30 pages, 507 KiB

Open AccessEditor’s ChoiceReview

Breast Cancer—Epidemiology, Risk Factors, Classification, Prognostic Markers, and Current Treatment Strategies—An Updated Review

by Sergiusz Łukasiewicz, Marcin Czeczelewski, Alicja Forma, Jacek Baj, Robert Sitarz and Andrzej Stanisławek

Cancers 2021, 13(17), 4287; https://doi.org/10.3390/cancers13174287 - 25 Aug 2021

Cited by 512 | Viewed by 61499

Abstract

Breast cancer (BC) is the most frequently diagnosed cancer in women worldwide with more than 2 million new cases in 2020. Its incidence and death rates have increased over the last three decades due to the change in risk factor profiles, better cancer [...] Read more.

Breast cancer (BC) is the most frequently diagnosed cancer in women worldwide with more than 2 million new cases in 2020. Its incidence and death rates have increased over the last three decades due to the change in risk factor profiles, better cancer registration, and cancer detection. The number of risk factors of BC is significant and includes both the modifiable factors and non-modifiable factors. Currently, about 80% of patients with BC are individuals aged >50. Survival depends on both stage and molecular subtype. Invasive BCs comprise wide spectrum tumors that show a variation concerning their clinical presentation, behavior, and morphology. Based on mRNA gene expression levels, BC can be divided into molecular subtypes (Luminal A, Luminal B, HER2-enriched, and basal-like). The molecular subtypes provide insights into new treatment strategies and patient stratifications that impact the management of BC patients. The eighth edition of TNM classification outlines a new staging system for BC that, in addition to anatomical features, acknowledges biological factors. Treatment of breast cancer is complex and involves a combination of different modalities including surgery, radiotherapy, chemotherapy, hormonal therapy, or biological therapies delivered in diverse sequences. Full article

(This article belongs to the Special Issue Advanced Breast Cancer: From Biology to Cure)

18 pages, 325 KiB

Open AccessEditor’s ChoiceReview

Glucose Transporters as a Target for Anticancer Therapy

by Monika Pliszka and Leszek Szablewski

Cancers 2021, 13(16), 4184; https://doi.org/10.3390/cancers13164184 - 20 Aug 2021

Cited by 87 | Viewed by 5955

Abstract

Tumor growth causes cancer cells to become hypoxic. A hypoxic condition is a hallmark of cancer. Metabolism of cancer cells differs from metabolism of normal cells. Cancer cells prefer the process of glycolysis as a source of ATP. Process of glycolysis generates only [...] Read more.

Tumor growth causes cancer cells to become hypoxic. A hypoxic condition is a hallmark of cancer. Metabolism of cancer cells differs from metabolism of normal cells. Cancer cells prefer the process of glycolysis as a source of ATP. Process of glycolysis generates only two molecules of ATP per one molecule of glucose, whereas the complete oxidative breakdown of one molecule of glucose yields 36 molecules of ATP. Therefore, cancer cells need more molecules of glucose in comparison with normal cells. Increased uptake of glucose by these cells is due to overexpression of glucose transporters, especially GLUT1 and GLUT3, that are hypoxia responsive, as well as other glucose transport proteins. Increased expression of these carrier proteins may be used in anticancer therapy. This phenomenon is used in diagnostic techniques such as FDG-PET. It is also suggested, and there are observations, that therapeutic inhibition of glucose transporters may be a method in treatment of cancer patients. On the other hand, there are described cases, in which upregulation of glucose transporters, as, for example, NIS, which is used in radioiodine therapy, can help patients with cancer. The aim of this review is the presentation of possibilities, and how glucose transporters can be used in anticancer therapy. Full article

(This article belongs to the Special Issue Biological Basis of Anti-tumor Therapies)

15 pages, 730 KiB

Open AccessEditor’s ChoiceReview

The Pathogenic Role of PI3K/AKT Pathway in Cancer Onset and Drug Resistance: An Updated Review

by Federica Rascio, Federica Spadaccino, Maria Teresa Rocchetti, Giuseppe Castellano, Giovanni Stallone, Giuseppe Stefano Netti and Elena Ranieri

Cancers 2021, 13(16), 3949; https://doi.org/10.3390/cancers13163949 - 5 Aug 2021

Cited by 139 | Viewed by 14456

Abstract

The PI3K/AKT pathway is one of the most frequently over-activated intracellular pathways in several human cancers. This pathway, acting on different downstream target proteins, contributes to the carcinogenesis, proliferation, invasion, and metastasis of tumour cells. A multi-level impairment, involving mutation and genetic alteration, [...] Read more.

The PI3K/AKT pathway is one of the most frequently over-activated intracellular pathways in several human cancers. This pathway, acting on different downstream target proteins, contributes to the carcinogenesis, proliferation, invasion, and metastasis of tumour cells. A multi-level impairment, involving mutation and genetic alteration, aberrant regulation of miRNAs sequences, and abnormal phosphorylation of cascade factors, has been found in multiple cancer types. The deregulation of this pathway counteracts common therapeutic strategies and contributes to multidrug resistance. In this review, we underline the involvement of this pathway in patho-physiological cell survival mechanisms, emphasizing its key role in the development of drug resistance. We also provide an overview of the potential inhibition strategies currently available. Full article

(This article belongs to the Special Issue Targeting PI3K Signaling in Cancer)

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16 pages, 2849 KiB

Open AccessEditor’s ChoiceArticle

Nobiletin and Xanthohumol Sensitize Colorectal Cancer Stem Cells to Standard Chemotherapy

by Alice Turdo, Antonino Glaviano, Giacomo Pepe, Federica Calapà, Stefania Raimondo, Micol Eleonora Fiori, Daniela Carbone, Manuela Giovanna Basilicata, Veronica Di Sarno, Carmine Ostacolo, Barbara Parrino, Stella Cascioferro, Camilla Pecoraro, Simone Di Franco, Diana Bellavia, Miriam Gaggianesi, Veronica Veschi, Melania Lo Iacono, Gloria Ganduscio, Vincenzo Davide Pantina, Laura Rosa Mangiapane, Maria Rita Bongiorno, Riccardo Alessandro, Matilde Todaro, Ruggero De Maria, Patrizia Diana, Pietro Campiglia and Giorgio Stassi Show full author list Hide full author list

