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Editor’s Choice Articles

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

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21 pages, 585 KiB  
Review
Targeted Therapies in Advanced Biliary Tract Cancer: An Evolving Paradigm
by Sakti Chakrabarti, Mandana Kamgar and Amit Mahipal
Cancers 2020, 12(8), 2039; https://doi.org/10.3390/cancers12082039 - 24 Jul 2020
Cited by 54 | Viewed by 4992
Abstract
Biliary tract cancers (BTCs) are a heterogeneous group of adenocarcinomas that originate from the epithelial lining of the biliary tree. BTCs are characterized by presentation with advanced disease precluding curative surgery, rising global incidence, and a poor prognosis. Chemotherapy is the mainstay of [...] Read more.
Biliary tract cancers (BTCs) are a heterogeneous group of adenocarcinomas that originate from the epithelial lining of the biliary tree. BTCs are characterized by presentation with advanced disease precluding curative surgery, rising global incidence, and a poor prognosis. Chemotherapy is the mainstay of the current treatment, which results in a median overall survival of less than one year, underscoring the need for novel therapeutic agents and strategies. Next-generation sequencing-based molecular profiling has shed light on the underpinnings of the complex pathophysiology of BTC and has uncovered numerous actionable targets, leading to the discovery of new therapies tailored to the molecular targets. Therapies targeting fibroblast growth factor receptor (FGFR) fusion, isocitrate dehydrogenase (IDH) mutations, the human epidermal growth factor receptor (HER) family, DNA damage repair (DDR) pathways, and BRAF mutations have produced early encouraging results in selected patients. Current clinical trials evaluating targeted therapies, as monotherapies and in combination with other agents, are paving the way for novel treatment options. Genomic profiling of cell-free circulating tumor DNA that can assist in the identification of an actionable target is another exciting area of development. In this review, we provide a contemporaneous appraisal of the evolving targeted therapies and the ongoing clinical trials that will likely transform the therapeutic paradigm of BTC. Full article
(This article belongs to the Special Issue Research Progress of Biliary Tract Cancers)
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36 pages, 2920 KiB  
Review
Gold Nanoparticles as a Potent Radiosensitizer: A Transdisciplinary Approach from Physics to Patient
by Sébastien Penninckx, Anne-Catherine Heuskin, Carine Michiels and Stéphane Lucas
Cancers 2020, 12(8), 2021; https://doi.org/10.3390/cancers12082021 - 23 Jul 2020
Cited by 103 | Viewed by 6362
Abstract
Over the last decade, a growing interest in the improvement of radiation therapies has led to the development of gold-based nanomaterials as radiosensitizer. Although the radiosensitization effect was initially attributed to a dose enhancement mechanism, an increasing number of studies challenge this mechanistic [...] Read more.
Over the last decade, a growing interest in the improvement of radiation therapies has led to the development of gold-based nanomaterials as radiosensitizer. Although the radiosensitization effect was initially attributed to a dose enhancement mechanism, an increasing number of studies challenge this mechanistic hypothesis and evidence the importance of chemical and biological contributions. Despite extensive experimental validation, the debate regarding the mechanism(s) of gold nanoparticle radiosensitization is limiting its clinical translation. This article reviews the current state of knowledge by addressing how gold nanoparticles exert their radiosensitizing effects from a transdisciplinary perspective. We also discuss the current and future challenges to go towards a successful clinical translation of this promising therapeutic approach. Full article
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21 pages, 1306 KiB  
Review
A Comprehensive Review of Cancer MicroRNA Therapeutic Delivery Strategies
by Alexis Forterre, Hiroaki Komuro, Shakhlo Aminova and Masako Harada
Cancers 2020, 12(7), 1852; https://doi.org/10.3390/cancers12071852 - 9 Jul 2020
Cited by 144 | Viewed by 7418
Abstract
In the field of molecular oncology, microRNAs (miRNAs) and their role in regulating physiological processes and cancer pathogenesis have been a revolutionary discovery over the last decade. It is now considered that miRNA dysregulation influences critical molecular pathways involved in tumor progression, invasion, [...] Read more.
In the field of molecular oncology, microRNAs (miRNAs) and their role in regulating physiological processes and cancer pathogenesis have been a revolutionary discovery over the last decade. It is now considered that miRNA dysregulation influences critical molecular pathways involved in tumor progression, invasion, angiogenesis and metastasis in a wide range of cancer types. Hence, altering miRNA levels in cancer cells has promising potential as a therapeutic intervention, which is discussed in many other articles in this Special Issue. Some of the most significant hurdles in therapeutic miRNA usage are the stability and the delivery system. In this review, we cover a comprehensive update on the challenges and strategies for the development of therapeutic miRNA delivery systems that includes virus-based delivery, non-viral delivery (artificial lipid-based vesicles, polymer-based or chemical structures), and recently emerged extracellular vesicle (EV)-based delivery systems. Full article
(This article belongs to the Special Issue MicroRNA Therapeutics: Towards a New Era for the Management of Cancer)
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13 pages, 503 KiB  
Article
Presenting Features and Early Mortality from SARS-CoV-2 Infection in Cancer Patients during the Initial Stage of the COVID-19 Pandemic in Europe
by David J. Pinato, Alvin J. X. Lee, Federica Biello, Elia Seguí, Juan Aguilar-Company, Anna Carbó, Riccardo Bruna, Mark Bower, Gianpiero Rizzo, Sarah Benafif, Carme Carmona, Neha Chopra, Claudia Andrea Cruz, Francesca D’Avanzo, Joanne S. Evans, Myria Galazi, Isabel Garcia-Fructuoso, Alessia Dalla Pria, Thomas Newsom-Davis, Diego Ottaviani, Andrea Patriarca, Roxana Reyes, Rachel Sharkey, Christopher C. T. Sng, Yien Ning Sophia Wong, Daniela Ferrante, Lorenza Scotti, Gian Carlo Avanzi, Mattia Bellan, Luigi Mario Castello, Javier Marco-Hernández, Meritxell Mollà, Mario Pirisi, Isabel Ruiz-Camps, Pier Paolo Sainaghi, Gianluca Gaidano, Joan Brunet, Josep Tabernero, Aleix Prat and Alessandra Gennariadd Show full author list remove Hide full author list
Cancers 2020, 12(7), 1841; https://doi.org/10.3390/cancers12071841 - 8 Jul 2020
Cited by 56 | Viewed by 6640
Abstract
We describe the outcomes in cancer patients during the initial outbreak of the COVID-19 in Europe from the retrospective, multi-center observational OnCovid study. We identified 204 cancer patients from eight centers in the United Kingdom, Italy, and Spain aged >18 (mean = 69) [...] Read more.
We describe the outcomes in cancer patients during the initial outbreak of the COVID-19 in Europe from the retrospective, multi-center observational OnCovid study. We identified 204 cancer patients from eight centers in the United Kingdom, Italy, and Spain aged >18 (mean = 69) and diagnosed with COVID-19 between 26 February and 1 April 2020. A total of 127 (62%) were male, 184 (91%) had a diagnosis of solid malignancy, and 103 (51%) had non-metastatic disease. A total of 161 (79%) had >1 co-morbidity. A total of 141 (69%) patients had >1 COVID-19 complication. A total of 36 (19%) were escalated to high-dependency or intensive care. A total of 59 (29%) died, 53 (26%) were discharged, and 92 (45%) were in-hospital survivors. Mortality was higher in patients aged >65 (36% vs. 16%), in those with >2 co-morbidities (40% vs. 18%) and developing >1 complication from COVID-19 (38% vs. 4%, p = 0.004). Multi-variable analyses confirmed age > 65 and >2 co-morbidities to predict for patient mortality independent of tumor stage, active malignancy, or anticancer therapy. During the early outbreak of SARS-CoV-2 infection in Europe co-morbid burden and advancing age predicted for adverse disease course in cancer patients. The ongoing OnCovid study will allow us to compare risks and outcomes in cancer patients between the initial and later stages of the COVID-19 pandemic. Full article
(This article belongs to the Section Cancer Epidemiology and Prevention)
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33 pages, 2255 KiB  
Review
MHC Class I Downregulation in Cancer: Underlying Mechanisms and Potential Targets for Cancer Immunotherapy
by Annelisa M. Cornel, Iris L. Mimpen and Stefan Nierkens
Cancers 2020, 12(7), 1760; https://doi.org/10.3390/cancers12071760 - 2 Jul 2020
Cited by 220 | Viewed by 20878
Abstract
In recent years, major advances have been made in cancer immunotherapy. This has led to significant improvement in prognosis of cancer patients, especially in the hematological setting. Nonetheless, translation of these successes to solid tumors was found difficult. One major mechanism through which [...] Read more.
In recent years, major advances have been made in cancer immunotherapy. This has led to significant improvement in prognosis of cancer patients, especially in the hematological setting. Nonetheless, translation of these successes to solid tumors was found difficult. One major mechanism through which solid tumors can avoid anti-tumor immunity is the downregulation of major histocompatibility complex class I (MHC-I), which causes reduced recognition by- and cytotoxicity of CD8+ T-cells. Downregulation of MHC-I has been described in 40–90% of human tumors, often correlating with worse prognosis. Epigenetic and (post-)transcriptional dysregulations relevant in the stabilization of NFkB, IRFs, and NLRC5 are often responsible for MHC-I downregulation in cancer. The intrinsic reversible nature of these dysregulations provides an opportunity to restore MHC-I expression and facilitate adaptive anti-tumor immunity. In this review, we provide an overview of the mechanisms underlying reversible MHC-I downregulation and describe potential strategies to counteract this reduction in MHC-I antigen presentation in cancer. Full article
(This article belongs to the Special Issue Cancer-Induced Immune Suppression: An Achilles’ Heel of Current Immunotherapy)
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28 pages, 2670 KiB  
Review
Roles of Histone Deacetylases and Inhibitors in Anticancer Therapy
by Flávia Alves Verza, Umashankar Das, Ana Lúcia Fachin, Jonathan R. Dimmock and Mozart Marins
Cancers 2020, 12(6), 1664; https://doi.org/10.3390/cancers12061664 - 23 Jun 2020
Cited by 79 | Viewed by 5932
Abstract
Histones are the main structural proteins of eukaryotic chromatin. Histone acetylation/ deacetylation are the epigenetic mechanisms of the regulation of gene expression and are catalyzed by histone acetyltransferases (HAT) and histone deacetylases (HDAC). These epigenetic alterations of DNA structure influence the action of [...] Read more.
Histones are the main structural proteins of eukaryotic chromatin. Histone acetylation/ deacetylation are the epigenetic mechanisms of the regulation of gene expression and are catalyzed by histone acetyltransferases (HAT) and histone deacetylases (HDAC). These epigenetic alterations of DNA structure influence the action of transcription factors which can induce or repress gene transcription. The HATs catalyze acetylation and the events related to gene transcription and are also responsible for transporting newly synthesized histones from the cytoplasm to the nucleus. The activity of HDACs is mainly involved in silencing gene expression and according to their specialized functions are divided into classes I, II, III and IV. The disturbance of the expression and mutations of HDAC genes causes the aberrant transcription of key genes regulating important cancer pathways such as cell proliferation, cell-cycle regulation and apoptosis. In view of their role in cancer pathways, HDACs are considered promising therapeutic targets and the development of HDAC inhibitors is a hot topic in the search for new anticancer drugs. The present review will focus on HDACs I, II and IV, the best known inhibitors and potential alternative inhibitors derived from natural and synthetic products which can be used to influence HDAC activity and the development of new cancer therapies. Full article
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38 pages, 1489 KiB  
Review
EMT-Associated Heterogeneity in Circulating Tumor Cells: Sticky Friends on the Road to Metastasis
by Anthony Genna, Aline M. Vanwynsberghe, Amélie V. Villard, Charles Pottier, Julien Ancel, Myriam Polette and Christine Gilles
Cancers 2020, 12(6), 1632; https://doi.org/10.3390/cancers12061632 - 19 Jun 2020
Cited by 74 | Viewed by 5893
Abstract
Epithelial–mesenchymal transitions (EMTs) generate hybrid phenotypes with an enhanced ability to adapt to diverse microenvironments encountered during the metastatic spread. Accordingly, EMTs play a crucial role in the biology of circulating tumor cells (CTCs) and contribute to their heterogeneity. Here, we review major [...] Read more.
