Cancers

21 pages, 2543 KiB

Open AccessEditor’s ChoiceArticle

Aminopeptidase Expression in Multiple Myeloma Associates with Disease Progression and Sensitivity to Melflufen

by Juho J. Miettinen, Romika Kumari, Gunnhildur Asta Traustadottir, Maiju-Emilia Huppunen, Philipp Sergeev, Muntasir M. Majumder, Alexander Schepsky, Thorarinn Gudjonsson, Juha Lievonen, Despina Bazou, Paul Dowling, Peter O`Gorman, Ana Slipicevic, Pekka Anttila, Raija Silvennoinen, Nina N. Nupponen, Fredrik Lehmann and Caroline A. Heckman

Cancers 2021, 13(7), 1527; https://doi.org/10.3390/cancers13071527 - 26 Mar 2021

Cited by 41 | Viewed by 6956

Abstract

Multiple myeloma (MM) is characterized by extensive immunoglobulin production leading to an excessive load on protein homeostasis in tumor cells. Aminopeptidases contribute to proteolysis by catalyzing the hydrolysis of amino acids from proteins or peptides and function downstream of the ubiquitin–proteasome pathway. Notably, [...] Read more.

Multiple myeloma (MM) is characterized by extensive immunoglobulin production leading to an excessive load on protein homeostasis in tumor cells. Aminopeptidases contribute to proteolysis by catalyzing the hydrolysis of amino acids from proteins or peptides and function downstream of the ubiquitin–proteasome pathway. Notably, aminopeptidases can be utilized in the delivery of antibody and peptide-conjugated drugs, such as melflufen, currently in clinical trials. We analyzed the expression of 39 aminopeptidase genes in MM samples from 122 patients treated at Finnish cancer centers and 892 patients from the CoMMpass database. Based on ranked abundance, LAP3, ERAP2, METAP2, TTP2, and DPP7 were highly expressed in MM. ERAP2, XPNPEP1, DPP3, RNPEP, and CTSV were differentially expressed between relapsed/refractory and newly diagnosed MM samples (p < 0.05). Sensitivity to melflufen was detected ex vivo in 11/15 MM patient samples, and high sensitivity was observed, especially in relapsed/refractory samples. Survival analysis revealed that high expression of XPNPEP1, RNPEP, DPP3, and BLMH (p < 0.05) was associated with shorter overall survival. Hydrolysis analysis demonstrated that melflufen is a substrate for aminopeptidases LAP3, LTA4H, RNPEP, and ANPEP. The sensitivity of MM cell lines to melflufen was reduced by aminopeptidase inhibitors. These results indicate critical roles of aminopeptidases in disease progression and the activity of melflufen in MM. Full article

(This article belongs to the Special Issue Novel Therapeutic Strategies in Multiple Myeloma (MM))

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23 pages, 775 KiB

Open AccessEditor’s ChoiceReview

Dysregulation of the Ubiquitin Proteasome System in Human Malignancies: A Window for Therapeutic Intervention

by Chee Wai Fhu and Azhar Ali

Cancers 2021, 13(7), 1513; https://doi.org/10.3390/cancers13071513 - 25 Mar 2021

Cited by 36 | Viewed by 6978

Abstract

The ubiquitin proteasome system (UPS) governs the non-lysosomal degradation of oxidized, damaged, or misfolded proteins in eukaryotic cells. This process is tightly regulated through the activation and transfer of polyubiquitin chains to target proteins which are then recognized and degraded by the 26S [...] Read more.

The ubiquitin proteasome system (UPS) governs the non-lysosomal degradation of oxidized, damaged, or misfolded proteins in eukaryotic cells. This process is tightly regulated through the activation and transfer of polyubiquitin chains to target proteins which are then recognized and degraded by the 26S proteasome complex. The role of UPS is crucial in regulating protein levels through degradation to maintain fundamental cellular processes such as growth, division, signal transduction, and stress response. Dysregulation of the UPS, resulting in loss of ability to maintain protein quality through proteolysis, is closely related to the development of various malignancies and tumorigenesis. Here, we provide a comprehensive general overview on the regulation and roles of UPS and discuss functional links of dysregulated UPS in human malignancies. Inhibitors developed against components of the UPS, which include U.S. Food and Drug Administration FDA-approved and those currently undergoing clinical trials, are also presented in this review. Full article

(This article belongs to the Special Issue The Role of the Ubiquitin-Proteasome-System in Human Cancer)

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32 pages, 2266 KiB

Open AccessEditor’s ChoiceReview

Key Matrix Remodeling Enzymes: Functions and Targeting in Cancer

by Zoi Piperigkou, Konstantina Kyriakopoulou, Christos Koutsakis, Stylianos Mastronikolis and Nikos K. Karamanos

Cancers 2021, 13(6), 1441; https://doi.org/10.3390/cancers13061441 - 22 Mar 2021

Cited by 85 | Viewed by 7533

Abstract

Tissue functionality and integrity demand continuous changes in distribution of major components in the extracellular matrices (ECMs) under normal conditions aiming tissue homeostasis. Major matrix degrading proteolytic enzymes are matrix metalloproteinases (MMPs), plasminogen activators, atypical proteases such as intracellular cathepsins and glycolytic enzymes [...] Read more.

Tissue functionality and integrity demand continuous changes in distribution of major components in the extracellular matrices (ECMs) under normal conditions aiming tissue homeostasis. Major matrix degrading proteolytic enzymes are matrix metalloproteinases (MMPs), plasminogen activators, atypical proteases such as intracellular cathepsins and glycolytic enzymes including heparanase and hyaluronidases. Matrix proteases evoke epithelial-to-mesenchymal transition (EMT) and regulate ECM turnover under normal procedures as well as cancer cell phenotype, motility, invasion, autophagy, angiogenesis and exosome formation through vital signaling cascades. ECM remodeling is also achieved by glycolytic enzymes that are essential for cancer cell survival, proliferation and tumor progression. In this article, the types of major matrix remodeling enzymes, their effects in cancer initiation, propagation and progression as well as their pharmacological targeting and ongoing clinical trials are presented and critically discussed. Full article

(This article belongs to the Collection Matrix Effectors and Cancer)

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18 pages, 727 KiB

Open AccessEditor’s ChoiceReview

CTLA-4 in Regulatory T Cells for Cancer Immunotherapy

by Navid Sobhani, Dana Rae Tardiel-Cyril, Aram Davtyan, Daniele Generali, Raheleh Roudi and Yong Li

Cancers 2021, 13(6), 1440; https://doi.org/10.3390/cancers13061440 - 22 Mar 2021

Cited by 195 | Viewed by 21882

Abstract

Immune checkpoint inhibitors (ICIs) have obtained durable responses in many cancers, making it possible to foresee their potential in improving the health of cancer patients. However, immunotherapies are currently limited to a minority of patients and there is a need to develop a [...] Read more.

Immune checkpoint inhibitors (ICIs) have obtained durable responses in many cancers, making it possible to foresee their potential in improving the health of cancer patients. However, immunotherapies are currently limited to a minority of patients and there is a need to develop a better understanding of the basic molecular mechanisms and functions of pivotal immune regulatory molecules. Immune checkpoint cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and regulatory T (T_reg) cells play pivotal roles in hindering the anticancer immunity. T_reg cells suppress antigen-presenting cells (APCs) by depleting immune stimulating cytokines, producing immunosuppressive cytokines and constitutively expressing CTLA-4. CTLA-4 molecules bind to CD80 and CD86 with a higher affinity than CD28 and act as competitive inhibitors of CD28 in APCs. The purpose of this review is to summarize state-of-the-art understanding of the molecular mechanisms underlining CTLA-4 immune regulation and the correlation of the ICI response with CTLA-4 expression in T_reg cells from preclinical and clinical studies for possibly improving CTLA-4-based immunotherapies, while highlighting the knowledge gap. Full article

(This article belongs to the Special Issue Cancer Immunology)

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26 pages, 1761 KiB

Open AccessEditor’s ChoiceReview

The Role of Cancer-Associated Fibroblasts in Tumor Progression

by Rushikesh S. Joshi, Samanvi S. Kanugula, Sweta Sudhir, Matheus P. Pereira, Saket Jain and Manish K. Aghi

Cancers 2021, 13(6), 1399; https://doi.org/10.3390/cancers13061399 - 19 Mar 2021

Cited by 157 | Viewed by 13854

Abstract

In the era of genomic medicine, cancer treatment has become more personalized as novel therapeutic targets and pathways are identified. Research over the past decade has shown the increasing importance of how the tumor microenvironment (TME) and the extracellular matrix (ECM), which is [...] Read more.

In the era of genomic medicine, cancer treatment has become more personalized as novel therapeutic targets and pathways are identified. Research over the past decade has shown the increasing importance of how the tumor microenvironment (TME) and the extracellular matrix (ECM), which is a major structural component of the TME, regulate oncogenic functions including tumor progression, metastasis, angiogenesis, therapy resistance, and immune cell modulation, amongst others. Within the TME, cancer-associated fibroblasts (CAFs) have been identified in several systemic cancers as critical regulators of the malignant cancer phenotype. This review of the literature comprehensively profiles the roles of CAFs implicated in gastrointestinal, endocrine, head and neck, skin, genitourinary, lung, and breast cancers. The ubiquitous presence of CAFs highlights their significance as modulators of cancer progression and has led to the subsequent characterization of potential therapeutic targets, which may help advance the cancer treatment paradigm to determine the next generation of cancer therapy. The aim of this review is to provide a detailed overview of the key roles that CAFs play in the scope of systemic disease, the mechanisms by which they enhance protumoral effects, and the primary CAF-related markers that may offer potential targets for novel therapeutics. Full article

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20 pages, 2808 KiB

Open AccessEditor’s ChoiceReview

Cancer and Aging: Two Tightly Interconnected Biological Processes

by Lieze Berben, Giuseppe Floris, Hans Wildiers and Sigrid Hatse

Cancers 2021, 13(6), 1400; https://doi.org/10.3390/cancers13061400 - 19 Mar 2021

Cited by 156 | Viewed by 10394

Abstract

Age is one of the main risk factors of cancer; several biological changes linked with the aging process can explain this. As our population is progressively aging, the proportion of older patients with cancer is increasing significantly. Due to the heterogeneity of general [...] Read more.

Age is one of the main risk factors of cancer; several biological changes linked with the aging process can explain this. As our population is progressively aging, the proportion of older patients with cancer is increasing significantly. Due to the heterogeneity of general health and functional status amongst older persons, treatment of cancer is a major challenge in this vulnerable population. Older patients often experience more side effects of anticancer treatments. Over-treatment should be avoided to ensure an optimal quality of life. On the other hand, under-treatment due to fear of toxicity is a frequent problem and can lead to an increased risk of relapse and worse survival. There is a delicate balance between benefits of therapy and risk of toxicity. Robust biomarkers that reflect the body’s biological age may aid in outlining optimal individual treatment regimens for older patients with cancer. In particular, the impact of age on systemic immunity and the tumor immune infiltrate should be considered, given the expanding role of immunotherapy in cancer treatment. In this review, we summarize current knowledge concerning the mechanistic connections between aging and cancer, as well as aging biomarkers that could be helpful in the field of geriatric oncology. Full article

(This article belongs to the Special Issue Geriatric Oncology: From Research to Clinical Practice)

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14 pages, 1013 KiB

Open AccessEditor’s ChoiceReview

Talimogene Laherparepvec (T-VEC): An Intralesional Cancer Immunotherapy for Advanced Melanoma

by Pier Francesco Ferrucci, Laura Pala, Fabio Conforti and Emilia Cocorocchio

Cancers 2021, 13(6), 1383; https://doi.org/10.3390/cancers13061383 - 18 Mar 2021

Cited by 221 | Viewed by 16409

Abstract

Direct intralesional injection of specific or even generic agents, has been proposed over the years as cancer immunotherapy, in order to treat cutaneous or subcutaneous metastasis. Such treatments usually induce an effective control of disease in injected lesions, but only occasionally were able [...] Read more.