Cancers 2021, 13(16), 3927; https://doi.org/10.3390/cancers13163927 - 4 Aug 2021

Cited by 24 | Viewed by 4783

Abstract

Colorectal cancer (CRC) mortality is mainly caused by patient refractoriness to common anti-cancer therapies and consequent metastasis formation. Besides, the notorious toxic side effects of chemotherapy are a concurrent obstacle to be tackled. Thus, new treatment approaches are needed to effectively improve patient [...] Read more.

Colorectal cancer (CRC) mortality is mainly caused by patient refractoriness to common anti-cancer therapies and consequent metastasis formation. Besides, the notorious toxic side effects of chemotherapy are a concurrent obstacle to be tackled. Thus, new treatment approaches are needed to effectively improve patient outcomes. Compelling evidence demonstrated that cancer stem cells (CSCs) are responsible for treatment failure and relapse. New natural treatment approaches showed capabilities to selectively target the CSC subpopulation by rendering them targetable by standard cytotoxic compounds. Herein we show the anti-cancer properties of the polymethoxyflavones and prenylflavonoids extracted from Citrus sinensis and Humulus lupulus, respectively. The natural biofunctional fractions, singularly and in combination, reduced the cell viability of CRC stem cells (CR-CSCs) and synergized with 5-fluorouracil and oxaliplatin (FOX) chemotherapy. These phenomena were accompanied by a reduced S and G2/M phase of the cell cycle and upregulation of cell death-related genes. Notably, both phytoextracts in combination with FOX thwarted stemness features in CR-CSCs as demonstrated by the impaired clonogenic potential and decreased Wnt pathway activation. Extracts lowered the expression of CD44v6 and affected the expansion of metastatic CR-CSCs in patients refractory to chemotherapy. Together, this study highlights the importance of polymethoxyflavones and prenylflavonoids as natural remedies to aid oncological therapies. Full article

(This article belongs to the Collection New Treatment for Colorectal Cancer)

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21 pages, 775 KiB

Open AccessEditor’s ChoiceReview

The Role of Chronic Inflammation in the Development of Breast Cancer

by David N. Danforth

Cancers 2021, 13(15), 3918; https://doi.org/10.3390/cancers13153918 - 3 Aug 2021

Cited by 60 | Viewed by 12749

Abstract

Chronic inflammation contributes to the malignant transformation of several malignancies and is an important component of breast cancer. The role of chronic inflammation in the initiation and development of breast cancer from normal breast tissue, however, is unclear and needs to be clarified. [...] Read more.

Chronic inflammation contributes to the malignant transformation of several malignancies and is an important component of breast cancer. The role of chronic inflammation in the initiation and development of breast cancer from normal breast tissue, however, is unclear and needs to be clarified. A review of the literature was conducted to define the chronic inflammatory processes in normal breast tissue at risk for breast cancer and in breast cancer, including the role of lymphocyte and macrophage infiltrates, chronic active adipocytes and fibroblasts, and processes that may promote chronic inflammation including the microbiome and factors related to genomic abnormalities and cellular injury. The findings indicate that in healthy normal breast tissue there is systemic evidence to suggest inflammatory changes are present and associated with breast cancer risk, and adipocytes and crown-like structures in normal breast tissue may be associated with chronic inflammatory changes. The microbiome, genomic abnormalities, and cellular changes are present in healthy normal breast tissue, with the potential to elicit inflammatory changes, while infiltrating lymphocytes are uncommon in these tissues. Chronic inflammatory changes occur prominently in breast cancer tissues, with important contributions from tumor-infiltrating lymphocytes and tumor-associated macrophages, cancer-associated adipocytes and crown-like structures, and cancer-associated fibroblasts, while the microbiome and DNA damage may serve to promote inflammatory events. Together, these findings suggest that chronic inflammation may play a role in influencing the initiation, development and conduct of breast cancer, although several chronic inflammatory processes in breast tissue may occur later in breast carcinogenesis. Full article

(This article belongs to the Section Cancer Causes, Screening and Diagnosis)

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20 pages, 6827 KiB

Open AccessEditor’s ChoiceArticle

Identification of Cancer Hub Gene Signatures Associated with Immune-Suppressive Tumor Microenvironment and Ovatodiolide as a Potential Cancer Immunotherapeutic Agent

by Jia-Hong Chen, Alexander T. H. Wu, Bashir Lawal, David T. W. Tzeng, Jih-Chin Lee, Ching-Liang Ho and Tsu-Yi Chao

Cancers 2021, 13(15), 3847; https://doi.org/10.3390/cancers13153847 - 30 Jul 2021

Cited by 24 | Viewed by 3979

Abstract

Despite the significant advancement in therapeutic strategies, breast, colorectal, gastric, lung, liver, and prostate cancers remain the most prevalent cancers in terms of incidence and mortality worldwide. The major causes ascribed to these burdens are lack of early diagnosis, high metastatic tendency, and [...] Read more.