Epithelial–mesenchymal transitions (EMTs) generate hybrid phenotypes with an enhanced ability to adapt to diverse microenvironments encountered during the metastatic spread. Accordingly, EMTs play a crucial role in the biology of circulating tumor cells (CTCs) and contribute to their heterogeneity. Here, we review major EMT-driven properties that may help hybrid Epithelial/Mesenchymal CTCs to survive in the bloodstream and accomplish early phases of metastatic colonization. We then discuss how interrogating EMT in CTCs as a companion biomarker could help refine cancer patient management, further supporting the relevance of CTCs in personalized medicine. Full article
(This article belongs to the Special Issue Circulating Tumor Cells' Heterogeneity and Precision Oncology)
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28 pages, 1261 KiB  
Review
Combined PARP Inhibition and Immune Checkpoint Therapy in Solid Tumors
by Florent Peyraud and Antoine Italiano
Cancers 2020, 12(6), 1502; https://doi.org/10.3390/cancers12061502 - 9 Jun 2020
Cited by 152 | Viewed by 9173
Abstract
Genomic instability is a hallmark of cancer related to DNA damage response (DDR) deficiencies, offering vulnerabilities for targeted treatment. Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) interfere with the efficient repair of DNA damage, particularly in tumors with existing defects in DNA repair, and [...] Read more.
Genomic instability is a hallmark of cancer related to DNA damage response (DDR) deficiencies, offering vulnerabilities for targeted treatment. Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) interfere with the efficient repair of DNA damage, particularly in tumors with existing defects in DNA repair, and induce synthetic lethality. PARPi are active across a range of tumor types harboring BRCA mutations and also BRCA-negative cancers, such as ovarian, breast or prostate cancers with homologous recombination deficiencies (HRD). Depending on immune contexture, immune checkpoint inhibitors (ICIs), such as anti-PD1/PD-L1 and anti-CTLA-4, elicit potent antitumor effects and have been approved in various cancers types. Although major breakthroughs have been performed with either PARPi or ICIs alone in multiple cancers, primary or acquired resistance often leads to tumor escape. PARPi-mediated unrepaired DNA damages modulate the tumor immune microenvironment by a range of molecular and cellular mechanisms, such as increasing genomic instability, immune pathway activation, and PD-L1 expression on cancer cells, which might promote responsiveness to ICIs. In this context, PARPi and ICIs represent a rational combination. In this review, we summarize the basic and translational biology supporting the combined strategy. We also detail preclinical results and early data of ongoing clinical trials indicating the synergistic effect of PARPi and ICIs. Moreover, we discuss the limitations and the future direction of the combination. Full article
(This article belongs to the Special Issue PARPs, PAR and NAD Metabolism and Their Inhibitors in Cancer)
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29 pages, 1234 KiB  
Review
BCMA-Targeting Therapy: Driving a New Era of Immunotherapy in Multiple Myeloma
by Shih-Feng Cho, Liang Lin, Lijie Xing, Yuyin Li, Tengteng Yu, Kenneth C Anderson and Yu-Tzu Tai
Cancers 2020, 12(6), 1473; https://doi.org/10.3390/cancers12061473 - 5 Jun 2020
Cited by 40 | Viewed by 8424
Abstract
The treatment of multiple myeloma (MM) has entered into a new era of immunotherapy. Novel immunotherapies will significantly improve patient outcome via simultaneously targeting malignant plasma cell (PC) and reversing immunocompromised bone marrow (BM) microenvironment. B-cell maturation antigen (BCMA), selectively expressed in PCs [...] Read more.
The treatment of multiple myeloma (MM) has entered into a new era of immunotherapy. Novel immunotherapies will significantly improve patient outcome via simultaneously targeting malignant plasma cell (PC) and reversing immunocompromised bone marrow (BM) microenvironment. B-cell maturation antigen (BCMA), selectively expressed in PCs and a key receptor for A proliferation-inducing ligand (APRIL), is highly expressed in MM cells from patients at all stages. The APRIL/BCMA signal cascades promote the survival and drug resistance of MM cells and further modulate immunosuppressive BM milieu. Impressively, anti-BCMA immunotherapeutic reagents, including chimeric antigen receptor (CAR), antibody-drug conjugate (ADC) and bispecific T cell engager (BiTE) have all shown high response rates in their first clinical trials in relapse and refractory patients with very limited treatment options. These results rapidly inspired numerous development of next-generation anti-BCMA biotherapeutics, i.e., bispecific molecule, bispecific or trispecific antibodies, a novel form of CAR T/NK cells and T Cell Antigen Coupler (TAC) receptors, antibody-coupled T cell receptor (ACTR) as well as a cancer vaccine. We here highlight seminal preclinical and clinical studies on novel BCMA-based immunotherapies as effective monotherapy and discuss their potential in combination with current anti-MM and novel checkpoint drugs in earlier disease stages to further achieve durable responses in patients. Full article
(This article belongs to the Special Issue Antigens and Cancer Therapy)
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29 pages, 1482 KiB  
Review
The Role of the Gut Microbiome in Colorectal Cancer Development and Therapy Response
by Lidia Sánchez-Alcoholado, Bruno Ramos-Molina, Ana Otero, Aurora Laborda-Illanes, Rafael Ordóñez, José Antonio Medina, Jaime Gómez-Millán and María Isabel Queipo-Ortuño
Cancers 2020, 12(6), 1406; https://doi.org/10.3390/cancers12061406 - 29 May 2020
Cited by 186 | Viewed by 14617
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide and the leading cause of cancer-related deaths. Recently, several studies have demonstrated that gut microbiota can alter CRC susceptibility and progression by modulating mechanisms such as inflammation and DNA damage, and by producing [...] Read more.
Colorectal cancer (CRC) is the third most common cancer worldwide and the leading cause of cancer-related deaths. Recently, several studies have demonstrated that gut microbiota can alter CRC susceptibility and progression by modulating mechanisms such as inflammation and DNA damage, and by producing metabolites involved in tumor progression or suppression. Dysbiosis of gut microbiota has been observed in patients with CRC, with a decrease in commensal bacterial species (butyrate-producing bacteria) and an enrichment of detrimental bacterial populations (pro-inflammatory opportunistic pathogens). CRC is characterized by altered production of bacterial metabolites directly involved in cancer metabolism including short-chain fatty acids and polyamines. Emerging evidence suggests that diet has an important impact on the risk of CRC development. The intake of high-fiber diets and the supplementation of diet with polyunsaturated fatty acids, polyphenols and probiotics, which are known to regulate gut microbiota, could be not only a potential mechanism for the reduction of CRC risk in a primary prevention setting, but may also be important to enhance the response to cancer therapy when used as adjuvant to conventional treatment for CRC. Therefore, a personalized modulation of the pattern of gut microbiome by diet may be a promising approach to prevent the development and progression of CRC and to improve the efficacy of antitumoral therapy. Full article
(This article belongs to the Section Systematic Review or Meta-Analysis in Cancer Research)
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14 pages, 285 KiB  
Review
PSMA Theranostics: Review of the Current Status of PSMA-Targeted Imaging and Radioligand Therapy
by Wallace Jones, Kelly Griffiths, Pedro C. Barata and Channing J. Paller
Cancers 2020, 12(6), 1367; https://doi.org/10.3390/cancers12061367 - 26 May 2020
Cited by 76 | Viewed by 6670
Abstract
Prostate-specific membrane antigen (PSMA) has been the subject of extensive investigation in the past two decades as a promising molecular target for prostate cancer (PCa). Its appealing molecular features have enabled the development of a novel diagnostic and therapeutic—thus “theranostic”—approach to PCa. There [...] Read more.
Prostate-specific membrane antigen (PSMA) has been the subject of extensive investigation in the past two decades as a promising molecular target for prostate cancer (PCa). Its appealing molecular features have enabled the development of a novel diagnostic and therapeutic—thus “theranostic”—approach to PCa. There is now substantial evidence of the high sensitivity of PSMA-targeted imaging for PCa lesions and growing evidence of the therapeutic efficacy of PSMA radioligand therapy for metastatic castration-resistant prostate cancer. This article presents a broad overview of the current status of PSMA theranostics, including current evidence, potential clinical impact, and active areas of research. Full article
(This article belongs to the Special Issue New Therapies for Prostate Cancer)
18 pages, 1731 KiB  
Review
Pancreatic Cancer Associated Fibroblasts (CAF): Under-Explored Target for Pancreatic Cancer Treatment
by Jeffrey Norton, Deshka Foster, Malini Chinta, Ashley Titan and Michael Longaker
Cancers 2020, 12(5), 1347; https://doi.org/10.3390/cancers12051347 - 25 May 2020
Cited by 83 | Viewed by 8392
Abstract
Pancreatic cancer is the 4th leading cause of cancer deaths in the United States. The pancreatic cancer phenotype is primarily a consequence of oncogenes disturbing the resident pancreas parenchymal cell repair program. Many solid tumor types including pancreatic cancer have severe tumor fibrosis [...] Read more.
Pancreatic cancer is the 4th leading cause of cancer deaths in the United States. The pancreatic cancer phenotype is primarily a consequence of oncogenes disturbing the resident pancreas parenchymal cell repair program. Many solid tumor types including pancreatic cancer have severe tumor fibrosis called desmoplasia. Desmoplastic stroma is coopted by the tumor as a support structure and CAFs aid in tumor growth, invasion, and metastases. This stroma is caused by cancer associated fibroblasts (CAFs), which lay down extensive connective tissue in and around the tumor cells. CAFs represent a heterogeneous population of cells that produce various paracrine molecules such as transforming growth factor-beta (TGF-beta) and platelet derived growth factors (PDGFs) that aid tumor growth, local invasion, and development of metastases. The hard, fibrotic shell of desmoplasia serves as a barrier to the infiltration of both chemo- and immunotherapy drugs and host immune cells to the tumor. Although there have been recent improvements in chemotherapy and surgical techniques for management of pancreatic cancer, the majority of patients will die from this disease. Therefore, new treatment strategies are clearly needed. CAFs represent an under-explored potential therapeutic target. This paper discusses what we know about the role of CAFs in pancreatic cancer cell growth, invasion, and metastases. Additionally, we present different strategies that are being and could be explored as anti-CAF treatments for pancreatic cancer. Full article
(This article belongs to the Special Issue A Special Issue on Tumor Stroma )
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20 pages, 3732 KiB  
Article
The Dynamic Relationship of Breast Cancer Cells and Fibroblasts in Fibronectin Accumulation at Primary and Metastatic Tumor Sites
by Sarah Libring, Aparna Shinde, Monica K. Chanda, Maryam Nuru, Heather George, Aya M. Saleh, Ammara Abdullah, Tamara L. Kinzer-Ursem, Sarah Calve, Michael K. Wendt and Luis Solorio
Cancers 2020, 12(5), 1270; https://doi.org/10.3390/cancers12051270 - 17 May 2020
Cited by 71 | Viewed by 8448
Abstract
In breast cancer (BC), tissue stiffening via fibronectin (FN) and collagen accumulation is associated with advanced disease progression at both the primary tumor and metastatic sites. Here, we evaluate FN production in 15 BC cell lines, representing a variety of subtypes, phenotypes, metastatic [...] Read more.