Direct intralesional injection of specific or even generic agents, has been proposed over the years as cancer immunotherapy, in order to treat cutaneous or subcutaneous metastasis. Such treatments usually induce an effective control of disease in injected lesions, but only occasionally were able to demonstrate a systemic abscopal effect on distant metastases. The usual availability of tissue for basic and translational research is a plus in utilizing this approach, which has been used in primis for the treatment of locally advanced melanoma. Melanoma is an immunogenic tumor that could often spread superficially causing in-transit metastasis and involving draining lymph nodes, being an interesting model to study new drugs with different modality of administration from normal available routes. Talimogene laherperepvec (T-VEC) is an injectable modified oncolytic herpes virus being developed for intratumoral injection, that produces granulocyte-macrophage colony-stimulating factor (GM-CSF) and enhances local and systemic antitumor immune responses. After infection, selected viral replication happens in tumor cells leading to tumor cell lysis and activating a specific T-cell driven immune response. For this reason, a probable synergistic effect with immune checkpoints inhibition have been described. Pre-clinical studies in melanoma confirmed that T-VEC preferentially infects melanoma cells and exerts its antitumor activity through directly mediating cell death and by augmenting local and even distant immune responses. T-VEC has been assessed in monotherapy in Phase II and III clinical trials demonstrating a tolerable side-effect profile, a promising efficacy in both injected and uninjected lesions, but a mild effect at a systemic level. In fact, despite improved local disease control and a trend toward superior overall survival in respect to the comparator GM-CSF (which was injected subcutaneously daily for two weeks), responses as a single agent therapy have been uncommon in patients with visceral metastases. For this reason, T-VEC is currently being evaluated in combinations with other immune checkpoint inhibitors such as ipilimumab and pembrolizumab, with interesting confirmation of activity even systemically. Full article

(This article belongs to the Collection Mechanism of Immunotherapy in Cancers)

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18 pages, 647 KiB

Open AccessEditor’s ChoiceReview

Agonistic CD40 Antibodies in Cancer Treatment

by Dijana Djureinovic, Meina Wang and Harriet M. Kluger

Cancers 2021, 13(6), 1302; https://doi.org/10.3390/cancers13061302 - 15 Mar 2021

Cited by 77 | Viewed by 14262

Abstract

CD40 is expressed on a variety of antigen-presenting cells. Stimulation of CD40 results in inflammation by upregulation of other costimulatory molecules, increased antigen presentation, maturation (licensing) of dendritic cells, and activation of CD8+ T cells. Here we analyzed gene expression data from The [...] Read more.

CD40 is expressed on a variety of antigen-presenting cells. Stimulation of CD40 results in inflammation by upregulation of other costimulatory molecules, increased antigen presentation, maturation (licensing) of dendritic cells, and activation of CD8+ T cells. Here we analyzed gene expression data from The Cancer Genome Atlas in melanoma, renal cell carcinoma, and pancreatic adenocarcinoma and found correlations between CD40 and several genes involved in antigen presentation and T cell function, supporting further exploration of CD40 agonists to treat cancer. Agonist CD40 antibodies have induced anti-tumor effects in several tumor models and the effect has been more pronounced when used in combination with other treatments (immune checkpoint inhibition, chemotherapy, and colony-stimulating factor 1 receptor inhibition). The reduction in tumor growth and ability to reprogram the tumor microenvironment in preclinical models lays the foundation for clinical development of agonistic CD40 antibodies (APX005M, ChiLob7/4, ADC-1013, SEA-CD40, selicrelumab, and CDX-1140) that are currently being evaluated in early phase clinical trials. In this article, we focus on CD40 expression and immunity in cancer, agonistic human CD40 antibodies, and their pre-clinical and clinical development. With the broad pro-inflammatory effects of CD40 and its ligand on dendritic cells and macrophages, and downstream B and T cell activation, agonists of this pathway may enhance the anti-tumor activity of other systemic therapies. Full article

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

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15 pages, 529 KiB

Open AccessEditor’s ChoiceReview

Targeting BCL-2 in Cancer: Advances, Challenges, and Perspectives

by Shirin Hafezi and Mohamed Rahmani

Cancers 2021, 13(6), 1292; https://doi.org/10.3390/cancers13061292 - 14 Mar 2021

Cited by 180 | Viewed by 12709

Abstract

The major form of cell death in normal as well as malignant cells is apoptosis, which is a programmed process highly regulated by the BCL-2 family of proteins. This includes the antiapoptotic proteins (BCL-2, BCL-XL, MCL-1, BCLW, and BFL-1) and the proapoptotic proteins, [...] Read more.

The major form of cell death in normal as well as malignant cells is apoptosis, which is a programmed process highly regulated by the BCL-2 family of proteins. This includes the antiapoptotic proteins (BCL-2, BCL-XL, MCL-1, BCLW, and BFL-1) and the proapoptotic proteins, which can be divided into two groups: the effectors (BAX, BAK, and BOK) and the BH3-only proteins (BIM, BAD, NOXA, PUMA, BID, BIK, HRK). Notably, the BCL-2 antiapoptotic proteins are often overexpressed in malignant cells. While this offers survival advantages to malignant cells and strengthens their drug resistance capacity, it also offers opportunities for novel targeted therapies that selectively kill such cells. This review provides a comprehensive overview of the extensive preclinical and clinical studies targeting BCL-2 proteins with various BCL-2 proteins inhibitors with emphasis on venetoclax as a single agent, as well as in combination with other therapeutic agents. This review also discusses recent advances, challenges focusing on drug resistance, and future perspectives for effective targeting the Bcl-2 family of proteins in cancer. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy)

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17 pages, 5378 KiB

Open AccessEditor’s ChoiceReview

Stimuli-Responsive Hydrogels for Cancer Treatment: The Role of pH, Light, Ionic Strength and Magnetic Field

by Fernanda Andrade, Maria Mercé Roca-Melendres, Esteban F. Durán-Lara, Diana Rafael and Simó Schwartz, Jr.

Cancers 2021, 13(5), 1164; https://doi.org/10.3390/cancers13051164 - 9 Mar 2021

Cited by 151 | Viewed by 9888

Abstract

Cancer remains as the second leading cause of death, worldwide. Despite the enormous important advances observed in the last decades, advanced stages of the disease remain incurable. The severe side effects associated to systemic high doses of chemotherapy and the development of drug [...] Read more.

Cancer remains as the second leading cause of death, worldwide. Despite the enormous important advances observed in the last decades, advanced stages of the disease remain incurable. The severe side effects associated to systemic high doses of chemotherapy and the development of drug resistance impairs a safe and efficiency anticancer therapy. Therefore, new formulations are continuously under research and development to improve anticancer drugs therapeutic index through localized delivery at tumor sites. Among a wide range of possibilities, hydrogels have recently gained special attention due to their potential to allow in situ sustained and controlled anticancer drug release. In particular, stimuli-responsive hydrogels which are able to change their physical state from liquid to gel accordingly to external factors such as temperature, pH, light, ionic strength, and magnetic field, among others. Some of these formulations presented promising results for the localized control and treatment of cancer. The present work aims to discuss the main properties and application of stimuli-responsive hydrogels in cancer treatment and summarize the most important advances observed in the last decades focusing on the use of pH-, light-, ionic strength-, and magnetic-responsive hydrogels. Full article

(This article belongs to the Section Cancer Therapy)

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9 pages, 423 KiB

Open AccessEditor’s ChoiceReview

Immune Checkpoint Inhibition in Metastatic Colorectal Cancer Harboring Microsatellite Instability or Mismatch Repair Deficiency

by Romain Cohen, Raphaël Colle, Thomas Pudlarz, Maximilien Heran, Alex Duval, Magali Svrcek and Thierry André

Cancers 2021, 13(5), 1149; https://doi.org/10.3390/cancers13051149 - 8 Mar 2021

Cited by 36 | Viewed by 4557

Abstract

Microsatellite instability (MSI) is a tumor phenotype related to a deficient DNA mismatch repair system (dMMR). This phenotype, observed in 5% of metastatic mCRC but 10–18% of localized CRC, is associated with high tumor mutational burden with highly immunogenic neoantigens. It has emerged [...] Read more.

Microsatellite instability (MSI) is a tumor phenotype related to a deficient DNA mismatch repair system (dMMR). This phenotype, observed in 5% of metastatic mCRC but 10–18% of localized CRC, is associated with high tumor mutational burden with highly immunogenic neoantigens. It has emerged as a major predictive biomarker for the efficacy of ICIs. In this review, we will present a comprehensive overview of the literature concerning the efficacy of ICIs in MSI/dMMR mCRC, with a focus on new developments in first-line metastatic setting. Then, we will present current and future challenges of immuno-oncology for patients with MSI/dMMR metastatic CRC. Full article

(This article belongs to the Special Issue Microsatellite Instability and Cancers)

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20 pages, 1016 KiB

Open AccessEditor’s ChoiceReview

by Bohai Feng and Jochen Hess

Cancers 2021, 13(5), 1162; https://doi.org/10.3390/cancers13051162 - 8 Mar 2021

Cited by 14 | Viewed by 4458

Abstract

Immunotherapy by immune checkpoint inhibition has become a main pillar in the armamentarium to treat head and neck cancer and is based on the premise that the host immune system can be reactivated to successfully eliminate cancer cells. However, the response rate remains [...] Read more.

Immunotherapy by immune checkpoint inhibition has become a main pillar in the armamentarium to treat head and neck cancer and is based on the premise that the host immune system can be reactivated to successfully eliminate cancer cells. However, the response rate remains low and only a small subset of head and neck cancer patients achieves a durable clinical benefit. The availability of multi-omics data and emerging computational technologies facilitate not only a deeper understanding of the cellular composition in the tumor immune microenvironment but also enables the study of molecular principles in the complex regulation of immune surveillance versus tolerance. These knowledges will pave the way to apply immunotherapy more precisely and effectively. This review aims to provide a holistic view on how the immune landscape dictates the tumor fate and vice versa, and how integrative analysis of multi-omics data contribute to our current knowledge on the accuracy of predictive biomarkers and on a broad range of factors influencing the response to immunotherapy in head and neck cancer. Full article

(This article belongs to the Section Cancer Pathophysiology)

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52 pages, 2723 KiB

Open AccessEditor’s ChoiceReview

Hypoxia-Induced Cancer Cell Responses Driving Radioresistance of Hypoxic Tumors: Approaches to Targeting and Radiosensitizing

by Alexander E. Kabakov and Anna O. Yakimova

Cancers 2021, 13(5), 1102; https://doi.org/10.3390/cancers13051102 - 4 Mar 2021

Cited by 111 | Viewed by 13144

Abstract

Within aggressive malignancies, there usually are the “hypoxic zones”—poorly vascularized regions where tumor cells undergo oxygen deficiency through inadequate blood supply. Besides, hypoxia may arise in tumors as a result of antiangiogenic therapy or transarterial embolization. Adapting to hypoxia, tumor cells acquire a [...] Read more.