Despite the significant advancement in therapeutic strategies, breast, colorectal, gastric, lung, liver, and prostate cancers remain the most prevalent cancers in terms of incidence and mortality worldwide. The major causes ascribed to these burdens are lack of early diagnosis, high metastatic tendency, and drug resistance. Therefore, exploring reliable early diagnostic and prognostic biomarkers universal to most cancer types is a clinical emergency. Consequently, in the present study, the differentially expressed genes (DEGs) from the publicly available microarray datasets of six cancer types (liver, lung colorectal, gastric, prostate, and breast cancers), termed hub cancers, were analyzed to identify the universal DEGs, termed hub genes. Gene set enrichment analysis (GSEA) and KEGG mapping of the hub genes suggested their crucial involvement in the tumorigenic properties, including distant metastases, treatment failure, and survival prognosis. Notably, our results suggested high frequencies of genetic and epigenetic alterations of the DEGs in association with tumor staging, immune evasion, poor prognosis, and therapy resistance. Translationally, we intended to identify a drug candidate with the potential for targeting the hub genes. Using a molecular docking platform, we estimated that ovatodiolide, a bioactive anti-cancer phytochemical, has high binding affinities to the binding pockets of the hub genes. Collectively, our results suggested that the hub genes were associated with establishing an immune-suppressive tumor microenvironment favorable for disease progression and promising biomarkers for the early diagnosis and prognosis in multiple cancer types and could serve as potential druggable targets for ovatodiolide. Full article

(This article belongs to the Special Issue Bioinformatics, Big Data and Cancer)

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15 pages, 543 KiB

Open AccessEditor’s ChoiceReview

Role of Oncogenic Pathways on the Cancer Immunosuppressive Microenvironment and Its Clinical Implications in Hepatocellular Carcinoma

by Naoshi Nishida

Cancers 2021, 13(15), 3666; https://doi.org/10.3390/cancers13153666 - 21 Jul 2021

Cited by 27 | Viewed by 4536

Abstract

The tumor immune microenvironment, including hepatocellular carcinoma (HCC), is complex, consisting of crosstalk among tumor components such as the cancer cells, stromal cells and immune cells. It is conceivable that phenotypic changes in cancer cells by genetic and epigenetic alterations affect the cancer–stroma [...] Read more.

The tumor immune microenvironment, including hepatocellular carcinoma (HCC), is complex, consisting of crosstalk among tumor components such as the cancer cells, stromal cells and immune cells. It is conceivable that phenotypic changes in cancer cells by genetic and epigenetic alterations affect the cancer–stroma interaction and anti-cancer immunity through the expression of immune checkpoint molecules, growth factors, cytokines, chemokines and metabolites that may act on the immune system in tumors. Therefore, predicting the outcome of ICI therapy requires a thorough understanding of the oncogenic signaling pathways in cancer and how they affect tumor immune evasion. In this review, we have detailed how oncogenic signaling pathways can play a role in altering the condition of the cellular components of the tumor immune microenvironment such as tumor-associated macrophages, regulatory T cells and myeloid-derived suppressor cells. The RAS/MAPK, PI3K/Akt, Wnt/β-catenin and JAK/STAT pathways have all been implicated in anti-tumor immunity. We also found that factors that reflect the immune microenvironment of the tumor, including the status of oncogenic pathways such as the volume of tumor-infiltrating T cells, expression of the immune checkpoint protein PD-1 and its ligand PD-L1, and activation of the Wnt/β-catenin signaling pathway, predict a response to ICI therapy in HCC cases. Full article

(This article belongs to the Special Issue Molecular Pathways in Cancers)

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14 pages, 7498 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Pyroptosis in Cancer: Friend or Foe?

by Xiuxia Lu, Tianhui Guo and Xing Zhang

Cancers 2021, 13(14), 3620; https://doi.org/10.3390/cancers13143620 - 20 Jul 2021

Cited by 48 | Viewed by 4759

Abstract

Pyroptosis is an inflammatory form of programmed cell death that is mediated by pore-forming proteins such as the gasdermin family (GSDMs), including GSDMA-E. Upon cleavage by activated caspases or granzyme proteases, the N-terminal of GSDMs oligomerizes in membranes to form pores, resulting in [...] Read more.

Pyroptosis is an inflammatory form of programmed cell death that is mediated by pore-forming proteins such as the gasdermin family (GSDMs), including GSDMA-E. Upon cleavage by activated caspases or granzyme proteases, the N-terminal of GSDMs oligomerizes in membranes to form pores, resulting in pyroptosis. Though all the gasdermin proteins have been studied in cancer, the role of pyroptosis in cancer remains mysterious, with conflicting findings. Numerous studies have shown that various stimuli, such as pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and chemotherapeutic drugs, could trigger pyroptosis when the cells express GSDMs. However, it is not clear whether pyroptosis in cancer induced by chemotherapeutic drugs or CAR T cell therapy is beneficial or harmful for anti-tumor immunity. This review discusses the discovery of pyroptosis as well as its role in inflammatory diseases and cancer, with an emphasis on tumor immunity. Full article

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42 pages, 4899 KiB

Open AccessEditor’s ChoiceReview

Light Technology for Efficient and Effective Photodynamic Therapy: A Critical Review

by José Francisco Algorri, Mario Ochoa, Pablo Roldán-Varona, Luís Rodríguez-Cobo and José Miguel López-Higuera

Cancers 2021, 13(14), 3484; https://doi.org/10.3390/cancers13143484 - 13 Jul 2021

Cited by 93 | Viewed by 11119

Abstract

Photodynamic therapy (PDT) is a cancer treatment with strong potential over well-established standard therapies in certain cases. Non-ionising radiation, localisation, possible repeated treatments, and stimulation of immunological response are some of the main beneficial features of PDT. Despite the great potential, its application [...] Read more.