In breast cancer (BC), tissue stiffening via fibronectin (FN) and collagen accumulation is associated with advanced disease progression at both the primary tumor and metastatic sites. Here, we evaluate FN production in 15 BC cell lines, representing a variety of subtypes, phenotypes, metastatic potentials, and chemotherapeutic sensitivities. We demonstrate that intracellular and soluble FN is initially lost during tumorigenic transformation but is rescued in all lines with epithelial-mesenchymal plasticity (EMP). Importantly, we establish that no BC cell line was able to independently organize a robust FN matrix. Non-transformed mammary epithelial cells were also unable to deposit FN matrices unless transglutaminase 2, a FN crosslinking enzyme, was overexpressed. Instead, BC cells manipulated the FN matrix production of fibroblasts in a phenotypic-dependent manner. In addition, varied accumulation levels were seen depending if the fibroblasts were conditioned to model paracrine signaling or endocrine signaling of the metastatic niche. In the former, fibroblasts conditioned by BC cultures with high EMP resulted in the largest FN matrix accumulation. In contrast, mesenchymal BC cells produced extracellular vesicles (EV) that resulted in the highest levels of matrix formation by conditioned fibroblasts. Overall, we demonstrate a dynamic relationship between tumor and stromal cells within the tumor microenvironment, in which the levels and fibrillarization of FN in the extracellular matrix are modulated during the particular stages of disease progression. Full article
(This article belongs to the Special Issue A Special Issue on Tumor Stroma )
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14 pages, 880 KiB  
Review
The Effects of Obesity on Anti-Cancer Immunity and Cancer Immunotherapy
by Matthew J. Woodall, Silke Neumann, Katrin Campbell, Sharon T. Pattison and Sarah L. Young
Cancers 2020, 12(5), 1230; https://doi.org/10.3390/cancers12051230 - 14 May 2020
Cited by 74 | Viewed by 6400
Abstract
Cancer is one of the leading causes of morbidity and mortality worldwide. Traditional treatments include surgery, chemotherapy and radiation therapy, and more recently targeted therapies including immunotherapy are becoming routine care for some cancers. Immunotherapy aims to upregulate the patient’s own immune system, [...] Read more.
Cancer is one of the leading causes of morbidity and mortality worldwide. Traditional treatments include surgery, chemotherapy and radiation therapy, and more recently targeted therapies including immunotherapy are becoming routine care for some cancers. Immunotherapy aims to upregulate the patient’s own immune system, enabling it to destroy cancerous cells. Obesity is a metabolic disorder characterized by significant weight that is an important contributor to many different diseases, including cancers. Obesity impacts the immune system and causes, among other things, a state of chronic low-grade inflammation. This is hypothesized to impact the efficacy of the immunotherapies. This review discusses the effects of obesity on the immune system and cancer immunotherapy, including the current evidence on the effect of obesity on immune checkpoint blockade, something which currently published reviews on this topic have not delved into. Data from several studies show that even though obesity causes a state of chronic low-grade inflammation with reductions in effector immune populations, it has a beneficial effect on patient survival following anti-PD-1/PD-L1 and anti-CTLA-4 treatment. However, research in this field is just emerging and further work is needed to expand our understanding of which cancer patients are likely to benefit from immunotherapy. Full article
(This article belongs to the Special Issue New Insights into Cancer Vaccines and Immunotherapy)
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14 pages, 295 KiB  
Review
Biliary Tract Cancer: Current Medical Treatment Strategies
by Ester Oneda, Mohammed Abu Hilal and Alberto Zaniboni
Cancers 2020, 12(5), 1237; https://doi.org/10.3390/cancers12051237 - 14 May 2020
Cited by 43 | Viewed by 4940
Abstract
Background: Biliary tract cancers (BTCs) include cholangiocarcinomas and gallbladder cancers usually present at an advanced stage, which are considered resectable in less than 20% of cases and characterised by poor prognosis. Methods: In this review, we discussed the most recent therapeutic options on [...] Read more.
Background: Biliary tract cancers (BTCs) include cholangiocarcinomas and gallbladder cancers usually present at an advanced stage, which are considered resectable in less than 20% of cases and characterised by poor prognosis. Methods: In this review, we discussed the most recent therapeutic options on the basis of the most updated and complete reviews and recent prospective studies in selected BTC patients. Results: Due to the high recurrence rate of BTCs, we suggest the new recommendations that have been made on adjuvant chemotherapy and radiotherapy treatment after surgery. New chemotherapy combinations in advanced-stage patients allow a better survival benefit than the standard treatment. Furthermore, the revelation of complex molecular events and their interactions and relationships with some risk factors allowed the development of targeted/toxic agents alone or combination with chemotherapy that is really promising. In unresectable patients, hepatic arterial infusion of high-dose chemotherapy or selective internal radiotherapy could offer a primary mass volume reduction or its resection with the maintenance of liver function. Conclusions: The therapeutic landscape for BTCs is blooming again, the knowledge of their biology is still growing, but the available data on chemotherapy, radiotherapy, locoregional treatments, and target therapies have added hopes to improve patient survival. Full article
18 pages, 2429 KiB  
Review
Inducing Angiogenesis, a Key Step in Cancer Vascularization, and Treatment Approaches
by Harman Saman, Syed Shadab Raza, Shahab Uddin and Kakil Rasul
Cancers 2020, 12(5), 1172; https://doi.org/10.3390/cancers12051172 - 6 May 2020
Cited by 93 | Viewed by 8723
Abstract
Angiogenesis is a term that describes the formation of new blood and lymphatic vessels from a pre-existing vasculature. This allows tumour cells to acquire sustenance in the form of nutrients and oxygen and the ability to evacuate metabolic waste. As one of the [...] Read more.
Angiogenesis is a term that describes the formation of new blood and lymphatic vessels from a pre-existing vasculature. This allows tumour cells to acquire sustenance in the form of nutrients and oxygen and the ability to evacuate metabolic waste. As one of the hallmarks of cancer, angiogenesis has been studied extensively in animal and human models to enable better understanding of cancer biology and the development of new anti-cancer treatments. Angiogenesis plays a crucial role in the process of tumour genesis, because solid tumour need a blood supply if they are to grow beyond a few millimeters in size. On the other hand, there is growing evidence that some solid tumour exploit existing normal blood supply and do not require a new vessel formation to grow and to undergo metastasis. This review of the literature will present the current understanding of this intricate process and the latest advances in the use of angiogenesis-targeting therapies in the fight against cancer. Full article
(This article belongs to the Special Issue Angiogenesis in Cancers)
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20 pages, 4638 KiB  
Article
A Novel 4-gene Score to Predict Survival, Distant Metastasis and Response to Neoadjuvant Therapy in Breast Cancer
by Masanori Oshi, Eriko Katsuta, Li Yan, John M.L. Ebos, Omar M. Rashid, Ryusei Matsuyama, Itaru Endo and Kazuaki Takabe
Cancers 2020, 12(5), 1148; https://doi.org/10.3390/cancers12051148 - 2 May 2020
Cited by 47 | Viewed by 5648
Abstract
We generated a 4-gene score with genes upregulated in LM2-4, a metastatic variant of MDA-MB-231 (DOK 4, HCCS, PGF, and SHCBP1) that was strongly associated with disease-free survival (DFS) in TCGA cohort (hazard ratio [HR]>1.2, p < 0.02). The 4-gene score correlated with [...] Read more.
We generated a 4-gene score with genes upregulated in LM2-4, a metastatic variant of MDA-MB-231 (DOK 4, HCCS, PGF, and SHCBP1) that was strongly associated with disease-free survival (DFS) in TCGA cohort (hazard ratio [HR]>1.2, p < 0.02). The 4-gene score correlated with overall survival of TCGA (HR = 1.44, p < 0.001), which was validated with DFS and disease-specific survival of METABRIC cohort. The 4-gene score was able to predict worse survival or clinically aggressive tumors, such as high Nottingham pathological grade and advanced cancer staging. High score was associated with worse survival in the hormonal receptor (HR)-positive/Her2-negative subtype. High score enriched cell proliferation-related gene sets in GSEA. The score was high in primary tumors that originated, in and metastasized to, brain and lung, and it predicted worse progression-free survival for metastatic tumors. Good tumor response to neoadjuvant chemotherapy or hormonal therapy was accompanied by score reduction. High scores were also predictive of response to neoadjuvant chemotherapy for HR-positive/Her2-negative subtype. High score tumors had increased expression of T cell exhaustion marker genes, suggesting that the score may also be a biomarker for immunotherapy response. Our novel 4-gene score with both prognostic and predictive values may, therefore, be clinically useful particularly in HR-positive breast cancer. Full article
(This article belongs to the Special Issue Novel Biomarkers and Molecular Targets in Cancer)
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22 pages, 1045 KiB  
Review
Warburg and Beyond: The Power of Mitochondrial Metabolism to Collaborate or Replace Fermentative Glycolysis in Cancer
by Shamir Cassim, Milica Vučetić, Maša Ždralević and Jacques Pouyssegur
Cancers 2020, 12(5), 1119; https://doi.org/10.3390/cancers12051119 - 30 Apr 2020
Cited by 120 | Viewed by 10624
Abstract
A defining hallmark of tumor phenotypes is uncontrolled cell proliferation, while fermentative glycolysis has long been considered as one of the major metabolic pathways that allows energy production and provides intermediates for the anabolic growth of cancer cells. Although such a vision has [...] Read more.
A defining hallmark of tumor phenotypes is uncontrolled cell proliferation, while fermentative glycolysis has long been considered as one of the major metabolic pathways that allows energy production and provides intermediates for the anabolic growth of cancer cells. Although such a vision has been crucial for the development of clinical imaging modalities, it has become now evident that in contrast to prior beliefs, mitochondria play a key role in tumorigenesis. Recent findings demonstrated that a full genetic disruption of the Warburg effect of aggressive cancers does not suppress but instead reduces tumor growth. Tumor growth then relies exclusively on functional mitochondria. Besides having fundamental bioenergetic functions, mitochondrial metabolism indeed provides appropriate building blocks for tumor anabolism, controls redox balance, and coordinates cell death. Hence, mitochondria represent promising targets for the development of novel anti-cancer agents. Here, after revisiting the long-standing Warburg effect from a historic and dynamic perspective, we review the role of mitochondria in cancer with particular attention to the cancer cell-intrinsic/extrinsic mechanisms through which mitochondria influence all steps of tumorigenesis, and briefly discuss the therapeutic potential of targeting mitochondrial metabolism for cancer therapy. Full article
(This article belongs to the Special Issue Metabolic Pathways and Redox Homeostasis in Cancer)
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38 pages, 1760 KiB  
Review
Current Approaches for Combination Therapy of Cancer: The Role of Immunogenic Cell Death
by Zahra Asadzadeh, Elham Safarzadeh, Sahar Safaei, Ali Baradaran, Ali Mohammadi, Khalil Hajiasgharzadeh, Afshin Derakhshani, Antonella Argentiero, Nicola Silvestris and Behzad Baradaran
Cancers 2020, 12(4), 1047; https://doi.org/10.3390/cancers12041047 - 23 Apr 2020
Cited by 164 | Viewed by 9596
Abstract
Cell death resistance is a key feature of tumor cells. One of the main anticancer therapies is increasing the susceptibility of cells to death. Cancer cells have developed a capability of tumor immune escape. Hence, restoring the immunogenicity of cancer cells can be [...] Read more.
Cell death resistance is a key feature of tumor cells. One of the main anticancer therapies is increasing the susceptibility of cells to death. Cancer cells have developed a capability of tumor immune escape. Hence, restoring the immunogenicity of cancer cells can be suggested as an effective approach against cancer. Accumulating evidence proposes that several anticancer agents provoke the release of danger-associated molecular patterns (DAMPs) that are determinants of immunogenicity and stimulate immunogenic cell death (ICD). It has been suggested that ICD inducers are two different types according to their various activities. Here, we review the well-characterized DAMPs and focus on the different types of ICD inducers and recent combination therapies that can augment the immunogenicity of cancer cells. Full article
(This article belongs to the Special Issue Immunogenic Cell Death and Immunotherapy in Cancers)
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20 pages, 1530 KiB  
Review
Targeting Aldehyde Dehydrogenases to Eliminate Cancer Stem Cells in Gynecologic Malignancies
by Vaishnavi Muralikrishnan, Thomas D. Hurley and Kenneth P. Nephew
Cancers 2020, 12(4), 961; https://doi.org/10.3390/cancers12040961 - 13 Apr 2020
Cited by 38 | Viewed by 8382
Abstract
Gynecologic cancers cause over 600,000 deaths annually in women worldwide. The development of chemoresistance after initial rounds of chemotherapy contributes to tumor relapse and death due to gynecologic malignancies. In this regard, cancer stem cells (CSCs), a subpopulation of stem cells with the [...] Read more.