Within aggressive malignancies, there usually are the “hypoxic zones”—poorly vascularized regions where tumor cells undergo oxygen deficiency through inadequate blood supply. Besides, hypoxia may arise in tumors as a result of antiangiogenic therapy or transarterial embolization. Adapting to hypoxia, tumor cells acquire a hypoxia-resistant phenotype with the characteristic alterations in signaling, gene expression and metabolism. Both the lack of oxygen by itself and the hypoxia-responsive phenotypic modulations render tumor cells more radioresistant, so that hypoxic tumors are a serious challenge for radiotherapy. An understanding of causes of the radioresistance of hypoxic tumors would help to develop novel ways for overcoming this challenge. Molecular targets for and various approaches to radiosensitizing hypoxic tumors are considered in the present review. It is here analyzed how the hypoxia-induced cellular responses involving hypoxia-inducible factor-1, heat shock transcription factor 1, heat shock proteins, glucose-regulated proteins, epigenetic regulators, autophagy, energy metabolism reprogramming, epithelial–mesenchymal transition and exosome generation contribute to the radioresistance of hypoxic tumors or may be inhibited for attenuating this radioresistance. The pretreatments with a multitarget inhibition of the cancer cell adaptation to hypoxia seem to be a promising approach to sensitizing hypoxic carcinomas, gliomas, lymphomas, sarcomas to radiotherapy and, also, liver tumors to radioembolization. Full article

(This article belongs to the Special Issue Novel Perspectives on Hypoxia in Cancer)

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32 pages, 1816 KiB

Open AccessEditor’s ChoiceReview

Bleeding by Bruton Tyrosine Kinase-Inhibitors: Dependency on Drug Type and Disease

by Philipp von Hundelshausen and Wolfgang Siess

Cancers 2021, 13(5), 1103; https://doi.org/10.3390/cancers13051103 - 4 Mar 2021

Cited by 65 | Viewed by 9633

Abstract

Bruton tyrosine kinase (Btk) is expressed in B-lymphocytes, myeloid cells and platelets, and Btk-inhibitors (BTKi) are used to treat patients with B-cell malignancies, developed against autoimmune diseases, have been proposed as novel antithrombotic drugs, and been tested in patients with severe COVID-19. However, [...] Read more.

Bruton tyrosine kinase (Btk) is expressed in B-lymphocytes, myeloid cells and platelets, and Btk-inhibitors (BTKi) are used to treat patients with B-cell malignancies, developed against autoimmune diseases, have been proposed as novel antithrombotic drugs, and been tested in patients with severe COVID-19. However, mild bleeding is frequent in patients with B-cell malignancies treated with the irreversible BTKi ibrutinib and the recently approved 2nd generation BTKi acalabrutinib, zanubrutinib and tirabrutinib, and also in volunteers receiving in a phase-1 study the novel irreversible BTKi BI-705564. In contrast, no bleeding has been reported in clinical trials of other BTKi. These include the brain-penetrant irreversible tolebrutinib and evobrutinib (against multiple sclerosis), the irreversible branebrutinib, the reversible BMS-986142 and fenebrutinib (targeting rheumatoid arthritis and lupus erythematodes), and the reversible covalent rilzabrutinib (against pemphigus and immune thrombocytopenia). Remibrutinib, a novel highly selective covalent BTKi, is currently in clinical studies of autoimmune dermatological disorders. This review describes twelve BTKi approved or in clinical trials. By focusing on their pharmacological properties, targeted disease, bleeding side effects and actions on platelets it attempts to clarify the mechanisms underlying bleeding. Specific platelet function tests in blood might help to estimate the probability of bleeding of newly developed BTKi. Full article

(This article belongs to the Special Issue Protein Kinase in Leukemia)

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18 pages, 1396 KiB

Open AccessEditor’s ChoiceReview

The Exciting New Field of HER2-Low Breast Cancer Treatment

by Daniel Eiger, Elisa Agostinetto, Rita Saúde-Conde and Evandro de Azambuja

Cancers 2021, 13(5), 1015; https://doi.org/10.3390/cancers13051015 - 1 Mar 2021

Cited by 120 | Viewed by 13911

Abstract

Since human epidermal growth factor receptor-2 (HER2) characterization, going through clinical research and regulatory approval of HER2-targeted therapies, much has elapsed and is still unfolding. Hitherto, only breast cancer (BC) patients with HER2 immunohistochemistry 3+ or with HER2 gene fluorescence in-situ hybridization (FISH) [...] Read more.

Since human epidermal growth factor receptor-2 (HER2) characterization, going through clinical research and regulatory approval of HER2-targeted therapies, much has elapsed and is still unfolding. Hitherto, only breast cancer (BC) patients with HER2 immunohistochemistry 3+ or with HER2 gene fluorescence in-situ hybridization (FISH) amplification (a.k.a., HER2-positive BC) have benefited from anti-HER2 agents. In recent years, however, much of the research effort has been expanded, with positive outcomes being reached for formerly known HER2-negative BC that yet express HER2 to some degree (HER2 immunohistochemistry 1+ or 2+, but FISH negative) and are currently being classified as HER2-low BC for the purpose of trial enrollment. In this sense, our aim is to review the body of evidence of HER2-low BC that led to the study of first-generation anti-HER2 agents, like trastuzumab, and how they have failed to achieve any clinical applicability in this setting. In addition, we review new data that is leading to the growing success of the new generation of drugs, especially the promising HER2-directed antibody–drug conjugates. A narrative review is also performed regarding the rationale behind the consolidated and ongoing clinical trials studying anti-HER2 agents in combination with unrelated agents, such as immunotherapy, endocrine therapy, and CDK4/6 inhibitors. Hopefully, all this ongoing research effort will be able to extend the survival benefits seen with anti-HER2 agents in HER2-positive disease, at least to some degree, to the greater proportion of patients with HER2-low BC. Full article

(This article belongs to the Section Cancer Therapy)

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15 pages, 4843 KiB

Open AccessEditor’s ChoiceArticle

Osteopontin Blockade Immunotherapy Increases Cytotoxic T Lymphocyte Lytic Activity and Suppresses Colon Tumor Progression

by John D. Klement, Dakota B. Poschel, Chunwan Lu, Alyssa D. Merting, Dafeng Yang, Priscilla S. Redd and Kebin Liu

Cancers 2021, 13(5), 1006; https://doi.org/10.3390/cancers13051006 - 28 Feb 2021

Cited by 40 | Viewed by 4951

Abstract

Human colorectal cancers are mostly microsatellite-stable with no response to anti-PD-1 blockade immunotherapy, necessitating the development of a new immunotherapy. Osteopontin (OPN) is elevated in human colorectal cancer and may function as an immune checkpoint. We aimed at elucidating the mechanism of action [...] Read more.

Human colorectal cancers are mostly microsatellite-stable with no response to anti-PD-1 blockade immunotherapy, necessitating the development of a new immunotherapy. Osteopontin (OPN) is elevated in human colorectal cancer and may function as an immune checkpoint. We aimed at elucidating the mechanism of action of OPN and determining the efficacy of OPN blockade immunotherapy in suppression of colon cancer. We report here that OPN is primarily expressed in tumor cells, myeloid cells, and innate lymphoid cells in human colorectal carcinoma. Spp1 knock out mice exhibit a high incidence and fast growth rate of carcinogen-induced tumors. Knocking out Spp1 in colon tumor cells increased tumor-specific CTL cytotoxicity in vitro and resulted in decreased tumor growth in vivo. The OPN protein level is elevated in the peripheral blood of tumor-bearing mice. We developed four OPN neutralization monoclonal antibodies based on their efficacy in blocking OPN inhibition of T cell activation. OPN clones 100D3 and 103D6 increased the efficacy of tumor-specific CTLs in killing colon tumor cells in vitro and suppressed colon tumor growth in tumor-bearing mice in vivo. Our data indicate that OPN blockade immunotherapy with 100D3 and 103D6 has great potential to be further developed for colorectal cancer immunotherapy and for rendering a colorectal cancer response to anti-PD-1 immunotherapy. Full article

(This article belongs to the Section Cancer Immunology and Immunotherapy)

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23 pages, 746 KiB

Open AccessEditor’s ChoiceSystematic Review

Fertility-Sparing Surgery in Gynecologic Cancer: A Systematic Review

by Teska Schuurman, Sanne Zilver, Sanne Samuels, Winnie Schats, Frédéric Amant, Nienke van Trommel and Christianne Lok

Cancers 2021, 13(5), 1008; https://doi.org/10.3390/cancers13051008 - 28 Feb 2021

Cited by 36 | Viewed by 6100

Abstract

Fertility-sparing surgery (FSS) is increasingly being offered to women with a gynecological malignancy who wish to preserve fertility. In this systematic review, we evaluate the best evidence currently available on oncological and reproductive outcome after FSS for early stage cervical cancer, epithelial ovarian [...] Read more.

Fertility-sparing surgery (FSS) is increasingly being offered to women with a gynecological malignancy who wish to preserve fertility. In this systematic review, we evaluate the best evidence currently available on oncological and reproductive outcome after FSS for early stage cervical cancer, epithelial ovarian cancer, and endometrial cancer. An extensive literature search was conducted using the electronic databases Medline (OVID), Embase, and Cochrane Library to identify eligible studies published up to December 2020. In total, 153 studies were included with 7544, 3944, and 1229 patients who underwent FSS for cervical, ovarian, and endometrial cancer, respectively. We assessed the different FSS techniques that are available to preserve fertility, i.e., omitting removal of the uterine body and preserving at least one ovary. Overall, recurrence rates after FSS are reassuring and therefore, these conservative procedures seem oncologically safe in the current selection of patients with low-stage and low-grade disease. However, generalized conclusions should be made with caution due to the methodology of available studies, i.e., mostly retrospective cohort studies with a heterogeneous patient population, inducing selection bias. Moreover, about half of patients do not pursue pregnancy despite FSS and the reasons for these decisions have not yet been well studied. International collaboration will facilitate the collection of solid evidence on FSS and the related decision-making process to optimize patient selection and counseling. Full article

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

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24 pages, 1366 KiB

Open AccessEditor’s ChoiceReview

Cancer-Associated Fibroblasts as a Common Orchestrator of Therapy Resistance in Lung and Pancreatic Cancer

by Andreas Domen, Delphine Quatannens, Sara Zanivan, Christophe Deben, Jonas Van Audenaerde, Evelien Smits, An Wouters, Filip Lardon, Geert Roeyen, Yannick Verhoeven, Annelies Janssens, Timon Vandamme, Peter van Dam, Marc Peeters and Hans Prenen

Cancers 2021, 13(5), 987; https://doi.org/10.3390/cancers13050987 - 27 Feb 2021

Cited by 50 | Viewed by 7207

Abstract

Cancer arises from mutations accruing within cancer cells, but the tumor microenvironment (TME) is believed to be a major, often neglected, factor involved in therapy resistance and disease progression. Cancer-associated fibroblasts (CAFs) are prominent and key components of the TME in most types [...] Read more.

Cancer arises from mutations accruing within cancer cells, but the tumor microenvironment (TME) is believed to be a major, often neglected, factor involved in therapy resistance and disease progression. Cancer-associated fibroblasts (CAFs) are prominent and key components of the TME in most types of solid tumors. Extensive research over the past decade revealed their ability to modulate cancer metastasis, angiogenesis, tumor mechanics, immunosuppression, and drug access through synthesis and remodeling of the extracellular matrix and production of growth factors. Thus, they are considered to impede the response to current clinical cancer therapies. Therefore, targeting CAFs to counteract these protumorigenic effects, and overcome the resistance to current therapeutic options, is an appealing and emerging strategy. In this review, we discuss how CAFs affect prognosis and response to clinical therapy and provide an overview of novel therapies involving CAF-targeting agents in lung and pancreatic cancer. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cancer Drug Resistance: Emerging Biomarkers and Promising Targets to Overcome Tumor Progression)

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33 pages, 1564 KiB

Open AccessEditor’s ChoiceReview

A Review of Circulating Tumour Cell Enrichment Technologies

by Amelia J. Rushton, Georgios Nteliopoulos, Jacqueline A. Shaw and R. Charles Coombes

Cancers 2021, 13(5), 970; https://doi.org/10.3390/cancers13050970 - 26 Feb 2021

Cited by 139 | Viewed by 9398

Abstract

Circulating tumour cells (CTCs) are the precursor cells for the formation of metastatic disease. With a simple blood draw, liquid biopsies enable the non-invasive sampling of CTCs from the blood, which have the potential to provide important insights into cancer detection and monitoring. [...] Read more.