Photodynamic therapy (PDT) is a cancer treatment with strong potential over well-established standard therapies in certain cases. Non-ionising radiation, localisation, possible repeated treatments, and stimulation of immunological response are some of the main beneficial features of PDT. Despite the great potential, its application remains challenging. Limited light penetration depth, non-ideal photosensitisers, complex dosimetry, and complicated implementations in the clinic are some limiting factors hindering the extended use of PDT. To surpass actual technological paradigms, radically new sources, light-based devices, advanced photosensitisers, measurement devices, and innovative application strategies are under extensive investigation. The main aim of this review is to highlight the advantages/pitfalls, technical challenges and opportunities of PDT, with a focus on technologies for light activation of photosensitisers, such as light sources, delivery devices, and systems. In this vein, a broad overview of the current status of superficial, interstitial, and deep PDT modalities—and a critical review of light sources and their effects on the PDT process—are presented. Insight into the technical advancements and remaining challenges of optical sources and light devices is provided from a physical and bioengineering perspective. Full article

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23 pages, 1553 KiB

Open AccessEditor’s ChoiceReview

Adipose Tissue-Derived Extracellular Vesicles and the Tumor Microenvironment: Revisiting the Hallmarks of Cancer

by João Alfredo Moraes, Carol Encarnação, Victor Aguiar Franco, Luiz Gabriel Xavier Botelho, Gabriella Pacheco Rodrigues, Isadora Ramos-Andrade, Christina Barja-Fidalgo and Mariana Renovato-Martins

Cancers 2021, 13(13), 3328; https://doi.org/10.3390/cancers13133328 - 2 Jul 2021

Cited by 25 | Viewed by 4640

Abstract

Extracellular vesicles (EVs) are crucial elements that sustain the communication between tumor cells and their microenvironment, and have emerged as a widespread mechanism of tumor formation and metastasis. In obesity, the adipose tissue becomes hypertrophic and hyperplastic, triggering increased production of pro-inflammatory adipokines, [...] Read more.

Extracellular vesicles (EVs) are crucial elements that sustain the communication between tumor cells and their microenvironment, and have emerged as a widespread mechanism of tumor formation and metastasis. In obesity, the adipose tissue becomes hypertrophic and hyperplastic, triggering increased production of pro-inflammatory adipokines, such as tumor necrosis factor α, interleukin 6, interleukin 1, and leptin. Furthermore, obese adipose tissue undergoes dysregulation in the cargo content of the released EVs, resulting in an increased content of pro-inflammatory proteins, fatty acids, and oncogenic microRNAs. These alterations drive obesity-associated inflammatory responses both locally and systemically. After being ignored for a long time, adipose tissues have recently received considerable attention as a major player in tumor microenvironment-linked obesity and cancer. The role of adipose tissue in the establishment and progression of cancer is reinforced by its high plasticity and inflammatory content. Such a relationship may be established by direct contact between adipocytes and cancer cells within the microenvironment or systemically, via EV-mediated cell-to-cell communication. Here, we highlight cues evidencing the influence of adipose tissue-derived EVs on the hallmarks of cancer, which are critical for tumor malignancy. Full article

(This article belongs to the Special Issue Extracellular Vesicles and the Tumour Microenvironment)

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17 pages, 1293 KiB

Open AccessEditor’s ChoiceReview

Mitochondrial Metabolism in Carcinogenesis and Cancer Therapy

by Hadia Moindjie, Sylvie Rodrigues-Ferreira and Clara Nahmias

Cancers 2021, 13(13), 3311; https://doi.org/10.3390/cancers13133311 - 1 Jul 2021

Cited by 32 | Viewed by 8729

Abstract

Carcinogenesis is a multi-step process that refers to transformation of a normal cell into a tumoral neoplastic cell. The mechanisms that promote tumor initiation, promotion and progression are varied, complex and remain to be understood. Studies have highlighted the involvement of oncogenic mutations, [...] Read more.

Carcinogenesis is a multi-step process that refers to transformation of a normal cell into a tumoral neoplastic cell. The mechanisms that promote tumor initiation, promotion and progression are varied, complex and remain to be understood. Studies have highlighted the involvement of oncogenic mutations, genomic instability and epigenetic alterations as well as metabolic reprogramming, in different processes of oncogenesis. However, the underlying mechanisms still have to be clarified. Mitochondria are central organelles at the crossroad of various energetic metabolisms. In addition to their pivotal roles in bioenergetic metabolism, they control redox homeostasis, biosynthesis of macromolecules and apoptotic signals, all of which are linked to carcinogenesis. In the present review, we discuss how mitochondria contribute to the initiation of carcinogenesis through gene mutations and production of oncometabolites, and how they promote tumor progression through the control of metabolic reprogramming and mitochondrial dynamics. Finally, we present mitochondrial metabolism as a promising target for the development of novel therapeutic strategies. Full article

(This article belongs to the Special Issue Carcinogenesis)

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21 pages, 1602 KiB

Open AccessEditor’s ChoiceReview

EGFR in Cancer: Signaling Mechanisms, Drugs, and Acquired Resistance

by Mary Luz Uribe, Ilaria Marrocco and Yosef Yarden

Cancers 2021, 13(11), 2748; https://doi.org/10.3390/cancers13112748 - 1 Jun 2021

Cited by 175 | Viewed by 24882

Abstract

The epidermal growth factor receptor (EGFR) has served as the founding member of the large family of growth factor receptors harboring intrinsic tyrosine kinase function. High abundance of EGFR and large internal deletions are frequently observed in brain tumors, whereas point mutations and [...] Read more.