Gynecologic cancers cause over 600,000 deaths annually in women worldwide. The development of chemoresistance after initial rounds of chemotherapy contributes to tumor relapse and death due to gynecologic malignancies. In this regard, cancer stem cells (CSCs), a subpopulation of stem cells with the ability to undergo self-renewal and clonal evolution, play a key role in tumor progression and drug resistance. Aldehyde dehydrogenases (ALDH) are a group of enzymes shown to be robust CSC markers in gynecologic and other malignancies. These enzymes also play functional roles in CSCs, including detoxification of aldehydes, scavenging of reactive oxygen species (ROS), and retinoic acid (RA) signaling, making ALDH an attractive therapeutic target in various clinical scenarios. In this review, we discuss the critical roles of the ALDH in driving stemness in different gynecologic malignancies. We review inhibitors of ALDH, both general and isoform-specific, which have been used to target CSCs in gynecologic cancers. Many of these inhibitors have been shown to be effective in preclinical models of gynecologic malignancies, supporting further development in the clinic. Furthermore, ALDH inhibitors, including 673A and CM037, synergize with chemotherapy to reduce tumor growth. Thus, ALDH-targeted therapies hold promise for improving patient outcomes in gynecologic malignancies. Full article
(This article belongs to the Special Issue Cancer Stem Cells and Personalized Medicine for Gynecologic Cancers)
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28 pages, 1355 KiB  
Review
Glioblastoma: Pathogenesis and Current Status of Chemotherapy and Other Novel Treatments
by Vilashini Rajaratnam, Mohammad Mohiminul Islam, Maixee Yang, Rachel Slaby, Hilda Martinez Ramirez and Shama Parveen Mirza
Cancers 2020, 12(4), 937; https://doi.org/10.3390/cancers12040937 - 10 Apr 2020
Cited by 86 | Viewed by 10791
Abstract
Glioblastoma is one of the most common and detrimental forms of solid brain tumor, with over 10,000 new cases reported every year in the United States. Despite aggressive multimodal treatment approaches, the overall survival period is reported to be less than 15 months [...] Read more.
Glioblastoma is one of the most common and detrimental forms of solid brain tumor, with over 10,000 new cases reported every year in the United States. Despite aggressive multimodal treatment approaches, the overall survival period is reported to be less than 15 months after diagnosis. A widely used approach for the treatment of glioblastoma is surgical removal of the tumor, followed by radiotherapy and chemotherapy. While there are several drugs available that are approved by the Food and Drug Administration (FDA), significant efforts have been made in recent years to develop new chemotherapeutic agents for the treatment of glioblastoma. This review describes the molecular targets and pathogenesis as well as the current progress in chemotherapeutic development and other novel therapies in the clinical setting for the treatment of glioblastoma. Full article
(This article belongs to the Special Issue Tumors of the Central Nervous System: An Update)
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31 pages, 2085 KiB  
Review
Metabolic Heterogeneity of Cancer Cells: An Interplay between HIF-1, GLUTs, and AMPK
by Nurbubu T. Moldogazieva, Innokenty M. Mokhosoev and Alexander A. Terentiev
Cancers 2020, 12(4), 862; https://doi.org/10.3390/cancers12040862 - 2 Apr 2020
Cited by 100 | Viewed by 16387
Abstract
It has been long recognized that cancer cells reprogram their metabolism under hypoxia conditions due to a shift from oxidative phosphorylation (OXPHOS) to glycolysis in order to meet elevated requirements in energy and nutrients for proliferation, migration, and survival. However, data accumulated over [...] Read more.
It has been long recognized that cancer cells reprogram their metabolism under hypoxia conditions due to a shift from oxidative phosphorylation (OXPHOS) to glycolysis in order to meet elevated requirements in energy and nutrients for proliferation, migration, and survival. However, data accumulated over recent years has increasingly provided evidence that cancer cells can revert from glycolysis to OXPHOS and maintain both reprogrammed and oxidative metabolism, even in the same tumor. This phenomenon, denoted as cancer cell metabolic plasticity or hybrid metabolism, depends on a tumor micro-environment that is highly heterogeneous and influenced by an intensity of vasculature and blood flow, oxygen concentration, and nutrient and energy supply, and requires regulatory interplay between multiple oncogenes, transcription factors, growth factors, and reactive oxygen species (ROS), among others. Hypoxia-inducible factor-1 (HIF-1) and AMP-activated protein kinase (AMPK) represent key modulators of a switch between reprogrammed and oxidative metabolism. The present review focuses on cross-talks between HIF-1, glucose transporters (GLUTs), and AMPK with other regulatory proteins including oncogenes such as c-Myc, p53, and KRAS; growth factor-initiated protein kinase B (PKB)/Akt, phosphatidyl-3-kinase (PI3K), and mTOR signaling pathways; and tumor suppressors such as liver kinase B1 (LKB1) and TSC1 in controlling cancer cell metabolism. The multiple switches between metabolic pathways can underlie chemo-resistance to conventional anti-cancer therapy and should be taken into account in choosing molecular targets to discover novel anti-cancer drugs. Full article
(This article belongs to the Special Issue Metabolic Pathways and Redox Homeostasis in Cancer)
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38 pages, 550 KiB  
Review
Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy
by Tareq Saleh, Sarah Bloukh, Valerie J. Carpenter, Enas Alwohoush, Jomana Bakeer, Sarah Darwish, Belal Azab and David A. Gewirtz
Cancers 2020, 12(4), 822; https://doi.org/10.3390/cancers12040822 - 29 Mar 2020
Cited by 172 | Viewed by 13992
Abstract
For the past two decades, cellular senescence has been recognized as a central component of the tumor cell response to chemotherapy and radiation. Traditionally, this form of senescence, termed Therapy-Induced Senescence (TIS), was linked to extensive nuclear damage precipitated by classical genotoxic chemotherapy. [...] Read more.
For the past two decades, cellular senescence has been recognized as a central component of the tumor cell response to chemotherapy and radiation. Traditionally, this form of senescence, termed Therapy-Induced Senescence (TIS), was linked to extensive nuclear damage precipitated by classical genotoxic chemotherapy. However, a number of other forms of therapy have also been shown to induce senescence in tumor cells independently of direct genomic damage. This review attempts to provide a comprehensive summary of both conventional and targeted anticancer therapeutics that have been shown to induce senescence in vitro and in vivo. Still, the utility of promoting senescence as a therapeutic endpoint remains under debate. Since senescence represents a durable form of growth arrest, it might be argued that senescence is a desirable outcome of cancer therapy. However, accumulating evidence suggesting that cells have the capacity to escape from TIS would support an alternative conclusion, that senescence provides an avenue whereby tumor cells can evade the potentially lethal action of anticancer drugs, allowing the cells to enter a temporary state of dormancy that eventually facilitates disease recurrence, often in a more aggressive state. Furthermore, TIS is now strongly connected to tumor cell remodeling, potentially to tumor dormancy, acquiring more ominous malignant phenotypes and accounts for several untoward adverse effects of cancer therapy. Here, we argue that senescence represents a barrier to effective anticancer treatment, and discuss the emerging efforts to identify and exploit agents with senolytic properties as a strategy for elimination of the persistent residual surviving tumor cell population, with the goal of mitigating the tumor-promoting influence of the senescent cells and to thereby reduce the likelihood of cancer relapse. Full article
(This article belongs to the Special Issue Senescence and Cancer)
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25 pages, 358 KiB  
Review
Early Triple Negative Breast Cancer: Conventional Treatment and Emerging Therapeutic Landscapes
by Anna Diana, Francesca Carlino, Elisena Franzese, Olga Oikonomidou, Carmen Criscitiello, Ferdinando De Vita, Fortunato Ciardiello and Michele Orditura
Cancers 2020, 12(4), 819; https://doi.org/10.3390/cancers12040819 - 29 Mar 2020
Cited by 59 | Viewed by 7783
Abstract
Triple negative breast cancers (TNBCs) are characterized by worse prognosis, higher propensity to earlier metastases, and shorter survival after recurrence compared with other breast cancer subtypes. Anthracycline- and taxane-based chemotherapy is still the mainstay of treatment in early stages, although several escalation approaches [...] Read more.
Triple negative breast cancers (TNBCs) are characterized by worse prognosis, higher propensity to earlier metastases, and shorter survival after recurrence compared with other breast cancer subtypes. Anthracycline- and taxane-based chemotherapy is still the mainstay of treatment in early stages, although several escalation approaches have been evaluated to improve survival outcomes. The addition of platinum salts to standard neoadjuvant chemotherapy (NACT) remains controversial due to the lack of clear survival advantage, and the use of adjuvant capecitabine represents a valid treatment option in TNBC patients with residual disease after NACT. Recently, several clinical trials showed promising results through the use of poly ADP-ribose polymerase (PARP) inhibitors and by incorporating immunotherapy with chemotherapy, enriching treatment options beyond conventional cytotoxic agents. In this review, we provided an overview on the current standard of care and a comprehensive update of the recent advances in the management of early stage TNBC and focused on the latest emerging biomarkers and their clinical application to select the best therapeutic strategy in this hard-to-treat population. Full article
(This article belongs to the Special Issue Triple-Negative Breast Cancer: Molecular Characteristics, Treatment Challenges and Solutions)
15 pages, 293 KiB  
Review
Recent Advances in Immunotherapy for Hepatocellular Carcinoma
by Shigeharu Nakano, Yuji Eso, Hirokazu Okada, Atsushi Takai, Ken Takahashi and Hiroshi Seno
Cancers 2020, 12(4), 775; https://doi.org/10.3390/cancers12040775 - 25 Mar 2020
Cited by 61 | Viewed by 6555
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death since most patients are diagnosed at advanced stage and the current systemic treatment options using molecular-targeted drugs remain unsatisfactory. However, the recent success of cancer immunotherapies has revolutionized the landscape of [...] Read more.
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death since most patients are diagnosed at advanced stage and the current systemic treatment options using molecular-targeted drugs remain unsatisfactory. However, the recent success of cancer immunotherapies has revolutionized the landscape of cancer therapy. Since HCC is characterized by metachronous multicentric occurrence, immunotherapies that induce systemic and durable responses could be an appealing treatment option. Despite the suppressive milieu of the liver and tumor immunosurveillance escape mechanisms, clinical studies of checkpoint inhibitors in patients with advanced HCC have yielded promising results. Here, we provide an update on recent advances in HCC immunotherapies. First, we describe the unique tolerogenic properties of hepatic immunity and its interaction with HCC and then review the status of already or nearly available immune checkpoint blockade-based therapies as well as other immunotherapy strategies at the preclinical or clinical trial stage. Full article
(This article belongs to the Special Issue Immunotherapy in Hepatocellular Carcinoma)
27 pages, 1353 KiB  
Review
The Emerging Roles of RNA Modifications in Glioblastoma
by Zhen Dong and Hongjuan Cui
Cancers 2020, 12(3), 736; https://doi.org/10.3390/cancers12030736 - 20 Mar 2020
Cited by 88 | Viewed by 8650
Abstract
Glioblastoma (GBM) is a grade IV glioma that is the most malignant brain tumor type. Currently, there are no effective and sufficient therapeutic strategies for its treatment because its pathological mechanism is not fully characterized. With the fast development of the Next Generation [...] Read more.
Glioblastoma (GBM) is a grade IV glioma that is the most malignant brain tumor type. Currently, there are no effective and sufficient therapeutic strategies for its treatment because its pathological mechanism is not fully characterized. With the fast development of the Next Generation Sequencing (NGS) technology, more than 170 kinds of covalent ribonucleic acid (RNA) modifications are found to be extensively present in almost all living organisms and all kinds of RNAs, including ribosomal RNAs (rRNAs), transfer RNAs (tRNAs) and messenger RNAs (mRNAs). RNA modifications are also emerging as important modulators in the regulation of biological processes and pathological progression, and study of the epi-transcriptome has been a new area for researchers to explore their connections with the initiation and progression of cancers. Recently, RNA modifications, especially m6A, and their RNA-modifying proteins (RMPs) such as methyltransferase like 3 (METTL3) and α-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5), have also emerged as important epigenetic mechanisms for the aggressiveness and malignancy of GBM, especially the pluripotency of glioma stem-like cells (GSCs). Although the current study is just the tip of an iceberg, these new evidences will provide new insights for possible GBM treatments. In this review, we summarize the recent studies about RNA modifications, such as N6-methyladenosine (m6A), N6,2′O-dimethyladenosine (m6Am), 5-methylcytosine (m5C), N1-methyladenosine (m1A), inosine (I) and pseudouridine (ψ) as well as the corresponding RMPs including the writers, erasers and readers that participate in the tumorigenesis and development of GBM, so as to provide some clues for GBM treatment. Full article
(This article belongs to the Special Issue Brain Tumors)
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17 pages, 1030 KiB  
Review
Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy
by Charles Pottier, Margaux Fresnais, Marie Gilon, Guy Jérusalem, Rémi Longuespée and Nor Eddine Sounni
Cancers 2020, 12(3), 731; https://doi.org/10.3390/cancers12030731 - 20 Mar 2020
Cited by 274 | Viewed by 20726
Abstract
Receptor tyrosine kinases (RTKs) are key regulatory signaling proteins governing cancer cell growth and metastasis. During the last two decades, several molecules targeting RTKs were used in oncology as a first or second line therapy in different types of cancer. However, their effectiveness [...] Read more.