Circulating tumour cells (CTCs) are the precursor cells for the formation of metastatic disease. With a simple blood draw, liquid biopsies enable the non-invasive sampling of CTCs from the blood, which have the potential to provide important insights into cancer detection and monitoring. Since gaining FDA approval in 2004, the CellSearch system has been used to determine the prognosis of patients with metastatic breast, prostate and colorectal cancers. This utilises the cell surface marker Epithelial Cell Adhesion Molecule (EpCAM), to enrich CTCs, and many other technologies have adopted this approach. More recently, the role of mesenchymal-like CTCs in metastasis formation has come to light. It has been suggested that these cells are more aggressive metastatic precursors than their epithelial counterparts; however, mesenchymal CTCs remain undetected by EpCAM-based enrichment methods. This has prompted the development of a variety of ‘label free’ enrichment technologies, which exploit the unique physical properties of CTCs (such as size and deformability) compared to other blood components. Here, we review a wide range of both immunocapture and label free CTC enrichment technologies, summarising the most significant advantages and disadvantages of each. We also highlight the important characteristics that technologies should possess for routine clinical use, since future developments could have important clinical implications, with the potential to direct personalised therapies for patients with cancer. Full article

(This article belongs to the Special Issue Chemical Modulation and Analytical Detection of Cancer Stem Cells, Circulating Tumour Cells, and Other Non-bulk Cancer Cell Types)

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21 pages, 6157 KiB

Open AccessEditor’s ChoiceArticle

ARID1A and CTNNB1/β-Catenin Molecular Status Affects the Clinicopathologic Features and Prognosis of Endometrial Carcinoma: Implications for an Improved Surrogate Molecular Classification

by Antonio De Leo, Dario de Biase, Jacopo Lenzi, Giovanna Barbero, Daniela Turchetti, Marco Grillini, Gloria Ravegnini, Sabrina Angelini, Claudio Zamagni, Sara Coluccelli, Giulia Dondi, Pierandrea De Iaco, Anna Myriam Perrone, Giovanni Tallini, Donatella Santini and Claudio Ceccarelli

Cancers 2021, 13(5), 950; https://doi.org/10.3390/cancers13050950 - 25 Feb 2021

Cited by 49 | Viewed by 5526

Abstract

The collaborative Cancer Genome Atlas (TCGA) project identified four distinct prognostic groups of endometrial carcinoma (EC) based on molecular alterations: (i) the ultramutated subtype that encompasses POLE mutated (POLE) cases; (ii) the hypermutated subtype, characterized by MisMatch Repair deficiency (MMRd); (iii) [...] Read more.

The collaborative Cancer Genome Atlas (TCGA) project identified four distinct prognostic groups of endometrial carcinoma (EC) based on molecular alterations: (i) the ultramutated subtype that encompasses POLE mutated (POLE) cases; (ii) the hypermutated subtype, characterized by MisMatch Repair deficiency (MMRd); (iii) the copy-number high subtype, with p53 abnormal/mutated features (p53abn); (iv) the copy-number low subtype, known as No Specific Molecular Profile (NSMP). Although the prognostic value of TCGA molecular classification, NSMP carcinomas present a wide variability in molecular alterations and biological aggressiveness. This study aims to investigate the impact of ARID1A and CTNNB1/β-catenin alterations by targeted Next-generation sequencing (NGS) and immunohistochemistry (IHC) in a consecutive series of 125 molecularly classified ECs. NGS and IHC were used to assign surrogate TCGA groups and to identify molecular alterations of multiple target genes including POLE, PTEN, ARID1A, CTNNB1, TP53. Associations with clinicopathologic parameters, molecular subtypes, and outcomes identified NSMP category as the most heterogeneous group in terms of clinicopathologic features and outcome. Integration of surrogate TCGA molecular classification with ARID1A and β-catenin analysis showed NSMP cases with ARID1A mutation characterized by the worst outcome with early recurrence, while NSMP tumors with ARID1A wild-type and β-catenin alteration had indolent clinicopathologic features and no recurrence. This study indicates how the identification of ARID1A and β-catenin alterations in EC represents a simple and effective way to characterize NSMP tumor aggressiveness and metastatic potential. Full article

(This article belongs to the Special Issue Endometrial Cancer: Old Questions and New Perspectives)

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23 pages, 9320 KiB

Open AccessEditor’s ChoiceArticle

Multi-Omics Data Analysis of Gene Expressions and Alterations, Cancer-Associated Fibroblast and Immune Infiltrations, Reveals the Onco-Immune Prognostic Relevance of STAT3/CDK2/4/6 in Human Malignancies

by Bashir Lawal, Li-Ching Lin, Jih-Chin Lee, Jia-Hong Chen, Tanios S. Bekaii-Saab, Alexander T. H. Wu and Ching-Liang Ho

Cancers 2021, 13(5), 954; https://doi.org/10.3390/cancers13050954 - 25 Feb 2021

Cited by 32 | Viewed by 4067

Abstract

Signal transducer and activator of transcription 3 (STAT3)/Cyclin-dependent kinases are multifunctional proteins that play an important implicative role in cancer initiations, progression, drug resistance, and metastasis, and has been extensively explored in cancer therapy. However, the genetic alterations of STAT3/CDK2/4/6 and its role [...] Read more.

Signal transducer and activator of transcription 3 (STAT3)/Cyclin-dependent kinases are multifunctional proteins that play an important implicative role in cancer initiations, progression, drug resistance, and metastasis, and has been extensively explored in cancer therapy. However, the genetic alterations of STAT3/CDK2/4/6 and its role in predicting immune infiltration and immunotherapeutic response are yet to be well exploited. In this study, we use in silico methods to analyze differential expression, prognostic value, genetic and epigenetic alterations, association with tumor-infiltrating immune cells, and cancer-associated fibroblast (CAF) infiltrations of STAT3/CDK2/4/6 in multiple cancer types. Our results revealed that the expression of STAT3/CDK2/4/6 was altered in various cancers and is associated with poor overall and disease-free survival of the cohorts. Moreover, genetic alterations in STAT3/CDK2/4/6 co-occurred with a number of other genetic alterations and are associated with poorer prognoses of the cohorts. The protein-protein interaction (PPI) network analysis suggests CDK2/4/6/STAT3 may directly interact with factors that promote tumorigenesis and immune response. We found that STAT3/CDK2/4/6 expressions were associated with infiltrations of CAF and the various immune cells in multiple cancers and it’s associated with poor response to immunotherapy. Collectively, our study suggested that STAT3/CDK2/4/6 are important onco-immune signatures that play central roles in tumor immune invasion, poor prognoses and, immune therapy response. Findings from the present study may therefore be clinically useful in prognosis assessment and follow-up management of immunotherapy. Full article

(This article belongs to the Collection The Biomarkers for the Diagnosis and Prognosis in Cancer)

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13 pages, 1908 KiB

Open AccessEditor’s ChoiceArticle

Feedforward Artificial Neural Network-Based Colorectal Cancer Detection Using Hyperspectral Imaging: A Step towards Automatic Optical Biopsy

by Boris Jansen-Winkeln, Manuel Barberio, Claire Chalopin, Katrin Schierle, Michele Diana, Hannes Köhler, Ines Gockel and Marianne Maktabi

Cancers 2021, 13(5), 967; https://doi.org/10.3390/cancers13050967 - 25 Feb 2021

Cited by 72 | Viewed by 5000

Abstract

Currently, colorectal cancer (CRC) is mainly identified via a visual assessment during colonoscopy, increasingly used artificial intelligence algorithms, or surgery. Subsequently, CRC is confirmed through a histopathological examination by a pathologist. Hyperspectral imaging (HSI), a non-invasive optical imaging technology, has shown promising results [...] Read more.

Currently, colorectal cancer (CRC) is mainly identified via a visual assessment during colonoscopy, increasingly used artificial intelligence algorithms, or surgery. Subsequently, CRC is confirmed through a histopathological examination by a pathologist. Hyperspectral imaging (HSI), a non-invasive optical imaging technology, has shown promising results in the medical field. In the current study, we combined HSI with several artificial intelligence algorithms to discriminate CRC. Between July 2019 and May 2020, 54 consecutive patients undergoing colorectal resections for CRC were included. The tumor was imaged from the mucosal side with a hyperspectral camera. The image annotations were classified into three groups (cancer, CA; adenomatous margin around the central tumor, AD; and healthy mucosa, HM). Classification and visualization were performed based on a four-layer perceptron neural network. Based on a neural network, the classification of CA or AD resulted in a sensitivity of 86% and a specificity of 95%, by means of leave-one-patient-out cross-validation. Additionally, significant differences in terms of perfusion parameters (e.g., oxygen saturation) related to tumor staging and neoadjuvant therapy were observed. Hyperspectral imaging combined with automatic classification can be used to differentiate between CRC and healthy mucosa. Additionally, the biological changes induced by chemotherapy to the tissue are detectable with HSI. Full article

(This article belongs to the Special Issue New Insights into Colorectal Cancer)

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45 pages, 3130 KiB

Open AccessEditor’s ChoiceReview

Isoforms of the p53 Family and Gastric Cancer: A Ménage à Trois for an Unfinished Affair

by Anais Blanchet, Agathe Bourgmayer, Jean-Emmanuel Kurtz, Georg Mellitzer and Christian Gaiddon

Cancers 2021, 13(4), 916; https://doi.org/10.3390/cancers13040916 - 22 Feb 2021

Cited by 47 | Viewed by 7023

Abstract

Gastric cancer is one of the most aggressive cancers, with a median survival of 12 months. This illustrates its complexity and the lack of therapeutic options, such as personalized therapy, because predictive markers do not exist. Thus, gastric cancer remains mostly treated with [...] Read more.

Gastric cancer is one of the most aggressive cancers, with a median survival of 12 months. This illustrates its complexity and the lack of therapeutic options, such as personalized therapy, because predictive markers do not exist. Thus, gastric cancer remains mostly treated with cytotoxic chemotherapies. In addition, less than 20% of patients respond to immunotherapy. TP53 mutations are particularly frequent in gastric cancer (±50% and up to 70% in metastatic) and are considered an early event in the tumorigenic process. Alterations in the expression of other members of the p53 family, i.e., p63 and p73, have also been described. In this context, the role of the members of the p53 family and their isoforms have been investigated over the years, resulting in conflicting data. For instance, whether mutations of TP53 or the dysregulation of its homologs may represent biomarkers for aggressivity or response to therapy still remains a matter of debate. This uncertainty illustrates the lack of information on the molecular pathways involving the p53 family in gastric cancer. In this review, we summarize and discuss the most relevant molecular and clinical data on the role of the p53 family in gastric cancer and enumerate potential therapeutic innovative strategies. Full article

(This article belongs to the Special Issue The Isoforms of the p53 Gene Family and Their Role in Cancer and Aging：Selection Papers from International p53/p63/p73 Isoforms Workshop)

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23 pages, 1862 KiB

Open AccessEditor’s ChoiceReview

Metabolism of Innate Immune Cells in Cancer

by Ronan Talty and Kelly Olino

Cancers 2021, 13(4), 904; https://doi.org/10.3390/cancers13040904 - 21 Feb 2021

Cited by 39 | Viewed by 6873

Abstract

Cancer cells possess specific metabolic requirements for their survival, proliferation, and progression. Within a shared microenvironment, immune cells depend on competing metabolic pathways for their development and effector function. As a result, local acidification, hypoxia, and nutrient depletion in the tumor microenvironment can [...] Read more.

Cancer cells possess specific metabolic requirements for their survival, proliferation, and progression. Within a shared microenvironment, immune cells depend on competing metabolic pathways for their development and effector function. As a result, local acidification, hypoxia, and nutrient depletion in the tumor microenvironment can alter the antitumor immune response and even promote resistance to immunotherapies such as immune checkpoint blockade and adoptive cell transfer. Although T cells are the primary effectors of the antitumor response, growing evidence demonstrates that innate immune cells are critical to successful tumor clearance. This review aims to summarize current research related to the innate immune system, metabolism, and cancer. We first discuss the specific metabolic requirements of innate immune cells for immune activation and suppression and conclude by highlighting ongoing clinical applications of these findings. Full article

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

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23 pages, 7264 KiB

Open AccessEditor’s ChoiceArticle

Shikonin Reduces Growth of Docetaxel-Resistant Prostate Cancer Cells Mainly through Necroptosis

by Sascha D. Markowitsch, Kira M. Juetter, Patricia Schupp, Kristine Hauschulte, Olesya Vakhrusheva, Kimberly Sue Slade, Anita Thomas, Igor Tsaur, Jindrich Cinatl, Jr., Martin Michaelis, Thomas Efferth, Axel Haferkamp and Eva Juengel

Cancers 2021, 13(4), 882; https://doi.org/10.3390/cancers13040882 - 20 Feb 2021

Cited by 47 | Viewed by 4532

Abstract

The prognosis for advanced prostate carcinoma (PCa) remains poor due to development of therapy resistance, and new treatment options are needed. Shikonin (SHI) from Traditional Chinese Medicine has induced antitumor effects in diverse tumor entities, but data related to PCa are scarce. Therefore, [...] Read more.