The epidermal growth factor receptor (EGFR) has served as the founding member of the large family of growth factor receptors harboring intrinsic tyrosine kinase function. High abundance of EGFR and large internal deletions are frequently observed in brain tumors, whereas point mutations and small insertions within the kinase domain are common in lung cancer. For these reasons EGFR and its preferred heterodimer partner, HER2/ERBB2, became popular targets of anti-cancer therapies. Nevertheless, EGFR research keeps revealing unexpected observations, which are reviewed herein. Once activated by a ligand, EGFR initiates a time-dependent series of molecular switches comprising downregulation of a large cohort of microRNAs, up-regulation of newly synthesized mRNAs, and covalent protein modifications, collectively controlling phenotype-determining genes. In addition to microRNAs, long non-coding RNAs and circular RNAs play critical roles in EGFR signaling. Along with driver mutations, EGFR drives metastasis in many ways. Paracrine loops comprising tumor and stromal cells enable EGFR to fuel invasion across tissue barriers, survival of clusters of circulating tumor cells, as well as colonization of distant organs. We conclude by listing all clinically approved anti-cancer drugs targeting either EGFR or HER2. Because emergence of drug resistance is nearly inevitable, we discuss the major evasion mechanisms. Full article

(This article belongs to the Special Issue EGFR Signaling in Cancer)

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24 pages, 790 KiB

Open AccessEditor’s ChoiceReview

STING Agonists as Cancer Therapeutics

by Afsaneh Amouzegar, Manoj Chelvanambi, Jessica N. Filderman, Walter J. Storkus and Jason J. Luke

Cancers 2021, 13(11), 2695; https://doi.org/10.3390/cancers13112695 (registering DOI) - 30 May 2021

Cited by 193 | Viewed by 20914

Abstract

The interrogation of intrinsic and adaptive resistance to cancer immunotherapy has identified lack of antigen presentation and type I interferon signaling as biomarkers of non-T-cell-inflamed tumors and clinical progression. A myriad of pre-clinical studies have implicated the cGAS/stimulator of interferon genes (STING) pathway, [...] Read more.

The interrogation of intrinsic and adaptive resistance to cancer immunotherapy has identified lack of antigen presentation and type I interferon signaling as biomarkers of non-T-cell-inflamed tumors and clinical progression. A myriad of pre-clinical studies have implicated the cGAS/stimulator of interferon genes (STING) pathway, a cytosolic DNA-sensing pathway that drives activation of type I interferons and other inflammatory cytokines, in the host immune response against tumors. The STING pathway is also increasingly understood to have other anti-tumor functions such as modulation of the vasculature and augmentation of adaptive immunity via the support of tertiary lymphoid structure development. Many natural and synthetic STING agonists have entered clinical development with the first generation of intra-tumor delivered cyclic dinucleotides demonstrating safety but only modest systemic activity. The development of more potent and selective STING agonists as well as novel delivery systems that would allow for sustained inflammation in the tumor microenvironment could potentially augment response rates to current immunotherapy approaches and overcome acquired resistance. In this review, we will focus on the latest developments in STING-targeted therapies and provide an update on the clinical development and application of STING agonists administered alone, or in combination with immune checkpoint blockade or other approaches. Full article

(This article belongs to the Special Issue Targeting Innate Immunity to Treat Cancer)

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28 pages, 14222 KiB

Open AccessEditor’s ChoiceReview

MicroRNA Therapeutics in Cancer: Current Advances and Challenges

by Soha Reda El Sayed, Justine Cristante, Laurent Guyon, Josiane Denis, Olivier Chabre and Nadia Cherradi

Cancers 2021, 13(11), 2680; https://doi.org/10.3390/cancers13112680 (registering DOI) - 29 May 2021

Cited by 86 | Viewed by 12205

Abstract

The discovery of microRNAs (miRNAs) in 1993 has challenged the dogma of gene expression regulation. MiRNAs affect most of cellular processes from metabolism, through cell proliferation and differentiation, to cell death. In cancer, deregulated miRNA expression leads to tumor development and progression by [...] Read more.

The discovery of microRNAs (miRNAs) in 1993 has challenged the dogma of gene expression regulation. MiRNAs affect most of cellular processes from metabolism, through cell proliferation and differentiation, to cell death. In cancer, deregulated miRNA expression leads to tumor development and progression by promoting acquisition of cancer hallmark traits. The multi-target action of miRNAs, which enable regulation of entire signaling networks, makes them attractive tools for the development of anti-cancer therapies. Hence, supplementing downregulated miRNA by synthetic oligonucleotides or silencing overexpressed miRNAs through artificial antagonists became a common strategy in cancer research. However, the ultimate success of miRNA therapeutics will depend on solving pharmacokinetic and targeted delivery issues. The development of a number of nanocarrier-based platforms holds significant promises to enhance the cell specific controlled delivery and safety profile of miRNA-based therapies. In this review, we provide among the most comprehensive assessments to date of promising nanomedicine platforms that have been tested preclinically, pertaining to the treatment of selected solid tumors including lung, liver, breast, and glioblastoma tumors as well as endocrine malignancies. The future challenges and potential applications in clinical oncology are discussed. Full article

(This article belongs to the Special Issue MicroRNA Therapeutics: Towards a New Era for the Management of Cancer)

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Graphical abstract

27 pages, 4214 KiB

Open AccessEditor’s ChoiceReview

Metronomic Chemotherapy

by Marina Elena Cazzaniga, Nicoletta Cordani, Serena Capici, Viola Cogliati, Francesca Riva and Maria Grazia Cerrito

Cancers 2021, 13(9), 2236; https://doi.org/10.3390/cancers13092236 - 6 May 2021

Cited by 58 | Viewed by 11300

Abstract

Metronomic chemotherapy treatment (mCHT) refers to the chronic administration of low doses chemotherapy that can sustain prolonged, and active plasma levels of drugs, producing favorable tolerability and it is a new promising therapeutic approach in solid and in hematologic tumors. mCHT has not [...] Read more.