Receptor tyrosine kinases (RTKs) are key regulatory signaling proteins governing cancer cell growth and metastasis. During the last two decades, several molecules targeting RTKs were used in oncology as a first or second line therapy in different types of cancer. However, their effectiveness is limited by the appearance of resistance or adverse effects. In this review, we summarize the main features of RTKs and their inhibitors (RTKIs), their current use in oncology, and mechanisms of resistance. We also describe the technological advances of artificial intelligence, chemoproteomics, and microfluidics in elaborating powerful strategies that could be used in providing more efficient and selective small molecules inhibitors of RTKs. Finally, we discuss the interest of therapeutic combination of different RTKIs or with other molecules for personalized treatments, and the challenge for effective combination with less toxic and off-target effects. Full article
(This article belongs to the Special Issue Non-canonical Kinases and Substrates in Cancer Progression)
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26 pages, 704 KiB  
Review
The Cancer Stem Cell in Hepatocellular Carcinoma
by Lucas-Alexander Schulte, Juan Carlos López-Gil, Bruno Sainz, Jr. and Patrick C. Hermann
Cancers 2020, 12(3), 684; https://doi.org/10.3390/cancers12030684 - 14 Mar 2020
Cited by 38 | Viewed by 6368
Abstract
The recognition of intra-tumoral cellular heterogeneity has given way to the concept of the cancer stem cell (CSC). According to this concept, CSCs are able to self-renew and differentiate into all of the cancer cell lineages present within the tumor, placing the CSC [...] Read more.
The recognition of intra-tumoral cellular heterogeneity has given way to the concept of the cancer stem cell (CSC). According to this concept, CSCs are able to self-renew and differentiate into all of the cancer cell lineages present within the tumor, placing the CSC at the top of a hierarchical tree. The observation that these cells—in contrast to bulk tumor cells—are able to exclusively initiate new tumors, initiate metastatic spread and resist chemotherapy implies that CSCs are solely responsible for tumor recurrence and should be therapeutically targeted. Toward this end, dissecting and understanding the biology of CSCs should translate into new clinical therapeutic approaches. In this article, we review the CSC concept in cancer, with a special focus on hepatocellular carcinoma. Full article
(This article belongs to the Special Issue Liver Cancer and Potential Therapeutic Targets)
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13 pages, 1601 KiB  
Review
ATM-Deficient Cancers Provide New Opportunities for Precision Oncology
by Nicholas R. Jette, Mehul Kumar, Suraj Radhamani, Greydon Arthur, Siddhartha Goutam, Steven Yip, Michael Kolinsky, Gareth J. Williams, Pinaki Bose and Susan P. Lees-Miller
Cancers 2020, 12(3), 687; https://doi.org/10.3390/cancers12030687 - 14 Mar 2020
Cited by 78 | Viewed by 8462
Abstract
Poly-ADP ribose polymerase (PARP) inhibitors are currently used in the treatment of several cancers carrying mutations in the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2, with many more potential applications under study and in clinical trials. Here, we discuss the [...] Read more.
Poly-ADP ribose polymerase (PARP) inhibitors are currently used in the treatment of several cancers carrying mutations in the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2, with many more potential applications under study and in clinical trials. Here, we discuss the potential for extending PARP inhibitor therapies to tumours with deficiencies in the DNA damage-activated protein kinase, Ataxia-Telangiectasia Mutated (ATM). We highlight our recent findings that PARP inhibition alone is cytostatic but not cytotoxic in ATM-deficient cancer cells and that the combination of a PARP inhibitor with an ATR (ATM, Rad3-related) inhibitor is required to induce cell death. Full article
(This article belongs to the Special Issue PARPs, PAR and NAD Metabolism and Their Inhibitors in Cancer)
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16 pages, 1905 KiB  
Article
Characterization of Human NK Cell-Derived Exosomes: Role of DNAM1 Receptor in Exosome-Mediated Cytotoxicity against Tumor
by Anna Laura Di Pace, Nicola Tumino, Francesca Besi, Claudia Alicata, Libenzio Adrian Conti, Enrico Munari, Enrico Maggi, Paola Vacca and Lorenzo Moretta
Cancers 2020, 12(3), 661; https://doi.org/10.3390/cancers12030661 - 12 Mar 2020
Cited by 103 | Viewed by 8122
Abstract
Despite the pivotal role of natural killer (NK) cells in defenses against tumors, their exploitation in cancer treatment is still limited due to their reduced ability to reaching tumor sites and the inhibitory effects of tumor microenvironment (TME) on their function. In this [...] Read more.
Despite the pivotal role of natural killer (NK) cells in defenses against tumors, their exploitation in cancer treatment is still limited due to their reduced ability to reaching tumor sites and the inhibitory effects of tumor microenvironment (TME) on their function. In this study, we have characterized the exosomes from IL2- or IL15-cultured human NK cells. Both cytokines induced comparable amounts of exosomes with similar cargo composition. Analysis of molecules contained within or exposed at the exosome surface, allowed the identification of molecules playing important roles in the NK cell function including IFN-γ, Lymphocyte Function-Associated Antigen (LFA-1), DNAX Accessory Molecule-1 (DNAM1) and Programmed Cell Death Protein (PD-1). Importantly, we show that DNAM1 is involved in exosome-mediated cytotoxicity as revealed by experiments using blocking antibodies to DNAM1 or DNAM1 ligands. In addition, antibody-mediated inhibition of exosome cytotoxicity results in a delay in target cell apoptosis. We also provide evidence that NK-exosomes may exert their cytolytic activity after short time interval and even at low concentrations. Regarding their possible use in immunotherapy, NK exosomes, detectable in peripheral blood, can diffuse into tissues and exert their cytolytic effect at tumor sites. This property offers a clue to integrate cancer treatments with NK exosomes. Full article
(This article belongs to the Special Issue Targeting Innate Immunity Cells in Cancer)
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23 pages, 1368 KiB  
Review
Inflammatory Mechanisms of HCC Development
by Maria Grazia Refolo, Caterina Messa, Vito Guerra, Brian Irving Carr and Rosalba D’Alessandro
Cancers 2020, 12(3), 641; https://doi.org/10.3390/cancers12030641 - 10 Mar 2020
Cited by 112 | Viewed by 10869
Abstract
HCC (hepatocellular carcinoma) is the second leading cause of cancer deaths worldwide, with several etiologic causes, mostly inflammation-associated. Different inflammatory responses in the liver can be triggered by different etiological agents. The inflammatory process can be resolved or be persistent, depending on the [...] Read more.
HCC (hepatocellular carcinoma) is the second leading cause of cancer deaths worldwide, with several etiologic causes, mostly inflammation-associated. Different inflammatory responses in the liver can be triggered by different etiological agents. The inflammatory process can be resolved or be persistent, depending on the etiology and multiple other factors. Chronic inflammation, tissue remodeling, genetic alterations, and modifications in cellular signaling are considered to be key processes promoting immunosuppression. The progressive immunosuppression leads to the inactivation of anti-tumor immunity involved in HCC carcinogenesis and progression. Tumor cellular processes including DNA damage, necrosis, and ER (endoplasmic reticulum) stress can affect both immune-surveillance and cancer-promoting inflammation, supporting a mutual interdependence. Here, we review the current understanding of how chronic liver injury and inflammation is triggered and sustained, and how inflammation is linked to HCC. The identification of many hepatic microenvironmental inflammatory processes and their effector molecules, has resulted in extensive translational work and promising clinical trials of new immunomodulatory agents. Full article
(This article belongs to the Special Issue Liver Cancer and Potential Therapeutic Targets)
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19 pages, 782 KiB  
Review
The Application of Deep Learning in Cancer Prognosis Prediction
by Wan Zhu, Longxiang Xie, Jianye Han and Xiangqian Guo
Cancers 2020, 12(3), 603; https://doi.org/10.3390/cancers12030603 - 5 Mar 2020
Cited by 217 | Viewed by 23442
Abstract
Deep learning has been applied to many areas in health care, including imaging diagnosis, digital pathology, prediction of hospital admission, drug design, classification of cancer and stromal cells, doctor assistance, etc. Cancer prognosis is to estimate the fate of cancer, probabilities of cancer [...] Read more.
Deep learning has been applied to many areas in health care, including imaging diagnosis, digital pathology, prediction of hospital admission, drug design, classification of cancer and stromal cells, doctor assistance, etc. Cancer prognosis is to estimate the fate of cancer, probabilities of cancer recurrence and progression, and to provide survival estimation to the patients. The accuracy of cancer prognosis prediction will greatly benefit clinical management of cancer patients. The improvement of biomedical translational research and the application of advanced statistical analysis and machine learning methods are the driving forces to improve cancer prognosis prediction. Recent years, there is a significant increase of computational power and rapid advancement in the technology of artificial intelligence, particularly in deep learning. In addition, the cost reduction in large scale next-generation sequencing, and the availability of such data through open source databases (e.g., TCGA and GEO databases) offer us opportunities to possibly build more powerful and accurate models to predict cancer prognosis more accurately. In this review, we reviewed the most recent published works that used deep learning to build models for cancer prognosis prediction. Deep learning has been suggested to be a more generic model, requires less data engineering, and achieves more accurate prediction when working with large amounts of data. The application of deep learning in cancer prognosis has been shown to be equivalent or better than current approaches, such as Cox-PH. With the burst of multi-omics data, including genomics data, transcriptomics data and clinical information in cancer studies, we believe that deep learning would potentially improve cancer prognosis. Full article
(This article belongs to the Collection Application of Bioinformatics in Cancers)
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29 pages, 3529 KiB  
Review
Telomeres and Telomere Length: A General Overview
by Nalini Srinivas, Sivaramakrishna Rachakonda and Rajiv Kumar
Cancers 2020, 12(3), 558; https://doi.org/10.3390/cancers12030558 - 28 Feb 2020
Cited by 157 | Viewed by 19097
Abstract
Telomeres are highly conserved tandem nucleotide repeats that include proximal double-stranded and distal single-stranded regions that in complex with shelterin proteins afford protection at chromosomal ends to maintain genomic integrity. Due to the inherent limitations of DNA replication and telomerase suppression in most [...] Read more.
Telomeres are highly conserved tandem nucleotide repeats that include proximal double-stranded and distal single-stranded regions that in complex with shelterin proteins afford protection at chromosomal ends to maintain genomic integrity. Due to the inherent limitations of DNA replication and telomerase suppression in most somatic cells, telomeres undergo age-dependent incremental attrition. Short or dysfunctional telomeres are recognized as DNA double-stranded breaks, triggering cells to undergo replicative senescence. Telomere shortening, therefore, acts as a counting mechanism that drives replicative senescence by limiting the mitotic potential of cells. Telomere length, a complex hereditary trait, is associated with aging and age-related diseases. Epidemiological data, in general, support an association with varying magnitudes between constitutive telomere length and several disorders, including cancers. Telomere attrition is also influenced by oxidative damage and replicative stress caused by genetic, epigenetic, and environmental factors. Several single nucleotide polymorphisms at different loci, identified through genome-wide association studies, influence inter-individual variation in telomere length. In addition to genetic factors, environmental factors also influence telomere length during growth and development. Telomeres hold potential as biomarkers that reflect the genetic predisposition together with the impact of environmental conditions and as targets for anti-cancer therapies. Full article
(This article belongs to the Special Issue The Role of Telomeres and Telomerase in Cancer)
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11 pages, 1668 KiB  
Review
Association of Steroids Use with Survival in Patients Treated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis
by Fausto Petrelli, Diego Signorelli, Michele Ghidini, Antonio Ghidini, Elio Gregory Pizzutilo, Lorenzo Ruggieri, Mary Cabiddu, Karen Borgonovo, Giuseppina Dognini, Matteo Brighenti, Alessandro De Toma, Erika Rijavec, Marina Chiara Garassino, Francesco Grossi and Gianluca Tomasello
Cancers 2020, 12(3), 546; https://doi.org/10.3390/cancers12030546 - 27 Feb 2020
Cited by 192 | Viewed by 8829
Abstract
Immune checkpoint inhibitors (ICIs) can elicit toxicities by inhibiting negative regulators of adaptive immunity. Sometimes, management of toxicities may require systemic glucocorticoids. We performed a systematic review and meta-analysis of published studies to evaluate the correlation between steroids use, overall survival (OS), and [...] Read more.