The prognosis for advanced prostate carcinoma (PCa) remains poor due to development of therapy resistance, and new treatment options are needed. Shikonin (SHI) from Traditional Chinese Medicine has induced antitumor effects in diverse tumor entities, but data related to PCa are scarce. Therefore, the parental (=sensitive) and docetaxel (DX)-resistant PCa cell lines, PC3, DU145, LNCaP, and 22Rv1 were exposed to SHI [0.1–1.5 μM], and tumor cell growth, proliferation, cell cycling, cell death (apoptosis, necrosis, and necroptosis), and metabolic activity were evaluated. Correspondingly, the expression of regulating proteins was assessed. Exposure to SHI time- and dose-dependently inhibited tumor cell growth and proliferation in parental and DX-resistant PCa cells, accompanied by cell cycle arrest in the G2/M or S phase and modulation of cell cycle regulating proteins. SHI induced apoptosis and more dominantly necroptosis in both parental and DX-resistant PCa cells. This was shown by enhanced pRIP1 and pRIP3 expression and returned growth if applying the necroptosis inhibitor necrostatin-1. No SHI-induced alteration in metabolic activity of the PCa cells was detected. The significant antitumor effects induced by SHI to parental and DX-resistant PCa cells make the addition of SHI to standard therapy a promising treatment strategy for patients with advanced PCa. Full article

(This article belongs to the Special Issue Recent Scientific Developments in Metastatic Prostate Cancer)

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28 pages, 1534 KiB

Open AccessEditor’s ChoiceReview

MicroRNAs: Their Role in Metastasis, Angiogenesis, and the Potential for Biomarker Utility in Bladder Carcinomas

by Raneem Y. Hammouz, Damian Kołat, Żaneta Kałuzińska, Elżbieta Płuciennik and Andrzej K. Bednarek

Cancers 2021, 13(4), 891; https://doi.org/10.3390/cancers13040891 - 20 Feb 2021

Cited by 31 | Viewed by 3816

Abstract

Angiogenesis is the process of generating new capillaries from pre-existing blood vessels with a vital role in tumor growth and metastasis. MicroRNAs (miRNAs) are noncoding RNAs that exert post-transcriptional control of protein regulation. They participate in the development and progression of several cancers [...] Read more.

Angiogenesis is the process of generating new capillaries from pre-existing blood vessels with a vital role in tumor growth and metastasis. MicroRNAs (miRNAs) are noncoding RNAs that exert post-transcriptional control of protein regulation. They participate in the development and progression of several cancers including bladder cancer (BLCA). In cancer tissue, changes in microRNA expression exhibit tissue specificity with high levels of stability and detectability. miRNAs are less vulnerable to degradation, making them novel targets for therapeutic approaches. A suitable means of targeting aberrant activated signal transduction pathways in carcinogenesis of BLCA is possibly through altering the expression of key miRNAs that regulate them, exerting a strong effect on signal transduction. Precaution must be taken, as the complexity of miRNA regulation might result in targeting several downstream tumor suppressors or oncogenes, enhancing the effect further. Since exosomes contain both mRNA and miRNA, they could therefore possibly be more effective in targeting a recipient cell if they deliver a specific miRNA to modify the recipient cell protein production and gene expression. In this review, we discuss the molecules that have been shown to play a significant role in BLCA tumor development. We also discuss the roles of various miRNAs in BLCA angiogenesis and metastasis. Advances in the management of metastatic BLCA have been limited; miRNA mimics and molecules targeted at miRNAs (anti-miRs) as well as exosomes could serve as therapeutic modalities or as diagnostic biomarkers. Full article

(This article belongs to the Section Cancer Biomarkers)

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17 pages, 1902 KiB

Open AccessEditor’s ChoiceReview

Organoid and Spheroid Tumor Models: Techniques and Applications

by Sreenivasulu Gunti, Austin T.K. Hoke, Kenny P. Vu and Nyall R. London, Jr.

Cancers 2021, 13(4), 874; https://doi.org/10.3390/cancers13040874 - 19 Feb 2021

Cited by 312 | Viewed by 20896

Abstract

Techniques to develop three-dimensional cell culture models are rapidly expanding to bridge the gap between conventional cell culture and animal models. Organoid and spheroid cultures have distinct and overlapping purposes and differ in cellular sources and protocol for establishment. Spheroids are of lower [...] Read more.

Techniques to develop three-dimensional cell culture models are rapidly expanding to bridge the gap between conventional cell culture and animal models. Organoid and spheroid cultures have distinct and overlapping purposes and differ in cellular sources and protocol for establishment. Spheroids are of lower complexity structurally but are simple and popular models for drug screening. Organoids histologically and genetically resemble the original tumor from which they were derived. Ease of generation, ability for long-term culture and cryopreservation make organoids suitable for a wide range of applications. Organoids-on-chip models combine organoid methods with powerful designing and fabrication of micro-chip technology. Organoid-chip models can emulate the dynamic microenvironment of tumor pathophysiology as well as tissue–tissue interactions. In this review, we outline different tumor spheroid and organoid models and techniques to establish them. We also discuss the recent advances and applications of tumor organoids with an emphasis on tumor modeling, drug screening, personalized medicine and immunotherapy. Full article

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11 pages, 479 KiB

Open AccessEditor’s ChoiceArticle

Association between Immune Related Adverse Events and Outcome in Patients with Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors

by Agnese Paderi, Roberta Giorgione, Elisa Giommoni, Marinella Micol Mela, Virginia Rossi, Laura Doni, Andrea Minervini, Marco Carini, Serena Pillozzi and Lorenzo Antonuzzo

Cancers 2021, 13(4), 860; https://doi.org/10.3390/cancers13040860 - 18 Feb 2021

Cited by 50 | Viewed by 4495

Abstract

Background: It has been reported that the occurrence of immune-related adverse events (irAEs) in oncological patients treated with immune-checkpoint inhibitors (ICIs) may be associated with favorable clinical outcome. We reported the clinical correlation between irAEs and the efficacy of ICIs in a real-world [...] Read more.

Background: It has been reported that the occurrence of immune-related adverse events (irAEs) in oncological patients treated with immune-checkpoint inhibitors (ICIs) may be associated with favorable clinical outcome. We reported the clinical correlation between irAEs and the efficacy of ICIs in a real-world cohort of metastatic renal cell cancer (mRCC) patients. Methods: We retrospectively evaluated 43 patients with mRCC who were treated with nivolumab or with nivolumab plus ipilimumab. We considered seven specific classes of irAEs including pulmonary, hepatic, gastrointestinal, cutaneous, endocrine, rheumatological, and renal manifestations. We assessed progression-free survival (PFS) of specific irAEs classes compared to the no-irAEs group. Results: Twenty-nine out of 43 patients (67.4%) experienced a total of 49 irAEs registered. The most frequent irAE was thyroid dysfunction (n = 14). The median PFS after the beginning of therapy was significantly longer in patients with thyroid dysfunction and cutaneous reactions. In multivariate analysis, thyroid dysfunction was an independent factor for favorable outcome [HR: 0.29 (95% CI 0.11–0.77) p = 0.013]. Moreover, experiencing ≥2 irAEs in the same patient correlated in multivariate analysis with better outcome compared with none/one irAE [HR: 0.33 (95% CI 0.13–0.84) p = 0.020]. Conclusions: This retrospective study suggests an association between specific irAES (thyroid dysfunction and skin reaction) and efficacy of ICIs in metastatic RCC. Notably, multiple irAEs in a single patient were associated with better tumor response. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2021–2022)

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23 pages, 4571 KiB

Open AccessEditor’s ChoiceReview

Exosomes and Cell Communication: From Tumour-Derived Exosomes and Their Role in Tumour Progression to the Use of Exosomal Cargo for Cancer Treatment

by Andrea Nicolini, Paola Ferrari and Pier Mario Biava

Cancers 2021, 13(4), 822; https://doi.org/10.3390/cancers13040822 - 16 Feb 2021

Cited by 63 | Viewed by 5864

Abstract

Exosomes are nano-vesicle-shaped particles secreted by various cells, including cancer cells. Recently, the interest in exosomes among cancer researchers has grown enormously for their many potential roles, and many studies have focused on the bioactive molecules that they export as exosomal cargo. These [...] Read more.

Exosomes are nano-vesicle-shaped particles secreted by various cells, including cancer cells. Recently, the interest in exosomes among cancer researchers has grown enormously for their many potential roles, and many studies have focused on the bioactive molecules that they export as exosomal cargo. These molecules can function as biomarkers in diagnosis or play a relevant role in modulating the immune system and in promoting apoptosis, cancer development and progression. Others, considering exosomes potentially helpful for cancer treatment, have started to investigate them in experimental therapeutic trials. In this review, first, the biogenesis of exosomes and their main characteristics was briefly described. Then, the capability of tumour-derived exosomes and oncosomes in tumour microenvironments (TMEs) remodelling and pre-metastatic niche formation, as well as their interference with the immune system during cancer development, was examined. Finally, the potential role of exosomes for cancer therapy was discussed. Particularly, in addition, their use as carriers of natural substances and drugs with anticancer properties or carriers of boron neutron capture therapy (BNCT) and anticancer vaccines for immunotherapy, exosomes as biological reprogrammers of cancer cells have gained increased consensus. The principal aspects and the rationale of this intriguing therapeutic proposal are briefly considered. Full article

(This article belongs to the Special Issue Experimental and Clinical Advances in Counteracting Progression of Solid Cancers)

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14 pages, 1339 KiB

Open AccessEditor’s ChoiceReview

Tumor Heterogeneity: A Great Barrier in the Age of Cancer Immunotherapy

by Nader El-Sayes, Alyssa Vito and Karen Mossman

Cancers 2021, 13(4), 806; https://doi.org/10.3390/cancers13040806 - 15 Feb 2021

Cited by 121 | Viewed by 17676

Abstract

Throughout the history of oncology research, tumor heterogeneity has been a major hurdle for the successful treatment of cancer. As a result of aberrant changes in the tumor microenvironment such as high mutational burden, hypoxic conditions and abnormal vasculature, several malignant subpopulations often [...] Read more.

Throughout the history of oncology research, tumor heterogeneity has been a major hurdle for the successful treatment of cancer. As a result of aberrant changes in the tumor microenvironment such as high mutational burden, hypoxic conditions and abnormal vasculature, several malignant subpopulations often exist within a single tumor mass. Therapeutic intervention can also increase selective pressure towards subpopulations with acquired resistance. This phenomenon is often the cause of relapse in previously responsive patients, drastically changing the expected outcome of therapy. In the case of cancer immunotherapy, tumor heterogeneity is a substantial barrier as acquired resistance often takes the form of antigen escape and immunosuppression. In an effort to combat intrinsic resistance mechanisms, therapies are often combined as a multi-pronged approach to target multiple pathways simultaneously. These multi-therapy regimens have long been a mainstay of clinical oncology with chemotherapy cocktails but are more recently being investigated in the emerging landscape of immunotherapy. Furthermore, as high throughput technology becomes more affordable and accessible, researchers continue to deepen their understanding of the factors that influence tumor heterogeneity and shape the TME over the course of treatment regimens. In this review, we will investigate the factors that give rise to tumor heterogeneity and the impact it has on the field of immunotherapy. We will discuss how tumor heterogeneity causes resistance to various treatments and review the strategies currently being employed to overcome this challenging clinical hurdle. Finally, we will outline areas of research that should be prioritized to gain a better understanding of tumor heterogeneity and develop appropriate solutions. Full article

(This article belongs to the Special Issue Mechanisms of Cancer Immunotherapy and Immune-Escape)

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22 pages, 10975 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Clinical Candidates Targeting the ATR–CHK1–WEE1 Axis in Cancer

by Lukas Gorecki, Martin Andrs and Jan Korabecny

Cancers 2021, 13(4), 795; https://doi.org/10.3390/cancers13040795 - 14 Feb 2021

Cited by 61 | Viewed by 10306

Abstract

Selective killing of cancer cells while sparing healthy ones is the principle of the perfect cancer treatment and the primary aim of many oncologists, molecular biologists, and medicinal chemists. To achieve this goal, it is crucial to understand the molecular mechanisms that distinguish [...] Read more.