Metronomic chemotherapy treatment (mCHT) refers to the chronic administration of low doses chemotherapy that can sustain prolonged, and active plasma levels of drugs, producing favorable tolerability and it is a new promising therapeutic approach in solid and in hematologic tumors. mCHT has not only a direct effect on tumor cells, but also an action on cell microenvironment, by inhibiting tumor angiogenesis, or promoting immune response and for these reasons can be considered a multi-target therapy itself. Here we review the state of the art of mCHT use in some classical tumour types, such as breast and no small cell lung cancer (NSCLC), see what is new regarding most recent data in different cancer types, such as glioblastoma (GBL) and acute myeloid leukemia (AML), and new drugs with potential metronomic administration. Finally, a look at the strategic use of mCHT in the context of health emergencies, or in low –and middle-income countries (LMICs), where access to adequate healthcare is often not easy, is mandatory, as we always need to bear in in mind that equity in care must be a compulsory part of our medical work and research. Full article

(This article belongs to the Special Issue Clinical Trials in Breast Cancer)

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18 pages, 767 KiB

Open AccessEditor’s ChoiceReview

CD26/DPP-4: Type 2 Diabetes Drug Target with Potential Influence on Cancer Biology

by Emi Kawakita, Daisuke Koya and Keizo Kanasaki

Cancers 2021, 13(9), 2191; https://doi.org/10.3390/cancers13092191 - 2 May 2021

Cited by 23 | Viewed by 6231

Abstract

DPP-4/CD26, a membrane-bound glycoprotein, is ubiquitously expressed and has diverse biological functions. Because of its enzymatic action, such as the degradation of incretin hormones, DPP-4/CD26 is recognized as the significant therapeutic target for type 2 diabetes (T2DM); DPP-4 inhibitors have been used as [...] Read more.

DPP-4/CD26, a membrane-bound glycoprotein, is ubiquitously expressed and has diverse biological functions. Because of its enzymatic action, such as the degradation of incretin hormones, DPP-4/CD26 is recognized as the significant therapeutic target for type 2 diabetes (T2DM); DPP-4 inhibitors have been used as an anti-diabetic agent for a decade. The safety profile of DPP-4 inhibitors for a cardiovascular event in T2DM patients has been widely analyzed; however, a clear association between DPP-4 inhibitors and tumor biology is not yet established. Previous preclinical studies reported that DPP-4 suppression would impact tumor progression processes. With regard to this finding, we have shown that the DPP-4 inhibitor induces breast cancer metastasis and chemoresistance via an increase in its substrate C-X-C motif chemokine 12, and the consequent induction of epithelial-mesenchymal transition in the tumor. DPP-4/CD26 plays diverse pivotal roles beyond blood glucose control; thus, DPP-4 inhibitors can potentially impact cancer-bearing T2DM patients either favorably or unfavorably. In this review, we primarily focus on the possible undesirable effect of DPP-4 inhibition on tumor biology. Clinicians should note that the safety of DPP-4 inhibitors for diabetic patients with an existing cancer is an unresolved issue, and further mechanistic analysis is essential in this field. Full article

(This article belongs to the Special Issue CD26 and Cancer)

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19 pages, 1976 KiB

Open AccessEditor’s ChoiceReview

Next-Generation Sequencing with Liquid Biopsies from Treatment-Naïve Non-Small Cell Lung Carcinoma Patients

by Paul Hofman

Cancers 2021, 13(9), 2049; https://doi.org/10.3390/cancers13092049 - 23 Apr 2021

Cited by 21 | Viewed by 4098

Abstract

Recently, the liquid biopsy (LB), a non-invasive and easy to repeat approach, has started to compete with the tissue biopsy (TB) for detection of targets for administration of therapeutic strategies for patients with advanced stages of lung cancer at tumor progression. A LB [...] Read more.

Recently, the liquid biopsy (LB), a non-invasive and easy to repeat approach, has started to compete with the tissue biopsy (TB) for detection of targets for administration of therapeutic strategies for patients with advanced stages of lung cancer at tumor progression. A LB at diagnosis of late stage non-small cell lung carcinoma (NSCLC) is also being performed. It may be asked if a LB can be complementary (according to the clinical presentation or systematics) or even an alternative to a TB for treatment-naïve advanced NSCLC patients. Nucleic acid analysis with a TB by next-generation sequencing (NGS) is gradually replacing targeted sequencing methods for assessment of genomic alterations in lung cancer patients with tumor progression, but also at baseline. However, LB is still not often used in daily practice for NGS. This review addresses different aspects relating to the use of LB for NGS at diagnosis in advanced NSCLC, including its advantages and limitations. Full article

(This article belongs to the Special Issue Diagnostic and Predictive Biomarkers in Lung Cancer)

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22 pages, 1257 KiB

Open AccessEditor’s ChoiceReview

The Role of Tumor Microenvironment in Cancer Metastasis: Molecular Mechanisms and Therapeutic Opportunities

by Christiana M. Neophytou, Myrofora Panagi, Triantafyllos Stylianopoulos and Panagiotis Papageorgis

Cancers 2021, 13(9), 2053; https://doi.org/10.3390/cancers13092053 - 23 Apr 2021

Cited by 148 | Viewed by 11462

Abstract

The tumor microenvironment (TME) regulates essential tumor survival and promotion functions. Interactions between the cellular and structural components of the TME allow cancer cells to become invasive and disseminate from the primary site to distant locations, through a complex and multistep metastatic cascade. [...] Read more.

The tumor microenvironment (TME) regulates essential tumor survival and promotion functions. Interactions between the cellular and structural components of the TME allow cancer cells to become invasive and disseminate from the primary site to distant locations, through a complex and multistep metastatic cascade. Tumor-associated M2-type macrophages have growth-promoting and immunosuppressive functions; mesenchymal cells mass produce exosomes that increase the migratory ability of cancer cells; cancer associated fibroblasts (CAFs) reorganize the surrounding matrix creating migration-guiding tracks for cancer cells. In addition, the tumor extracellular matrix (ECM) exerts determinant roles in disease progression and cancer cell migration and regulates therapeutic responses. The hypoxic conditions generated at the primary tumor force cancer cells to genetically and/or epigenetically adapt in order to survive and metastasize. In the circulation, cancer cells encounter platelets, immune cells, and cytokines in the blood microenvironment that facilitate their survival and transit. This review discusses the roles of different cellular and structural tumor components in regulating the metastatic process, targeting approaches using small molecule inhibitors, nanoparticles, manipulated exosomes, and miRNAs to inhibit tumor invasion as well as current and future strategies to remodel the TME and enhance treatment efficacy to block the detrimental process of metastasis. Full article