Immune checkpoint inhibitors (ICIs) can elicit toxicities by inhibiting negative regulators of adaptive immunity. Sometimes, management of toxicities may require systemic glucocorticoids. We performed a systematic review and meta-analysis of published studies to evaluate the correlation between steroids use, overall survival (OS), and progression-free survival (PFS) in cancer patients treated with ICIs. Publications that compared steroids with non-steroid users in cancer patients treated with ICIs from inception to June 2019 were identified by searching the EMBASE, PubMed, SCOPUS, Web of Science, and Cochrane Library databases. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Patients (studies, n = 16; patients, n = 4045) taking steroids were at increased risk of death and progression compared to those not taking steroids (HR = 1.54, 95% CI: 1.24–1.91; p = 0.01 and HR = 1.34, 95% CI: 1.02–1.76; p = 0.03, respectively). The main negative effect on OS was associated with patients taking steroids for supportive care (HR = 2.5, 95% CI 1.41–4.43; p < 0.01) or brain metastases (HR = 1.51, 95% CI 1.22–1.87; p < 0.01). In contrast, steroids used to mitigate adverse events did not negatively affect OS. In conclusion, caution is needed when steroids are used for symptom control. In these patients, a negative impact of steroid use was observed for both OS and PFS. Full article
(This article belongs to the Collection Mechanism of Immunotherapy in Cancers)
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44 pages, 1351 KiB  
Review
Current Advances in the Treatment of BRAF-Mutant Melanoma
by Hima Patel, Nour Yacoub, Rosalin Mishra, Aaron White, Long Yuan, Samar Alanazi and Joan T. Garrett
Cancers 2020, 12(2), 482; https://doi.org/10.3390/cancers12020482 - 19 Feb 2020
Cited by 121 | Viewed by 12937
Abstract
Melanoma is the most lethal form of skin cancer. Melanoma is usually curable with surgery if detected early, however, treatment options for patients with metastatic melanoma are limited and the five-year survival rate for metastatic melanoma had been 15–20% before the advent of [...] Read more.
Melanoma is the most lethal form of skin cancer. Melanoma is usually curable with surgery if detected early, however, treatment options for patients with metastatic melanoma are limited and the five-year survival rate for metastatic melanoma had been 15–20% before the advent of immunotherapy. Treatment with immune checkpoint inhibitors has increased long-term survival outcomes in patients with advanced melanoma to as high as 50% although individual response can vary greatly. A mutation within the MAPK pathway leads to uncontrollable growth and ultimately develops into cancer. The most common driver mutation that leads to this characteristic overactivation in the MAPK pathway is the B-RAF mutation. Current combinations of BRAF and MEK inhibitors that have demonstrated improved patient outcomes include dabrafenib with trametinib, vemurafenib with cobimetinib or encorafenib with binimetinib. Treatment with BRAF and MEK inhibitors has met challenges as patient responses began to drop due to the development of resistance to these inhibitors which paved the way for development of immunotherapies and other small molecule inhibitor approaches to address this. Resistance to these inhibitors continues to push the need to expand our understanding of novel mechanisms of resistance associated with treatment therapies. This review focuses on the current landscape of how resistance occurs with the chronic use of BRAF and MEK inhibitors in BRAF-mutant melanoma and progress made in the fields of immunotherapies and other small molecules when used alone or in combination with BRAF and MEK inhibitors to delay or circumvent the onset of resistance for patients with stage III/IV BRAF mutant melanoma. Full article
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18 pages, 2015 KiB  
Article
Predictive Value of Soluble PD-1, PD-L1, VEGFA, CD40 Ligand and CD44 for Nivolumab Therapy in Advanced Non-Small Cell Lung Cancer: A Case-Control Study
by Manuela Tiako Meyo, Anne Jouinot, Etienne Giroux-Leprieur, Elizabeth Fabre, Marie Wislez, Marco Alifano, Karen Leroy, Pascaline Boudou-Rouquette, Camille Tlemsani, Nihel Khoudour, Jennifer Arrondeau, Audrey Thomas-Schoemann, Hélène Blons, Audrey Mansuet-Lupo, Diane Damotte, Michel Vidal, François Goldwasser, Jérôme Alexandre and Benoit Blanchet
Cancers 2020, 12(2), 473; https://doi.org/10.3390/cancers12020473 - 18 Feb 2020
Cited by 82 | Viewed by 5110
Abstract
A large interindividual variability has been observed in anti Programmed cell Death 1 (anti-PD1) therapies efficacy. The aim of this study is to assess the correlation of soluble PD-1 (sPD-1), soluble Programmed cell Death Ligand 1 (sPD-L1), Vascular Endothelial Growth Factor A (VEGFA), [...] Read more.
A large interindividual variability has been observed in anti Programmed cell Death 1 (anti-PD1) therapies efficacy. The aim of this study is to assess the correlation of soluble PD-1 (sPD-1), soluble Programmed cell Death Ligand 1 (sPD-L1), Vascular Endothelial Growth Factor A (VEGFA), soluble CD40 ligand (sCD40L) and soluble CD44 (sCD44), with survival in nivolumab-treated metastatic non-small cell lung cancer (NSCLC) patients. Plasma biomarkers were assayed at baseline and after two cycles of nivolumab. A cut-off of positivity for sPD-1, sPD-L1 and sCD40L expressions was defined as a plasma level above the lower limit of quantification. Baseline sPD-1 and sPD-L1 levels were subsequently analyzed in a control group of EGFR-mutated (Epidermal Growth Factor Receptor) NSCLC patients. Association between survival and biomarkers was investigated using Cox proportional hazard regression model. Eighty-seven patients were included (51 nivolumab-treated patients, 36 in EGFR-mutated group). In nivolumab group, baseline sPD-1, sPD-L1 and sCD40L were positive for 15(29.4%), 27(52.9%) and 18(50%) patients, respectively. We defined a composite criteria (sCombo) corresponding to sPD-1 and/or sPD-L1 positivity for each patient. In nivolumab group, baseline sCombo positivity was associated with shorter median progression-free survival (PFS) (78 days 95%CI (55–109) vs. 658 days (222-not reached); HR: 4.12 (1.95–8.71), p = 0.0002) and OS (HR: 3.99(1.63–9.80), p = 0.003). In multivariate analysis, baseline sCombo independently correlated with PFS (HR: 2.66 (1.17–6.08), p = 0.02) but not OS. In EGFR-mutated group, all patients were baseline sCombo positive; therefore this factor was not associated with survival. After two cycles of nivolumab, an increased or stable sPD-1 level independently correlated with longer PFS (HR: 0.49, 95%CI (0.30–0.80), p = 0.004) and OS (HR: 0.39, 95%CI (0.21–0.71), p = 0.002). VEGFA, sCD40L and sCD44 did not correlate with survival. We propose a composite biomarker using sPD-1and sPDL-1 to predict nivolumab efficacy in NSCLC patients. A larger validation study is warranted. Full article
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18 pages, 6010 KiB  
Article
Venetoclax, a BCL-2 Inhibitor, Enhances the Efficacy of Chemotherapeutic Agents in Wild-Type ABCG2-Overexpression-Mediated MDR Cancer Cells
by Jing-Quan Wang, Jonathan Y. Li, Qiu-Xu Teng, Zi-Ning Lei, Ning Ji, Qingbin Cui, Leli Zeng, Yihang Pan, Dong-Hua Yang and Zhe-Sheng Chen
Cancers 2020, 12(2), 466; https://doi.org/10.3390/cancers12020466 - 18 Feb 2020
Cited by 42 | Viewed by 5456
Abstract
Previous studies have shown that small-molecule BCL-2 inhibitors can have a synergistic interaction with ABCG2 substrates in chemotherapy. Venetoclax is a potent and selective BCL-2 inhibitor, approved by the FDA in 2016 for the treatment of patients with chronic lymphocytic leukemia (CLL). This [...] Read more.
Previous studies have shown that small-molecule BCL-2 inhibitors can have a synergistic interaction with ABCG2 substrates in chemotherapy. Venetoclax is a potent and selective BCL-2 inhibitor, approved by the FDA in 2016 for the treatment of patients with chronic lymphocytic leukemia (CLL). This study showed that, at a non-toxic concentration, venetoclax at 10 µM significantly reversed multidrug resistance (MDR) mediated by wild-type ABCG2, without significantly affecting MDR mediated by mutated ABCG2 (R482G and R482T) and ABCB1, while moderate or no reversal effects were observed at lower concentrations (0.5 to 1 µM). The results showed that venetoclax increased the intracellular accumulation of chemotherapeutic agents, which was the result of directly blocking the wild-type ABCG2 efflux function and inhibiting the ATPase activity of ABCG2. Our study demonstrated that venetoclax potentiates the efficacy of wild-type ABCG2 substrate drugs. These findings may provide useful guidance in combination therapy against wild-type ABCG2-mediated MDR cancer in clinical practice. Full article
(This article belongs to the Special Issue The Role of Drug Resistance-Associated Proteins in Cancer: from Conventional Anticancer Drugs to Targeting Drugs)
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13 pages, 1333 KiB  
Article
Multicenter External Validation of the Liverpool Uveal Melanoma Prognosticator Online: An OOG Collaborative Study
by Alda Cunha Rola, Azzam Taktak, Antonio Eleuteri, Helen Kalirai, Heinrich Heimann, Rumana Hussain, Laura J. Bonnett, Christopher J. Hill, Matthew Traynor, Martine J. Jager, Marina Marinkovic, Gregorius P.M. Luyten, Mehmet Dogrusöz, Emine Kilic, Annelies de Klein, Kyra Smit, Natasha M van Poppelen, Bertil E. Damato, Armin Afshar, Rudolf F. Guthoff, Björn O. Scheef, Vinodh Kakkassery, Svetlana Saakyan, Alexander Tsygankov, Carlo Mosci, Paolo Ligorio, Silvia Viaggi, Claudia H.D. Le Guin, Norbert Bornfeld, Nikolaos E. Bechrakis and Sarah E. Couplandadd Show full author list remove Hide full author list
Cancers 2020, 12(2), 477; https://doi.org/10.3390/cancers12020477 - 18 Feb 2020
Cited by 32 | Viewed by 4317
Abstract
Uveal melanoma (UM) is fatal in ~50% of patients as a result of disseminated disease. This study aims to externally validate the Liverpool Uveal Melanoma Prognosticator Online V3 (LUMPO3) to determine its reliability in predicting survival after treatment for choroidal melanoma when utilizing [...] Read more.