Selective killing of cancer cells while sparing healthy ones is the principle of the perfect cancer treatment and the primary aim of many oncologists, molecular biologists, and medicinal chemists. To achieve this goal, it is crucial to understand the molecular mechanisms that distinguish cancer cells from healthy ones. Accordingly, several clinical candidates that use particular mutations in cell-cycle progressions have been developed to kill cancer cells. As the majority of cancer cells have defects in G1 control, targeting the subsequent intra‑S or G2/M checkpoints has also been extensively pursued. This review focuses on clinical candidates that target the kinases involved in intra‑S and G2/M checkpoints, namely, ATR, CHK1, and WEE1 inhibitors. It provides insight into their current status and future perspectives for anticancer treatment. Overall, even though CHK1 inhibitors are still far from clinical establishment, promising accomplishments with ATR and WEE1 inhibitors in phase II trials present a positive outlook for patient survival. Full article

(This article belongs to the Section Cancer Therapy)

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25 pages, 1236 KiB

Open AccessEditor’s ChoiceReview

Preclinical and Clinical Status of PSMA-Targeted Alpha Therapy for Metastatic Castration-Resistant Prostate Cancer

by Asta Juzeniene, Vilde Yuli Stenberg, Øyvind Sverre Bruland and Roy Hartvig Larsen

Cancers 2021, 13(4), 779; https://doi.org/10.3390/cancers13040779 - 13 Feb 2021

Cited by 65 | Viewed by 8656

Abstract

Bone, lymph node, and visceral metastases are frequent in castrate-resistant prostate cancer patients. Since such patients have only a few months’ survival benefit from standard therapies, there is an urgent need for new personalized therapies. The prostate-specific membrane antigen (PSMA) is overexpressed in [...] Read more.

Bone, lymph node, and visceral metastases are frequent in castrate-resistant prostate cancer patients. Since such patients have only a few months’ survival benefit from standard therapies, there is an urgent need for new personalized therapies. The prostate-specific membrane antigen (PSMA) is overexpressed in prostate cancer and is a molecular target for imaging diagnostics and targeted radionuclide therapy (theragnostics). PSMA-targeted α therapies (PSMA-TAT) may deliver potent and local radiation more selectively to cancer cells than PSMA-targeted β⁻ therapies. In this review, we summarize both the recent preclinical and clinical advances made in the development of PSMA-TAT, as well as the availability of therapeutic α-emitting radionuclides, the development of small molecules and antibodies targeting PSMA. Lastly, we discuss the potentials, limitations, and future perspectives of PSMA-TAT. Full article

(This article belongs to the Collection Prostate Cancer—from Molecular Mechanisms to Clinical Care)

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14 pages, 2365 KiB

Open AccessEditor’s ChoiceArticle

Prognostic Significance of Gene Expression and DNA Methylation Markers in Circulating Tumor Cells and Paired Plasma Derived Exosomes in Metastatic Castration Resistant Prostate Cancer

by Martha Zavridou, Areti Strati, Evangelos Bournakis, Stavroula Smilkou, Victoria Tserpeli and Evi Lianidou

Cancers 2021, 13(4), 780; https://doi.org/10.3390/cancers13040780 - 13 Feb 2021

Cited by 56 | Viewed by 5498

Abstract

Liquid biopsy, based on the analysis of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), provides non-invasive real-time monitoring of tumor evolution and therapeutic efficacy. We performed for the first time a direct comparison study on gene expression and DNA methylation markers [...] Read more.

Liquid biopsy, based on the analysis of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), provides non-invasive real-time monitoring of tumor evolution and therapeutic efficacy. We performed for the first time a direct comparison study on gene expression and DNA methylation markers in CTCs and paired plasma-derived exosomes and evaluated their prognostic significance in metastatic castration resistant prostate cancer. This prospective liquid biopsy (LB) study was based on a group of 62 metastatic castration resistant prostate cancer (mCRPC) patients and 10 healthy donors (HD) as controls. Identical blood draws were used to: (a) enumerate CTC and tumor-derived extracellular vesicles (tdEVs) using CellSearch (CS) and (b) analyze CTCs and paired plasma-derived exosomes at the gene expression and DNA methylation level. CTCs were enumerated using CellSearch in 57/62 patients, with values ranging from 5 to 854 cells/7.5 mL PB. Our results revealed for the first time a significantly higher positivity of gene expression markers (CK-8, CK-18, TWIST1, PSMA, AR-FL, AR-V7, AR-567 and PD-L1 mRNA) in EpCAM-positive CTCs compared to plasma-derived exosomes. GSTP1, RASSF1A and SCHLAFEN were methylated both in CTC and exosomes. In CTCs, Kaplan–Meier analysis revealed that CK-19 (p = 0.009), PSMA (p = 0.001), TWIST1 (p = 0.001) expression and GSTP1 (p = 0.001) methylation were correlated with OS, while in exosomes GSTP1 (p = 0.007) and RASSF1A (p = 0.001) methylation was correlated with OS. Our direct comparison study of CTCs and exosomes at gene expression and DNA methylation level, revealed for the first time a significantly higher positivity in EpCAM-positive CTCs compared to plasma-derived exosomes. Future perspective of this study should be the evaluation of clinical utility of molecular biomarkers in CTCs and exosomes on independent multicentric cohorts with mCRPC patients. Full article

(This article belongs to the Special Issue Tumor Evolution: Progression, Metastasis and Therapeutic Response)

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24 pages, 1366 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Senolytics for Cancer Therapy: Is All that Glitters Really Gold?

by Valerie J. Carpenter, Tareq Saleh and David A. Gewirtz

Cancers 2021, 13(4), 723; https://doi.org/10.3390/cancers13040723 - 10 Feb 2021

Cited by 88 | Viewed by 9409

Abstract

Senolytics represent a group of mechanistically diverse drugs that can eliminate senescent cells, both in tumors and in several aging-related pathologies. Consequently, senolytic use has been proposed as a potential adjuvant approach to improve the response to senescence-inducing conventional and targeted cancer therapies. [...] Read more.

Senolytics represent a group of mechanistically diverse drugs that can eliminate senescent cells, both in tumors and in several aging-related pathologies. Consequently, senolytic use has been proposed as a potential adjuvant approach to improve the response to senescence-inducing conventional and targeted cancer therapies. Despite the unequivocal promise of senolytics, issues of universality, selectivity, resistance, and toxicity remain to be further clarified. In this review, we attempt to summarize and analyze the current preclinical literature involving the use of senolytics in senescent tumor cell models, and to propose tenable solutions and future directions to improve the understanding and use of this novel class of drugs. Full article

(This article belongs to the Special Issue Cancer Therapy-Induced Senescence: The Good, the Bad and the Ugly)

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16 pages, 1326 KiB

Open AccessEditor’s ChoiceReview

PARP Inhibitors in Small-Cell Lung Cancer: Rational Combinations to Improve Responses

by Erik H. Knelson, Shetal A. Patel and Jacob M. Sands

Cancers 2021, 13(4), 727; https://doi.org/10.3390/cancers13040727 - 10 Feb 2021

Cited by 45 | Viewed by 6205

Abstract

Despite recent advances in first-line treatment for small-cell lung cancer (SCLC), durable responses remain rare. The DNA repair enzyme poly-(ADP)-ribose polymerase (PARP) was identified as a therapeutic target in SCLC using unbiased preclinical screens and confirmed in human and mouse models. Early trials [...] Read more.

Despite recent advances in first-line treatment for small-cell lung cancer (SCLC), durable responses remain rare. The DNA repair enzyme poly-(ADP)-ribose polymerase (PARP) was identified as a therapeutic target in SCLC using unbiased preclinical screens and confirmed in human and mouse models. Early trials of PARP inhibitors, either alone or in combination with chemotherapy, showed promising but limited responses, suggesting that selecting patient subsets and treatment combinations will prove critical to further clinical development. Expression of SLFN11 and other components of the DNA damage response (DDR) pathway appears to select for improved responses. Combining PARP inhibitors with agents that damage DNA and inhibit DDR appears particularly effective in preclinical and early trial data, as well as strategies that enhance antitumor immunity downstream of DNA damage. A robust understanding of the mechanisms of DDR in SCLC, which exhibits intrinsic replication stress, will improve selection of agents and predictive biomarkers. The most effective combinations will target multiple nodes in the DNA damage/DDR/immune activation cascade to minimize toxicity from synthetic lethality. Full article

(This article belongs to the Special Issue Small Cell Lung Cancer: A New Era Is Beginning?)

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20 pages, 3480 KiB

Open AccessEditor’s ChoiceArticle

Blocking Migration of Polymorphonuclear Myeloid-Derived Suppressor Cells Inhibits Mouse Melanoma Progression

by Christopher Groth, Ludovica Arpinati, Merav E. Shaul, Nina Winkler, Klara Diester, Nicolas Gengenbacher, Rebekka Weber, Ihor Arkhypov, Samantha Lasser, Vera Petrova, Hellmut G. Augustin, Peter Altevogt, Jochen Utikal, Zvi G. Fridlender and Viktor Umansky

Cancers 2021, 13(4), 726; https://doi.org/10.3390/cancers13040726 - 10 Feb 2021

Cited by 24 | Viewed by 4905

Abstract

Background: Despite recent improvement in the treatment of malignant melanoma by immune-checkpoint inhibitors, the disease can progress due to an immunosuppressive tumor microenvironment (TME) mainly represented by myeloid-derived suppressor cells (MDSC). However, the relative contribution of the polymorphonuclear (PMN) and monocytic (M) MDSC [...] Read more.

Background: Despite recent improvement in the treatment of malignant melanoma by immune-checkpoint inhibitors, the disease can progress due to an immunosuppressive tumor microenvironment (TME) mainly represented by myeloid-derived suppressor cells (MDSC). However, the relative contribution of the polymorphonuclear (PMN) and monocytic (M) MDSC subsets to melanoma progression is not clear. Here, we compared both subsets regarding their immunosuppressive capacity and recruitment mechanisms. Furthermore, we inhibited PMN-MDSC migration in vivo to determine its effect on tumor progression. Methods: Using the RET transgenic melanoma mouse model, we investigated the immunosuppressive function of MDSC subsets and chemokine receptor expression on these cells. The effect of CXCR2 inhibition on PMN-MDSC migration and tumor progression was studied in RET transgenic mice and in C57BL/6 mice after surgical resection of primary melanomas. Results: Immunosuppressive capacity of intratumoral M- and PMN-MDSC was comparable in melanoma bearing mice. Anti-CXCR2 therapy prolonged survival of these mice and decreased the occurrence of distant metastasis. Furthermore, this therapy reduced the infiltration of melanoma lesions and pre-metastatic sites with PMN-MDSC that was associated with the accumulation of natural killer (NK) cells. Conclusions: We provide evidence for the tumor⁻promoting properties of PMN-MDSC as well as for the anti-tumor effects upon their targeting in melanoma bearing mice. Full article

(This article belongs to the Special Issue The Portrait of Cancer Immunotherapy: Tumor Microenvironment, Biomarkers and Immune Resistance)

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17 pages, 1321 KiB

Open AccessEditor’s ChoiceReview

Interplay between the Gut Microbiota and Inflammatory Mediators in the Development of Colorectal Cancer

by Gwangbeom Heo, Yunna Lee and Eunok Im

Cancers 2021, 13(4), 734; https://doi.org/10.3390/cancers13040734 - 10 Feb 2021

Cited by 23 | Viewed by 4889

Abstract

Inflammatory mediators modulate inflammatory pathways during the development of colorectal cancer. Inflammatory mediators secreted by both immune and tumor cells can influence carcinogenesis, progression, and tumor metastasis. The gut microbiota, which colonize the entire intestinal tract, especially the colon, are closely linked to [...] Read more.