(This article belongs to the Special Issue Targeting Cancer Metastasis)

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29 pages, 1162 KiB

Open AccessEditor’s ChoiceReview

Liquid Biopsy in Pancreatic Cancer: Are We Ready to Apply It in the Clinical Practice?

by Victoria Heredia-Soto, Nuria Rodríguez-Salas and Jaime Feliu

Cancers 2021, 13(8), 1986; https://doi.org/10.3390/cancers13081986 - 20 Apr 2021

Cited by 40 | Viewed by 5980

Abstract

Pancreatic ductal adenocarcinoma (PDAC) exhibits the poorest prognosis of all solid tumors, with a 5-year survival of less than 10%. To improve the prognosis, it is necessary to advance in the development of tools that help us in the early diagnosis, treatment selection, [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) exhibits the poorest prognosis of all solid tumors, with a 5-year survival of less than 10%. To improve the prognosis, it is necessary to advance in the development of tools that help us in the early diagnosis, treatment selection, disease monitoring, evaluation of the response and prognosis. Liquid biopsy (LB), in its different modalities, represents a particularly interesting tool for these purposes, since it is a minimally invasive and risk-free procedure that can detect both the presence of genetic material from the tumor and circulating tumor cells (CTCs) in the blood and therefore distantly reflect the global status of the disease. In this work we review the current status of the main LB modalities (ctDNA, exosomes, CTCs and cfRNAs) for detecting and monitoring PDAC. Full article

(This article belongs to the Special Issue Current Status and Future Perspectives of ctDNA-Based Liquid Biopsy in Cancers)

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27 pages, 2970 KiB

Open AccessEditor’s ChoiceReview

Cytoskeletal Dynamics in Epithelial-Mesenchymal Transition: Insights into Therapeutic Targets for Cancer Metastasis

by Arpita Datta, Shuo Deng, Vennila Gopal, Kenneth Chun-Hong Yap, Clarissa Esmeralda Halim, Mun Leng Lye, Mei Shan Ong, Tuan Zea Tan, Gautam Sethi, Shing Chuan Hooi, Alan Prem Kumar and Celestial T. Yap

Cancers 2021, 13(8), 1882; https://doi.org/10.3390/cancers13081882 - 14 Apr 2021

Cited by 79 | Viewed by 8313

Abstract

In cancer cells, a vital cellular process during metastasis is the transformation of epithelial cells towards motile mesenchymal cells called the epithelial to mesenchymal transition (EMT). The cytoskeleton is an active network of three intracellular filaments: actin cytoskeleton, microtubules, and intermediate filaments. These [...] Read more.

In cancer cells, a vital cellular process during metastasis is the transformation of epithelial cells towards motile mesenchymal cells called the epithelial to mesenchymal transition (EMT). The cytoskeleton is an active network of three intracellular filaments: actin cytoskeleton, microtubules, and intermediate filaments. These filaments play a central role in the structural design and cell behavior and are necessary for EMT. During EMT, epithelial cells undergo a cellular transformation as manifested by cell elongation, migration, and invasion, coordinated by actin cytoskeleton reorganization. The actin cytoskeleton is an extremely dynamic structure, controlled by a balance of assembly and disassembly of actin filaments. Actin-binding proteins regulate the process of actin polymerization and depolymerization. Microtubule reorganization also plays an important role in cell migration and polarization. Intermediate filaments are rearranged, switching to a vimentin-rich network, and this protein is used as a marker for a mesenchymal cell. Hence, targeting EMT by regulating the activities of their key components may be a potential solution to metastasis. This review summarizes the research done on the physiological functions of the cytoskeleton, its role in the EMT process, and its effect on multidrug-resistant (MDR) cancer cells—highlight some future perspectives in cancer therapy by targeting cytoskeleton. Full article

(This article belongs to the Special Issue Cell Motility and Cancer)

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17 pages, 712 KiB

Open AccessEditor’s ChoiceReview

Non-Small-Cell Lung Cancer: New Rare Targets—New Targeted Therapies—State of The Art and Future Directions

by Katarzyna Stencel, Izabela Chmielewska, Janusz Milanowski and Rodryg Ramlau

Cancers 2021, 13(8), 1829; https://doi.org/10.3390/cancers13081829 - 12 Apr 2021

Cited by 16 | Viewed by 4343

Abstract

Lung cancer is the most common cause of cancer-related death worldwide, and the prognosis for stage IV remains poor. The presence of genetic alterations in tumor cells, such as EGFR and BRAF gene mutations, as well as ALK and ROS1 gene rearrangements, are [...] Read more.

Lung cancer is the most common cause of cancer-related death worldwide, and the prognosis for stage IV remains poor. The presence of genetic alterations in tumor cells, such as EGFR and BRAF gene mutations, as well as ALK and ROS1 gene rearrangements, are indications for targeted therapies. Many such treatments are already registered and used on a wide scale. In comparison to standard chemotherapy, they can prolong not only progression-free survival but also overall survival. Moreover, they are able to provide excellent quality of life and rapid improvement of cancer-related symptoms such as dyspnea, cough and pain. Recent years have witnessed great advances in both molecular diagnostics and new molecular therapies for non-small-cell lung cancer. This review presents new therapeutic targets in NSCLC, as well as drugs of which the activity against NTRK, RET, MET or HER2 gene alterations (including EGFR exon 20 insertions) has either been confirmed or is currently being evaluated. Although these particular genetic alterations in NSCLC are generally rare, each accounting for 1–2% of patients, in total about half of all patients have molecular alterations and may ultimately receive targeted therapies. Full article

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

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34 pages, 1965 KiB

Open AccessEditor’s ChoiceReview

Plasmin and Plasminogen System in the Tumor Microenvironment: Implications for Cancer Diagnosis, Prognosis, and Therapy

by Alamelu G. Bharadwaj, Ryan W. Holloway, Victoria A. Miller and David M. Waisman

Cancers 2021, 13(8), 1838; https://doi.org/10.3390/cancers13081838 - 12 Apr 2021

Cited by 55 | Viewed by 6300

Abstract

The tumor microenvironment (TME) is now being widely accepted as the key contributor to a range of processes involved in cancer progression from tumor growth to metastasis and chemoresistance. The extracellular matrix (ECM) and the proteases that mediate the remodeling of the ECM [...] Read more.