Uveal melanoma (UM) is fatal in ~50% of patients as a result of disseminated disease. This study aims to externally validate the Liverpool Uveal Melanoma Prognosticator Online V3 (LUMPO3) to determine its reliability in predicting survival after treatment for choroidal melanoma when utilizing external data from other ocular oncology centers. Anonymized data of 1836 UM patients from seven international ocular oncology centers were analyzed with LUMPO3 to predict the 10-year survival for each patient in each external dataset. The analysts were masked to the patient outcomes. Model predictions were sent to an independent statistician to evaluate LUMPO3’s performance using discrimination and calibration methods. LUMPO3’s ability to discriminate between UM patients who died of metastatic UM and those who were still alive was fair-to-good, with C-statistics ranging from 0.64 to 0.85 at year 1. The pooled estimate for all external centers was 0.72 (95% confidence interval: 0.68 to 0.75). Agreement between observed and predicted survival probabilities was generally good given differences in case mix and survival rates between different centers. Despite the differences between the international cohorts of patients with primary UM, LUMPO3 is a valuable tool for predicting all-cause mortality in this disease when using data from external centers. Full article
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19 pages, 1765 KiB  
Article
Extracellular Vesicle microRNAs Contribute to the Osteogenic Inhibition of Mesenchymal Stem Cells in Multiple Myeloma
by Stefania Raimondo, Ornella Urzì, Alice Conigliaro, Giosuè Lo Bosco, Sofia Parisi, Melania Carlisi, Sergio Siragusa, Lavinia Raimondi, Angela De Luca, Gianluca Giavaresi and Riccardo Alessandro
Cancers 2020, 12(2), 449; https://doi.org/10.3390/cancers12020449 - 14 Feb 2020
Cited by 51 | Viewed by 4088
Abstract
Osteolytic bone disease is the major complication associated with the progression of multiple myeloma (MM). Recently, extracellular vesicles (EVs) have emerged as mediators of MM-associated bone disease by inhibiting the osteogenic differentiation of human mesenchymal stem cells (hMSCs). Here, we investigated a correlation [...] Read more.
Osteolytic bone disease is the major complication associated with the progression of multiple myeloma (MM). Recently, extracellular vesicles (EVs) have emerged as mediators of MM-associated bone disease by inhibiting the osteogenic differentiation of human mesenchymal stem cells (hMSCs). Here, we investigated a correlation between the EV-mediated osteogenic inhibition and MM vesicle content, focusing on miRNAs. By the use of a MicroRNA Card, we identified a pool of miRNAs, highly expressed in EVs, from MM cell line (MM1.S EVs), expression of which was confirmed in EVs from bone marrow (BM) plasma of patients affected by smoldering myeloma (SMM) and MM. Notably,we found that miR-129-5p, which targets different osteoblast (OBs) differentiation markers, is enriched in MM-EVs compared to SMM-EVs, thus suggesting a selective packaging correlated with pathological grade. We found that miR-129-5p can be transported to hMSCs by MM-EVs and, by the use of miRNA mimics, we investigated its role in recipient cells. Our data demonstrated that the increase of miR-129-5p levels in hMSCs under osteoblastic differentiation stimuli inhibited the expression of the transcription factor Sp1, previously described as a positive modulator of osteoblastic differentiation, and of its target the Alkaline phosphatase (ALPL), thus identifying miR-129-5p among the players of vesicle-mediated bone disease. Full article
(This article belongs to the Special Issue Recent Advances on the Pathobiology and Treatment of Multiple Myeloma)
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32 pages, 1513 KiB  
Review
Multiple Myeloma: Available Therapies and Causes of Drug Resistance
by Vanessa Pinto, Rui Bergantim, Hugo R. Caires, Hugo Seca, José E. Guimarães and M. Helena Vasconcelos
Cancers 2020, 12(2), 407; https://doi.org/10.3390/cancers12020407 - 10 Feb 2020
Cited by 141 | Viewed by 20529
Abstract
Multiple myeloma (MM) is the second most common blood cancer. Treatments for MM include corticosteroids, alkylating agents, anthracyclines, proteasome inhibitors, immunomodulatory drugs, histone deacetylase inhibitors and monoclonal antibodies. Survival outcomes have improved substantially due to the introduction of many of these drugs allied [...] Read more.
Multiple myeloma (MM) is the second most common blood cancer. Treatments for MM include corticosteroids, alkylating agents, anthracyclines, proteasome inhibitors, immunomodulatory drugs, histone deacetylase inhibitors and monoclonal antibodies. Survival outcomes have improved substantially due to the introduction of many of these drugs allied with their rational use. Nonetheless, MM patients successively relapse after one or more treatment regimens or become refractory, mostly due to drug resistance. This review focuses on the main drugs used in MM treatment and on causes of drug resistance, including cytogenetic, genetic and epigenetic alterations, abnormal drug transport and metabolism, dysregulation of apoptosis, autophagy activation and other intracellular signaling pathways, the presence of cancer stem cells, and the tumor microenvironment. Furthermore, we highlight the areas that need to be further clarified in an attempt to identify novel therapeutic targets to counteract drug resistance in MM patients. Full article
(This article belongs to the Special Issue Latest Development in Multiple Myeloma)
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14 pages, 8111 KiB  
Article
Expression of Tryptophan 2,3-Dioxygenase in Metastatic Uveal Melanoma
by Mizue Terai, Eric Londin, Ankit Rochani, Emma Link, Bao Lam, Gagan Kaushal, Alok Bhushan, Marlana Orloff and Takami Sato
Cancers 2020, 12(2), 405; https://doi.org/10.3390/cancers12020405 - 10 Feb 2020
Cited by 30 | Viewed by 3885
Abstract
Uveal melanoma (UM) is the most common primary eye malignancy in adults and up to 50% of patients subsequently develop systemic metastasis. Metastatic uveal melanoma (MUM) is highly resistant to immunotherapy. One of the mechanisms for resistance would be the immune-suppressive tumor microenvironment. [...] Read more.
Uveal melanoma (UM) is the most common primary eye malignancy in adults and up to 50% of patients subsequently develop systemic metastasis. Metastatic uveal melanoma (MUM) is highly resistant to immunotherapy. One of the mechanisms for resistance would be the immune-suppressive tumor microenvironment. Here, we have investigated the role of tryptophan 2,3-dioxygenase (TDO) in UM. Both TDO and indoleamine 2,3-dioxygenase (IDO) catalyze tryptophan and produce kynurenine, which could cause inhibition of T cell immune responses. We first studied the expression of TDO on tumor tissue specimens obtained from UM hepatic metastasis. High expression of TDO protein was confirmed in all hepatic metastasis. TDO was positive in both normal hepatocytes and the tumor cells with relatively higher expression in tumor cells. On the other hand, IDO protein remained undetectable in all of the MUM specimens. UM cell lines established from metastasis also expressed TDO protein and increasing kynurenine levels were detected in the supernatant of MUM cell culture. In TCGA database, higher TDO2 expression in primary UM significantly correlated to BAP1 mutation and monosomy 3. These results indicate that TDO might be one of the key mechanisms for resistance to immunotherapy in UM. Full article
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16 pages, 1717 KiB  
Review
PARP Inhibitors as Therapeutics: Beyond Modulation of PARylation
by Ahrum Min and Seock-Ah Im
Cancers 2020, 12(2), 394; https://doi.org/10.3390/cancers12020394 - 8 Feb 2020
Cited by 93 | Viewed by 9040
Abstract
Poly (ADP-ribose) polymerase (PARP) 1 is an essential molecule in DNA damage response by sensing DNA damage and docking DNA repair proteins on the damaged DNA site through a type of posttranslational modification, poly (ADP-Ribosyl)ation (PARylation). PARP inhibitors, which inhibit PARylation through competitively [...] Read more.
Poly (ADP-ribose) polymerase (PARP) 1 is an essential molecule in DNA damage response by sensing DNA damage and docking DNA repair proteins on the damaged DNA site through a type of posttranslational modification, poly (ADP-Ribosyl)ation (PARylation). PARP inhibitors, which inhibit PARylation through competitively binding to NAD+ binding site of PARP1 and PARP2, have improved clinical benefits for BRCA mutated tumors, leading to their accelerated clinical application. However, the antitumor activities of PARP inhibitors in clinical development are different, due to PARP trapping activity beyond blocking PARylation reactions. In this review, we comprehensively address the current state of knowledge regarding the mechanisms of action of PARP inhibitors. We will also discuss the different effects of PARP inhibitors in combination with cytotoxic chemotherapeutic agents regarding the mechanism of regulating PARylation. Full article
(This article belongs to the Special Issue PARPs, PAR and NAD Metabolism and Their Inhibitors in Cancer)
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32 pages, 3686 KiB  
Review
Non-Coding RNAs as Regulators and Markers for Targeting of Breast Cancer and Cancer Stem Cells
by Kirti S. Prabhu, Afsheen Raza, Thasni Karedath, Syed Shadab Raza, Hamna Fathima, Eiman I. Ahmed, Shilpa Kuttikrishnan, Lubna Therachiyil, Michal Kulinski, Said Dermime, Kulsoom Junejo, Martin Steinhoff and Shahab Uddin
Cancers 2020, 12(2), 351; https://doi.org/10.3390/cancers12020351 - 4 Feb 2020
Cited by 36 | Viewed by 5352
Abstract
Breast cancer is regarded as a heterogeneous and complicated disease that remains the prime focus in the domain of public health concern. Next-generation sequencing technologies provided a new perspective dimension to non-coding RNAs, which were initially considered to be transcriptional noise or a [...] Read more.
Breast cancer is regarded as a heterogeneous and complicated disease that remains the prime focus in the domain of public health concern. Next-generation sequencing technologies provided a new perspective dimension to non-coding RNAs, which were initially considered to be transcriptional noise or a product generated from erroneous transcription. Even though understanding of biological and molecular functions of noncoding RNA remains enigmatic, researchers have established the pivotal role of these RNAs in governing a plethora of biological phenomena that includes cancer-associated cellular processes such as proliferation, invasion, migration, apoptosis, and stemness. In addition to this, the transmission of microRNAs and long non-coding RNAs was identified as a source of communication to breast cancer cells either locally or systemically. The present review provides in-depth information with an aim at discovering the fundamental potential of non-coding RNAs, by providing knowledge of biogenesis and functional roles of micro RNA and long non-coding RNAs in breast cancer and breast cancer stem cells, as either oncogenic drivers or tumor suppressors. Furthermore, non-coding RNAs and their potential role as diagnostic and therapeutic moieties have also been summarized. Full article
(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)
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14 pages, 2618 KiB  
Article
Early Detection of Hyperprogressive Disease in Non-Small Cell Lung Cancer by Monitoring of Systemic T Cell Dynamics
by Hugo Arasanz, Miren Zuazo, Ana Bocanegra, María Gato, Maite Martínez-Aguillo, Idoia Morilla, Gonzalo Fernández, Berta Hernández, Paúl López, Nerea Alberdi, Carlos Hernández, Luisa Chocarro, Lucía Teijeira, Ruth Vera, Grazyna Kochan and David Escors
Cancers 2020, 12(2), 344; https://doi.org/10.3390/cancers12020344 - 4 Feb 2020
Cited by 59 | Viewed by 5760
Abstract
Hyperprogressive disease (HPD) is an adverse outcome of immunotherapy consisting of an acceleration of tumor growth associated with prompt clinical deterioration. The definitions based on radiological evaluation present important technical limitations. No biomarkers have been identified yet. In this study, 70 metastatic NSCLC [...] Read more.
Hyperprogressive disease (HPD) is an adverse outcome of immunotherapy consisting of an acceleration of tumor growth associated with prompt clinical deterioration. The definitions based on radiological evaluation present important technical limitations. No biomarkers have been identified yet. In this study, 70 metastatic NSCLC patients treated with anti-PD-1/PD-L1 immunotherapy after progression to platinum-based therapy were prospectively studied. Samples from peripheral blood were obtained before the first (baseline) and second cycles of treatment. Peripheral blood mononuclear cells (PBMCs) were isolated and differentiation stages of CD4 lymphocytes quantified by flow cytometry and correlated with HPD as identified with radiological criteria. A strong expansion of highly differentiated CD28− CD4 T lymphocytes (CD4 THD) between the first and second cycle of therapy was observed in HPD patients. After normalizing, the proportion of posttreatment/pretreatment CD4 THD was significantly higher in HPD when compared with the rest of patients (median 1.525 vs. 0.990; p = 0.0007), and also when stratifying by HPD, non-HPD progressors, and responders (1.525, 1.000 and 0.9700 respectively; p = 0.0025). A cut-off value of 1.3 identified HPD with 82% specificity and 70% sensitivity. An increase of CD28− CD4 T lymphocytes ≥ 1.3 (CD4 THD burst) was significantly associated with HPD (p = 0.008). The tumor growth ratio (TGR) was significantly higher in patients with expansion of CD4 THD burst compared to the rest of patients (median 2.67 vs. 0.86, p = 0.0049), and also when considering only progressors (median 2.67 vs. 1.03, p = 0.0126). A strong expansion of CD28− CD4 lymphocytes in peripheral blood within the first cycle of therapy is an early differential feature of HPD in NSCLC treated with immune-checkpoint inhibitors. The monitoring of T cell dynamics allows the early detection of this adverse outcome in clinical practice and complements radiological evaluation. Full article
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24 pages, 1444 KiB  
Review
The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias
by Alberto M. Martelli, Francesca Paganelli, Francesca Chiarini, Camilla Evangelisti and James A. McCubrey
Cancers 2020, 12(2), 333; https://doi.org/10.3390/cancers12020333 - 1 Feb 2020
Cited by 26 | Viewed by 6332
Abstract
The unfolded protein response (UPR) is an evolutionarily conserved adaptive response triggered by the stress of the endoplasmic reticulum (ER) due, among other causes, to altered cell protein homeostasis (proteostasis). UPR is mediated by three main sensors, protein kinase RNA-like endoplasmic reticulum kinase [...] Read more.