Inflammatory mediators modulate inflammatory pathways during the development of colorectal cancer. Inflammatory mediators secreted by both immune and tumor cells can influence carcinogenesis, progression, and tumor metastasis. The gut microbiota, which colonize the entire intestinal tract, especially the colon, are closely linked to colorectal cancer through an association with inflammatory mediators such as tumor necrosis factor, nuclear factor kappa B, interleukins, and interferons. This association may be a potential therapeutic target, since therapeutic interventions targeting the gut microbiota have been actively investigated in both the laboratory and in clinics and include fecal microbiota transplantation and probiotics. Full article

(This article belongs to the Special Issue Microbiota in Colorectal Cancer)

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34 pages, 15361 KiB

Open AccessEditor’s ChoiceReview

Microfluidic Organoids-on-a-Chip: Quantum Leap in Cancer Research

by Fahriye Duzagac, Gloria Saorin, Lorenzo Memeo, Vincenzo Canzonieri and Flavio Rizzolio

Cancers 2021, 13(4), 737; https://doi.org/10.3390/cancers13040737 - 10 Feb 2021

Cited by 72 | Viewed by 12109

Abstract

Organ-like cell clusters, so-called organoids, which exhibit self-organized and similar organ functionality as the tissue of origin, have provided a whole new level of bioinspiration for ex vivo systems. Microfluidic organoid or organs-on-a-chip platforms are a new group of micro-engineered promising models that [...] Read more.

Organ-like cell clusters, so-called organoids, which exhibit self-organized and similar organ functionality as the tissue of origin, have provided a whole new level of bioinspiration for ex vivo systems. Microfluidic organoid or organs-on-a-chip platforms are a new group of micro-engineered promising models that recapitulate 3D tissue structure and physiology and combines several advantages of current in vivo and in vitro models. Microfluidics technology is used in numerous applications since it allows us to control and manipulate fluid flows with a high degree of accuracy. This system is an emerging tool for understanding disease development and progression, especially for personalized therapeutic strategies for cancer treatment, which provide well-grounded, cost-effective, powerful, fast, and reproducible results. In this review, we highlight how the organoid-on-a-chip models have improved the potential of efficiency and reproducibility of organoid cultures. More widely, we discuss current challenges and development on organoid culture systems together with microfluidic approaches and their limitations. Finally, we describe the recent progress and potential utilization in the organs-on-a-chip practice. Full article

(This article belongs to the Special Issue Cancer Organoids in Basic Science and Translational Medicine)

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24 pages, 1625 KiB

Open AccessEditor’s ChoiceReview

Mechanisms of Resistance to Conventional Therapies for Osteosarcoma

by Louise Marchandet, Morgane Lallier, Céline Charrier, Marc Baud’huin, Benjamin Ory and François Lamoureux

Cancers 2021, 13(4), 683; https://doi.org/10.3390/cancers13040683 - 8 Feb 2021

Cited by 95 | Viewed by 6228

Abstract

Osteosarcoma (OS) is the most common primary bone tumor, mainly occurring in children and adolescents. Current standard therapy includes tumor resection associated with multidrug chemotherapy. However, patient survival has not evolved for the past decades. Since the 1970s, the 5-year survival rate is [...] Read more.

Osteosarcoma (OS) is the most common primary bone tumor, mainly occurring in children and adolescents. Current standard therapy includes tumor resection associated with multidrug chemotherapy. However, patient survival has not evolved for the past decades. Since the 1970s, the 5-year survival rate is around 75% for patients with localized OS but dramatically drops to 20% for bad responders to chemotherapy or patients with metastases. Resistance is one of the biological processes at the origin of therapeutic failure. Therefore, it is necessary to better understand and decipher molecular mechanisms of resistance to conventional chemotherapy in order to develop new strategies and to adapt treatments for patients, thus improving the survival rate. This review will describe most of the molecular mechanisms involved in OS chemoresistance, such as a decrease in intracellular accumulation of drugs, inactivation of drugs, improved DNA repair, modulations of signaling pathways, resistance linked to autophagy, disruption in genes expression linked to the cell cycle, or even implication of the micro-environment. We will also give an overview of potential therapeutic strategies to circumvent resistance development. Full article

(This article belongs to the Special Issue Research Advances and Therapeutic Strategies of Human Osteosarcoma)

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17 pages, 3954 KiB

Open AccessEditor’s ChoiceArticle

Soluble PD-L1 Is an Independent Prognostic Factor in Clear Cell Renal Cell Carcinoma

by Gorka Larrinaga, Jon Danel Solano-Iturri, Peio Errarte, Miguel Unda, Ana Loizaga-Iriarte, Amparo Pérez-Fernández, Enrique Echevarría, Aintzane Asumendi, Claudia Manini, Javier C. Angulo and José I. López

Cancers 2021, 13(4), 667; https://doi.org/10.3390/cancers13040667 - 7 Feb 2021

Cited by 41 | Viewed by 3867

Abstract

(1). Background: Immunohistochemical (IHC) evaluation of programmed death-1 (PD-1) and its ligand (PD-L1) is being used to evaluate advanced malignancies with potential response to immune checkpoint inhibitors. We evaluated both plasma and tissue expression of PD-1 and PD-L1 in the same cohort [...] Read more.

(1). Background: Immunohistochemical (IHC) evaluation of programmed death-1 (PD-1) and its ligand (PD-L1) is being used to evaluate advanced malignancies with potential response to immune checkpoint inhibitors. We evaluated both plasma and tissue expression of PD-1 and PD-L1 in the same cohort of patients, including non-metastatic and metastatic clear cell renal cell carcinoma (CCRCC). Concomitant plasma and tissue expression of PD-1 and PD-L1 was evaluated with emphasis on diagnostic and prognostic implications. (2) Methods: we analyzed PD-1 and PD-L1 IHC expression in tumor tissues and soluble forms (sPD-1 and sPD-L1) in plasma from 89 patients with CCRCC, of which 23 were metastatic and 16 received systemic therapy. The primary endpoint was evaluation of overall survival using Kaplan-Meier analysis and the Cox regression model. Plasma samples from healthy volunteers were also evaluated. (3) Results: Interestingly, sPD-1 and sPD-L1 levels were lower in cancer patients than in controls. sPD-1 and sPD-L1 levels and their counterpart tissue expression both at the tumor center and infiltrating front were not associated. Higher expression of both PD-1 and PD-L1 were associated with tumor grade, necrosis and tumor size. PD-1 was associated to tumor stage (pT) and PD-L1 to metastases. sPD-1 and sPD-L1 were not associated with clinico-pathological parameters, although both were higher in patients with synchronous metastases compared to metachronous ones and sPD-L1 was also higher for metastatic patients compared to non-metastatic patients. sPD-1 was also associated with the International Metastatic Renal Cell Cancer Database Consortium (IMDC) prognostic groups in metastatic CCRCC and also to the Morphology, Attenuation, Size and Structure (MASS) response criteria in metastatic patients treated with systemic therapy, mainly tyrosine-kinase inhibitors. Regarding prognosis, PD-L1 immunostaining at the tumor center with and without the tumor front was associated with worse survival, and so was sPD-L1 at a cut-off >793 ng/mL. Combination of positivity at both the tissue and plasma level increased the level of significance to predict prognosis. (4) Conclusions: Our findings corroborate the role of PD-L1 IHC to evaluate prognosis in CCRCC and present novel data on the usefulness of plasma sPD-L1 as a promising biomarker of survival in this neoplasia. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2021–2022)

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29 pages, 1712 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Focal Adhesion Kinase Fine Tunes Multifaced Signals toward Breast Cancer Progression

by Damiano Cosimo Rigiracciolo, Francesca Cirillo, Marianna Talia, Lucia Muglia, Jorge Silvio Gutkind, Marcello Maggiolini and Rosamaria Lappano

Cancers 2021, 13(4), 645; https://doi.org/10.3390/cancers13040645 - 5 Feb 2021

Cited by 41 | Viewed by 7361

Abstract

Breast cancer represents the most common diagnosed malignancy and the main leading cause of tumor-related death among women worldwide. Therefore, several efforts have been made in order to identify valuable molecular biomarkers for the prognosis and prediction of therapeutic responses in breast tumor [...] Read more.

Breast cancer represents the most common diagnosed malignancy and the main leading cause of tumor-related death among women worldwide. Therefore, several efforts have been made in order to identify valuable molecular biomarkers for the prognosis and prediction of therapeutic responses in breast tumor patients. In this context, emerging discoveries have indicated that focal adhesion kinase (FAK), a non-receptor tyrosine kinase, might represent a promising target involved in breast tumorigenesis. Of note, high FAK expression and activity have been tightly correlated with a poor clinical outcome and metastatic features in several tumors, including breast cancer. Recently, a role for the integrin-FAK signaling in mechanotransduction has been suggested and the function of FAK within the breast tumor microenvironment has been ascertained toward tumor angiogenesis and vascular permeability. FAK has been also involved in cancer stem cells (CSCs)-mediated initiation, maintenance and therapeutic responses of breast tumors. In addition, the potential of FAK to elicit breast tumor-promoting effects has been even associated with the capability to modulate immune responses. On the basis of these findings, several agents targeting FAK have been exploited in diverse preclinical tumor models. Here, we recapitulate the multifaceted action exerted by FAK and its prognostic significance in breast cancer. Moreover, we highlight the recent clinical evidence regarding the usefulness of FAK inhibitors in the treatment of breast tumors. Full article

(This article belongs to the Special Issue Lights and Shadows in the Communication between Hormones and Growth Factor Signaling in Cancer)

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15 pages, 2272 KiB

Open AccessEditor’s ChoiceArticle

Mutational Landscape of Virus- and UV-Associated Merkel Cell Carcinoma Cell Lines Is Comparable to Tumor Tissue

by Kai Horny, Patricia Gerhardt, Angela Hebel-Cherouny, Corinna Wülbeck, Jochen Utikal and Jürgen C. Becker

Cancers 2021, 13(4), 649; https://doi.org/10.3390/cancers13040649 - 5 Feb 2021

Cited by 18 | Viewed by 4072

Abstract

Merkel cell carcinoma (MCC) is a rare, highly aggressive cutaneous malignancy that is either associated with the integration of the Merkel cell polyomavirus or chronic UV exposure. These two types of carcinogenesis are reflected in characteristic mutational features present in MCC tumor lesions. [...] Read more.

Merkel cell carcinoma (MCC) is a rare, highly aggressive cutaneous malignancy that is either associated with the integration of the Merkel cell polyomavirus or chronic UV exposure. These two types of carcinogenesis are reflected in characteristic mutational features present in MCC tumor lesions. However, the genomic characteristics of MCC cell lines used as preclinical models are not well established. Thus, we analyzed the exomes of three virus-negative and six virus-positive MCC cell lines, all showing a classical neuroendocrine growth pattern. Virus-negative cell lines are characterized by a high tumor mutational burden (TMB), UV-light-induced DNA damage, functionally relevant coding mutations, e.g., in RB1 and TP53, and large amounts of copy number variations (CNVs). In contrast, virus-positive cell lines have a low TMB with few coding mutations and lack prominent mutational signatures, but harbor characteristic CNVs. One of the virus-negative cell lines has a local MYC amplification associated with high MYC mRNA expression. In conclusion, virus-positive and -negative MCC cell lines with a neuroendocrine growth pattern resemble mutational features observed in MCC tissue samples, which strengthens their utility for functional studies. Full article

(This article belongs to the Special Issue The Biological and Clinical Aspects of Merkel Cell Carcinoma)

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33 pages, 1094 KiB

Open AccessEditor’s ChoiceReview

Harnessing Tumor Necrosis Factor Alpha to Achieve Effective Cancer Immunotherapy

by María Florencia Mercogliano, Sofía Bruni, Florencia Mauro, Patricia Virginia Elizalde and Roxana Schillaci

Cancers 2021, 13(3), 564; https://doi.org/10.3390/cancers13030564 - 2 Feb 2021

Cited by 84 | Viewed by 9515

Abstract

Tumor necrosis factor alpha (TNFα) is a pleiotropic cytokine known to have contradictory roles in oncoimmunology. Indeed, TNFα has a central role in the onset of the immune response, inducing both activation and the effector function of macrophages, dendritic cells, natural killer (NK) [...] Read more.