The tumor microenvironment (TME) is now being widely accepted as the key contributor to a range of processes involved in cancer progression from tumor growth to metastasis and chemoresistance. The extracellular matrix (ECM) and the proteases that mediate the remodeling of the ECM form an integral part of the TME. Plasmin is a broad-spectrum, highly potent, serine protease whose activation from its precursor plasminogen is tightly regulated by the activators (uPA, uPAR, and tPA), the inhibitors (PAI-1, PAI-2), and plasminogen receptors. Collectively, this system is called the plasminogen activation system. The expression of the components of the plasminogen activation system by malignant cells and the surrounding stromal cells modulates the TME resulting in sustained cancer progression signals. In this review, we provide a detailed discussion of the roles of plasminogen activation system in tumor growth, invasion, metastasis, and chemoresistance with specific emphasis on their role in the TME. We particularly review the recent highlights of the plasminogen receptor S100A10 (p11), which is a pivotal component of the plasminogen activation system. Full article

(This article belongs to the Special Issue The Shaping of Cancer by the Tumour Microenvironment and Its Relevance for Cancer Therapy)

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60 pages, 1987 KiB

Open AccessEditor’s ChoiceReview

A Systematic Review of Glioblastoma-Targeted Therapies in Phases II, III, IV Clinical Trials

by Elisabete Cruz Da Silva, Marie-Cécile Mercier, Nelly Etienne-Selloum, Monique Dontenwill and Laurence Choulier

Cancers 2021, 13(8), 1795; https://doi.org/10.3390/cancers13081795 - 9 Apr 2021

Cited by 69 | Viewed by 6650

Abstract

Glioblastoma (GBM), the most frequent and aggressive glial tumor, is currently treated as first line by the Stupp protocol, which combines, after surgery, radiotherapy and chemotherapy. For recurrent GBM, in absence of standard treatment or available clinical trials, various protocols including cytotoxic drugs [...] Read more.

Glioblastoma (GBM), the most frequent and aggressive glial tumor, is currently treated as first line by the Stupp protocol, which combines, after surgery, radiotherapy and chemotherapy. For recurrent GBM, in absence of standard treatment or available clinical trials, various protocols including cytotoxic drugs and/or bevacizumab are currently applied. Despite these heavy treatments, the mean overall survival of patients is under 18 months. Many clinical studies are underway. Based on clinicaltrials.org and conducted up to 1 April 2020, this review lists, not only main, but all targeted therapies in phases II-IV of 257 clinical trials on adults with newly diagnosed or recurrent GBMs for the last twenty years. It does not involve targeted immunotherapies and therapies targeting tumor cell metabolism, that are well documented in other reviews. Without surprise, the most frequently reported drugs are those targeting (i) EGFR (40 clinical trials), and more generally tyrosine kinase receptors (85 clinical trials) and (ii) VEGF/VEGFR (75 clinical trials of which 53 involving bevacizumab). But many other targets and drugs are of interest. They are all listed and thoroughly described, on an one-on-one basis, in four sections related to targeting (i) GBM stem cells and stem cell pathways, (ii) the growth autonomy and migration, (iii) the cell cycle and the escape to cell death, (iv) and angiogenesis. Full article

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24 pages, 505 KiB

Open AccessEditor’s ChoiceSystematic Review

Systematic Review of Recurrent Osteosarcoma Systemic Therapy

by Ioanna Gazouli, Anastasios Kyriazoglou, Ioannis Kotsantis, Maria Anastasiou, Anastasios Pantazopoulos, Maria Prevezanou, Ioannis Chatzidakis, Georgios Kavourakis, Panagiota Economopoulou, Vasileios Kontogeorgakos, Panayiotis Papagelopoulos and Amanda Psyrri

Cancers 2021, 13(8), 1757; https://doi.org/10.3390/cancers13081757 - 7 Apr 2021

Cited by 29 | Viewed by 4673

Abstract

Osteosarcoma is the most frequent primary bone cancer, mainly affecting those of young ages. Although surgery combined with cytotoxic chemotherapy has significantly increased the chances of cure, recurrent and refractory disease still impose a tough therapeutic challenge. We performed a systematic literature review [...] Read more.

Osteosarcoma is the most frequent primary bone cancer, mainly affecting those of young ages. Although surgery combined with cytotoxic chemotherapy has significantly increased the chances of cure, recurrent and refractory disease still impose a tough therapeutic challenge. We performed a systematic literature review of the available clinical evidence, regarding treatment of recurrent and/or refractory osteosarcoma over the last two decades. Among the 72 eligible studies, there were 56 prospective clinical trials, primarily multicentric, single arm, phase I or II and non-randomized. Evaluated treatment strategies included cytotoxic chemotherapy, tyrosine kinase and mTOR inhibitors and other targeted agents, as well as immunotherapy and combinatorial approaches. Unfortunately, most treatments have failed to induce objective responses, albeit some of them may sustain disease control. No driver mutations have been recognized, to serve as effective treatment targets, and predictive biomarkers of potential treatment effectiveness are lacking. Hopefully, ongoing and future clinical and preclinical research will unlock the underlying biologic mechanisms of recurrent and refractory osteosarcoma, expanding the therapeutic choices available to pre-treated osteosarcoma patients. Full article

(This article belongs to the Section Cancer Therapy)

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