The unfolded protein response (UPR) is an evolutionarily conserved adaptive response triggered by the stress of the endoplasmic reticulum (ER) due, among other causes, to altered cell protein homeostasis (proteostasis). UPR is mediated by three main sensors, protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor 6α (ATF6α), and inositol-requiring enzyme-1α (IRE1α). Given that proteostasis is frequently disregulated in cancer, UPR is emerging as a critical signaling network in controlling the survival, selection, and adaptation of a variety of neoplasias, including breast cancer, prostate cancer, colorectal cancer, and glioblastoma. Indeed, cancer cells can escape from the apoptotic pathways elicited by ER stress by switching UPR into a prosurvival mechanism instead of cell death. Although most of the studies on UPR focused on solid tumors, this intricate network plays a critical role in hematological malignancies, and especially in multiple myeloma (MM), where treatment with proteasome inhibitors induce the accumulation of unfolded proteins that severely perturb proteostasis, thereby leading to ER stress, and, eventually, to apoptosis. However, UPR is emerging as a key player also in acute leukemias, where recent evidence points to the likelihood that targeting UPR-driven prosurvival pathways could represent a novel therapeutic strategy. In this review, we focus on the oncogene-specific regulation of individual UPR signaling arms, and we provide an updated outline of the genetic, biochemical, and preclinical therapeutic findings that support UPR as a relevant, novel target in acute leukemias. Full article
(This article belongs to the Special Issue Therapeutic Targeting of the Unfolded Protein Response in Cancer)
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12 pages, 1915 KiB  
Article
Targeting CD47 as a Novel Immunotherapy for Multiple Myeloma
by Jennifer Sun, Barbara Muz, Kinan Alhallak, Matea Markovic, Shannon Gurley, Zhe Wang, Nicole Guenthner, Katherine Wasden, Mark Fiala, Justin King, Daniel Kohnen, Noha Nabil Salama, Ravi Vij and Abdel Kareem Azab
Cancers 2020, 12(2), 305; https://doi.org/10.3390/cancers12020305 - 28 Jan 2020
Cited by 59 | Viewed by 6408
Abstract
Multiple myeloma (MM) remains to be incurable despite recent therapeutic advances. CD47, an immune checkpoint known as the “don’t eat me” signal, is highly expressed on the surface of various cancers, allowing cancer cells to send inhibitory signals to macrophages and impede phagocytosis [...] Read more.
Multiple myeloma (MM) remains to be incurable despite recent therapeutic advances. CD47, an immune checkpoint known as the “don’t eat me” signal, is highly expressed on the surface of various cancers, allowing cancer cells to send inhibitory signals to macrophages and impede phagocytosis and immune response. In this study, we hypothesized that blocking the “don’t eat me” signaling using an anti-CD47 monoclonal antibody will induce killing of MM cells. We report that CD47 expression was directly correlated with stage of the disease, from normal to MGUS to MM. Moreover, MM cells had remarkably higher CD47 expression than other cell populations in the bone marrow. These findings indicate that CD47 is specifically expressed on MM and can be used as a potential therapeutic target. Further, blocking of CD47 using an anti-CD47 antibody induced immediate activation of macrophages, which resulted in induction of phagocytosis and killing of MM cells in the 3D-tissue engineered bone marrow model, as early as 4 hours. These results suggest that macrophage checkpoint immunotherapy by blocking the CD47 “don’t eat me” signal is a novel and promising strategy for the treatment of MM, providing a basis for additional studies to validate these effects in vivo and in patients. Full article
(This article belongs to the Special Issue Recent Advances on the Pathobiology and Treatment of Multiple Myeloma)
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36 pages, 3139 KiB  
Review
A Comprehensive Picture of Extracellular Vesicles and Their Contents. Molecular Transfer to Cancer Cells
by Ancuta Jurj, Oana Zanoaga, Cornelia Braicu, Vladimir Lazar, Ciprian Tomuleasa, Alexandru Irimie and Ioana Berindan-Neagoe
Cancers 2020, 12(2), 298; https://doi.org/10.3390/cancers12020298 - 27 Jan 2020
Cited by 85 | Viewed by 8119
Abstract
Critical processes such as growth, invasion, and metastasis of cancer cells are sustained via bidirectional cell-to-cell communication in tissue complex environments. Such communication involves the secretion of soluble factors by stromal cells and/or cancer cells within the tumor microenvironment (TME). Both stromal and [...] Read more.
Critical processes such as growth, invasion, and metastasis of cancer cells are sustained via bidirectional cell-to-cell communication in tissue complex environments. Such communication involves the secretion of soluble factors by stromal cells and/or cancer cells within the tumor microenvironment (TME). Both stromal and cancer cells have been shown to export bilayer nanoparticles: encapsulated regulatory molecules that contribute to cell-to-cell communication. These nanoparticles are known as extracellular vesicles (EVs) being classified into exosomes, microvesicles, and apoptotic bodies. EVs carry a vast repertoire of molecules such as oncoproteins and oncopeptides, DNA fragments from parental to target cells, RNA species (mRNAs, microRNAs, and long non-coding RNA), and lipids, initiating phenotypic changes in TME. According to their specific cargo, EVs have crucial roles in several early and late processes associated with tumor development and metastasis. Emerging evidence suggests that EVs are being investigated for their implication in early cancer detection, monitoring cancer progression and chemotherapeutic response, and more relevant, the development of novel targeted therapeutics. In this study, we provide a comprehensive understanding of the biophysical properties and physiological functions of EVs, their implications in TME, and highlight the applicability of EVs for the development of cancer diagnostics and therapeutics. Full article
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21 pages, 2712 KiB  
Review
A Comprehensive Review of Calcium Electroporation—A Novel Cancer Treatment Modality
by Stine K. Frandsen, Mille Vissing and Julie Gehl
Cancers 2020, 12(2), 290; https://doi.org/10.3390/cancers12020290 - 25 Jan 2020
Cited by 79 | Viewed by 7079
Abstract
Calcium electroporation is a potential novel anti-cancer treatment where high calcium concentrations are introduced into cells by electroporation, a method where short, high voltage pulses induce transient permeabilisation of the plasma membrane allowing passage of molecules into the cytosol. Calcium is a tightly [...] Read more.
Calcium electroporation is a potential novel anti-cancer treatment where high calcium concentrations are introduced into cells by electroporation, a method where short, high voltage pulses induce transient permeabilisation of the plasma membrane allowing passage of molecules into the cytosol. Calcium is a tightly regulated, ubiquitous second messenger involved in many cellular processes including cell death. Electroporation increases calcium uptake leading to acute and severe ATP depletion associated with cancer cell death. This comprehensive review describes published data about calcium electroporation applied in vitro, in vivo, and clinically from the first publication in 2012. Calcium electroporation has been shown to be a safe and efficient anti-cancer treatment in clinical studies with cutaneous metastases and recurrent head and neck cancer. Normal cells have been shown to be less affected by calcium electroporation than cancer cells and this difference might be partly induced by differences in membrane repair, expression of calcium transporters, and cellular structural changes. Interestingly, both clinical data and preclinical studies have indicated a systemic immune response induced by calcium electroporation. New cancer treatments are needed, and calcium electroporation represents an inexpensive and efficient treatment with few side effects, that could potentially be used worldwide and for different tumor types. Full article
(This article belongs to the Special Issue Electric Field Based Therapies in Cancer Treatment: a Selection of Studies Presented at the 3rd World Congress on Electroporation)
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19 pages, 2416 KiB  
Article
Cancer Stem Cell Marker DCLK1 Correlates with Tumorigenic Immune Infiltrates in the Colon and Gastric Adenocarcinoma Microenvironments
by Xiangyan Wu, Dongfeng Qu, Nathaniel Weygant, Jun Peng and Courtney W. Houchen
Cancers 2020, 12(2), 274; https://doi.org/10.3390/cancers12020274 - 22 Jan 2020
Cited by 53 | Viewed by 5598
Abstract
Immunotherapy that has proven efficacy in several solid cancers plays a partial role in improving clinical outcomes of advanced gastrointestinal (GI) cancers. There is an unmet need to find new immune-related therapeutic targets. Doublecortin-like kinase 1 (DCLK1) marks tuft cells which are recognized [...] Read more.
Immunotherapy that has proven efficacy in several solid cancers plays a partial role in improving clinical outcomes of advanced gastrointestinal (GI) cancers. There is an unmet need to find new immune-related therapeutic targets. Doublecortin-like kinase 1 (DCLK1) marks tuft cells which are recognized as cancer-initiating cells and regulators of the type II immune response, and has been studied for its role in many cancers including colon and gastric cancers, but its role in tumor immunity remains unexplored. In the current study, we analyzed colon and gastric cancer RNA sequencing data from 283 and 415 patients, respectively, from The Cancer Genome Atlas (TCGA). High DCLK1 expression predicted the worse clinical outcomes in colon and gastric cancer patients and correlated with increased immune and stromal components. Further analysis indicated that DCLK1 was strongly linked to infiltration of multiple immune cell types, especially TAMs and Treg, and strongly correlated with increased CD8+ T cell inhibitors TGFB1 and CXCL12 and their receptors, suggesting it may contribute to TAM-mediated inhibition of CD8+ T cells. Interestingly, we found that DCLK1 was a prognostic biomarker in left-sided colon cancer, which has worse outcomes and demonstrates a reduced response to existing immunotherapies. In conclusion, our results demonstrate that DCLK1 is linked with functional regulation of the tumor microenvironment and may have potential as a prognostic biomarker and adjuvant target to promote immunotherapy sensitivity in colon and gastric cancer patients. Full article
(This article belongs to the Collection Mechanism of Immunotherapy in Cancers)
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19 pages, 734 KiB  
Review
Proteasome Inhibitors for the Treatment of Multiple Myeloma
by Shigeki Ito
Cancers 2020, 12(2), 265; https://doi.org/10.3390/cancers12020265 - 22 Jan 2020
Cited by 113 | Viewed by 10652
Abstract
Use of proteasome inhibitors (PIs) has been the therapeutic backbone of myeloma treatment over the past decade. Many PIs are being developed and evaluated in the preclinical and clinical setting. The first-in-class PI, bortezomib, was approved by the US food and drug administration [...] Read more.
Use of proteasome inhibitors (PIs) has been the therapeutic backbone of myeloma treatment over the past decade. Many PIs are being developed and evaluated in the preclinical and clinical setting. The first-in-class PI, bortezomib, was approved by the US food and drug administration in 2003. Carfilzomib is a next-generation PI, which selectively and irreversibly inhibits proteasome enzymatic activities in a dose-dependent manner. Ixazomib was the first oral PI to be developed and has a robust efficacy and favorable safety profile in patients with multiple myeloma. These PIs, together with other agents, including alkylators, immunomodulatory drugs, and monoclonal antibodies, have been incorporated into several regimens. This review summarizes the biological effects and the results of clinical trials investigating PI-based combination regimens and novel investigational inhibitors and discusses the future perspective in the treatment of multiple myeloma. Full article
(This article belongs to the Special Issue Latest Development in Multiple Myeloma)
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