Tumor necrosis factor alpha (TNFα) is a pleiotropic cytokine known to have contradictory roles in oncoimmunology. Indeed, TNFα has a central role in the onset of the immune response, inducing both activation and the effector function of macrophages, dendritic cells, natural killer (NK) cells, and B and T lymphocytes. Within the tumor microenvironment, however, TNFα is one of the main mediators of cancer-related inflammation. It is involved in the recruitment and differentiation of immune suppressor cells, leading to evasion of tumor immune surveillance. These characteristics turn TNFα into an attractive target to overcome therapy resistance and tackle cancer. This review focuses on the diverse molecular mechanisms that place TNFα as a source of resistance to immunotherapy such as monoclonal antibodies against cancer cells or immune checkpoints and adoptive cell therapy. We also expose the benefits of TNFα blocking strategies in combination with immunotherapy to improve the antitumor effect and prevent or treat adverse immune-related effects. Full article

(This article belongs to the Special Issue Challenges and Opportunities for Effective Cancer Immunotherapies)

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16 pages, 1830 KiB

Open AccessEditor’s ChoiceReview

The Role of Hypoxia in Glioblastoma Radiotherapy Resistance

by Agathe L. Chédeville and Patricia A. Madureira

Cancers 2021, 13(3), 542; https://doi.org/10.3390/cancers13030542 - 1 Feb 2021

Cited by 71 | Viewed by 5911

Abstract

Glioblastoma (GB) (grade IV astrocytoma) is the most malignant type of primary brain tumor with a 16 months median survival time following diagnosis. Despite increasing attention regarding the development of targeted therapies for GB that resulted in around 450 clinical trials currently undergoing, [...] Read more.

Glioblastoma (GB) (grade IV astrocytoma) is the most malignant type of primary brain tumor with a 16 months median survival time following diagnosis. Despite increasing attention regarding the development of targeted therapies for GB that resulted in around 450 clinical trials currently undergoing, radiotherapy still remains the most clinically effective treatment for these patients. Nevertheless, radiotherapy resistance (radioresistance) is commonly observed in GB patients leading to tumor recurrence and eventually patient death. It is therefore essential to unravel the molecular mechanisms underpinning GB cell radioresistance in order to develop novel strategies and combinational therapies focused on enhancing tumor cell sensitivity to radiotherapy. In this review, we present a comprehensive examination of the current literature regarding the role of hypoxia (O₂ partial pressure less than 10 mmHg), a main GB microenvironmental factor, in radioresistance with the ultimate goal of identifying potential molecular markers and therapeutic targets to overcome this issue in the future. Full article

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

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13 pages, 632 KiB

Open AccessEditor’s ChoiceReview

PD-L1, TMB, MSI, and Other Predictors of Response to Immune Checkpoint Inhibitors in Biliary Tract Cancer

by Alessandro Rizzo, Angela Dalia Ricci and Giovanni Brandi

Cancers 2021, 13(3), 558; https://doi.org/10.3390/cancers13030558 - 1 Feb 2021

Cited by 215 | Viewed by 10539

Abstract

Biliary tract cancer (BTC) represents the second most frequently diagnosed primary liver cancer worldwide following hepatocellular carcinoma, and the overall survival of patients with unresectable disease remains poor. In recent years, the advent of immune checkpoint inhibitors (ICIs) has revolutionized the therapeutic landscape [...] Read more.

Biliary tract cancer (BTC) represents the second most frequently diagnosed primary liver cancer worldwide following hepatocellular carcinoma, and the overall survival of patients with unresectable disease remains poor. In recent years, the advent of immune checkpoint inhibitors (ICIs) has revolutionized the therapeutic landscape of several malignancies with these agents, which have also been explored in advanced BTC, as monotherapy or in combination with other anticancer agents. However, clinical trials evaluating ICIs in BTC have shown conflicting results, and the clinical benefit provided by immunotherapy seems limited to a small subgroup of BTC patients. Thus, the identification of reliable predictors of the response to immunotherapy represents a significant challenge in this setting. This review provides an overview of the available evidence on the biomarkers predictive of the response to ICIs in patients with advanced BTC, especially focusing on programmed death-ligand 1 (PD-L1), tumor mutational burden (TMB), microsatellite instability (MSI), and other emerging biomarkers. Full article

(This article belongs to the Special Issue Surgical Treatment of Cholangiocarcinoma)

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16 pages, 2888 KiB

Open AccessEditor’s ChoiceArticle

Type 2 Innate Lymphoid Cells Protect against Colorectal Cancer Progression and Predict Improved Patient Survival

by Qiutong Huang, Nicolas Jacquelot, Adele Preaudet, Soroor Hediyeh-zadeh, Fernando Souza-Fonseca-Guimaraes, Andrew N. J. McKenzie, Philip M. Hansbro, Melissa J. Davis, Lisa A. Mielke, Tracy L. Putoczki and Gabrielle T. Belz

Cancers 2021, 13(3), 559; https://doi.org/10.3390/cancers13030559 - 1 Feb 2021

Cited by 40 | Viewed by 5922

Abstract

Chronic inflammation of the gastrointestinal (GI) tract contributes to colorectal cancer (CRC) progression. While the role of adaptive T cells in CRC is now well established, the role of innate immune cells, specifically innate lymphoid cells (ILCs), is not well understood. To define [...] Read more.

Chronic inflammation of the gastrointestinal (GI) tract contributes to colorectal cancer (CRC) progression. While the role of adaptive T cells in CRC is now well established, the role of innate immune cells, specifically innate lymphoid cells (ILCs), is not well understood. To define the role of ILCs in CRC we employed complementary heterotopic and chemically-induced CRC mouse models. We discovered that ILCs were abundant in CRC tumours and contributed to anti-tumour immunity. We focused on ILC2 and showed that ILC2-deficient mice developed a higher tumour burden compared with littermate wild-type controls. We generated an ILC2 gene signature and using machine learning models revealed that CRC patients with a high intratumor ILC2 gene signature had a favourable clinical prognosis. Collectively, our results highlight a critical role for ILC2 in CRC, suggesting a potential new avenue to improve clinical outcomes through ILC2-agonist based therapeutic approaches. Full article

(This article belongs to the Special Issue NK/ILCs in Tumors)

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22 pages, 26963 KiB

Open AccessEditor’s ChoiceReview

Tumor Hypoxia as a Barrier in Cancer Therapy: Why Levels Matter

by Tord Hompland, Christina Sæten Fjeldbo and Heidi Lyng

Cancers 2021, 13(3), 499; https://doi.org/10.3390/cancers13030499 - 28 Jan 2021

Cited by 134 | Viewed by 11876

Abstract

Hypoxia arises in tumor regions with insufficient oxygen supply and is a major barrier in cancer treatment. The distribution of hypoxia levels is highly heterogeneous, ranging from mild, almost non-hypoxic, to severe and anoxic levels. The individual hypoxia levels induce a variety of [...] Read more.

Hypoxia arises in tumor regions with insufficient oxygen supply and is a major barrier in cancer treatment. The distribution of hypoxia levels is highly heterogeneous, ranging from mild, almost non-hypoxic, to severe and anoxic levels. The individual hypoxia levels induce a variety of biological responses that impair the treatment effect. A stronger focus on hypoxia levels rather than the absence or presence of hypoxia in our investigations will help development of improved strategies to treat patients with hypoxic tumors. Current knowledge on how hypoxia levels are sensed by cancer cells and mediate cellular responses that promote treatment resistance is comprehensive. Recently, it has become evident that hypoxia also has an important, more unexplored role in the interaction between cancer cells, stroma and immune cells, influencing the composition and structure of the tumor microenvironment. Establishment of how such processes depend on the hypoxia level requires more advanced tumor models and methodology. In this review, we describe promising model systems and tools for investigations of hypoxia levels in tumors. We further present current knowledge and emerging research on cellular responses to individual levels, and discuss their impact in novel therapeutic approaches to overcome the hypoxia barrier. Full article

(This article belongs to the Special Issue Novel Perspectives on Hypoxia in Cancer)

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25 pages, 9574 KiB

Open AccessEditor’s ChoiceReview

Targeting Lysyl Oxidase Family Meditated Matrix Cross-Linking as an Anti-Stromal Therapy in Solid Tumours

by Yordanos F.I. Setargew, Kaitlin Wyllie, Rhiannon D. Grant, Jessica L. Chitty and Thomas R. Cox

Cancers 2021, 13(3), 491; https://doi.org/10.3390/cancers13030491 - 27 Jan 2021

Cited by 70 | Viewed by 10373

Abstract

The lysyl oxidase (LOX) family of enzymes are a major driver in the biogenesis of desmoplastic matrix at the primary tumour and secondary metastatic sites. With the increasing interest in and development of anti-stromal therapies aimed at improving clinical outcomes of cancer patients, [...] Read more.

The lysyl oxidase (LOX) family of enzymes are a major driver in the biogenesis of desmoplastic matrix at the primary tumour and secondary metastatic sites. With the increasing interest in and development of anti-stromal therapies aimed at improving clinical outcomes of cancer patients, the Lox family has emerged as a potentially powerful clinical target. This review examines how lysyl oxidase family dysregulation in solid cancers contributes to disease progression and poor patient outcomes, as well as an evaluation of the preclinical landscape of LOX family targeting therapeutics. We also discuss the suitability of the LOX family as a diagnostic and/or prognostic marker in solid tumours. Full article

(This article belongs to the Special Issue Treating the Cancer Matrix: Progress in the Identification of Potential Therapeutic Targets)

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23 pages, 1197 KiB

Open AccessEditor’s ChoiceReview

Radiotherapy–Immunotherapy Combination: How Will We Bridge the Gap Between Pre-Clinical Promise and Effective Clinical Delivery?

by Erminia Romano, Jamie Honeychurch and Timothy M. Illidge

Cancers 2021, 13(3), 457; https://doi.org/10.3390/cancers13030457 - 26 Jan 2021

Cited by 32 | Viewed by 4931

Abstract

Radiotherapy (RT) is highly effective at directly killing tumor cells and plays an important part in cancer treatments being delivered to around 50% of all cancer patients. The additional immunomodulatory properties of RT have been investigated, and if exploited effectively, have the potential [...] Read more.

Radiotherapy (RT) is highly effective at directly killing tumor cells and plays an important part in cancer treatments being delivered to around 50% of all cancer patients. The additional immunomodulatory properties of RT have been investigated, and if exploited effectively, have the potential to further improve the efficacy of RT and cancer outcomes. The initial results of combining RT with immunomodulatory agents have generated promising data in pre-clinical studies, which has in turn led to a large number of RT and immunotherapy clinical trials. The overarching aim of these combinations is to enhance anti-tumor immune responses and improve responses rates and patient outcomes. In order to maximize this undoubted opportunity, there remain a number of important questions that need to be addressed, including: (i) the optimal RT dose and fractionation schedule; (ii) the optimal RT target volume; (iii) the optimal immuno-oncology (IO) agent(s) to partner with RT; (iv) the optimal site(s)/route(s) of administration of IO agents; and finally, the optimal RT schedule. In this review, we will summarize progress to date and identify current gaps in knowledge that need to be addressed in order to facilitate effective clinical translation of RT and IO agent combinations. Full article

(This article belongs to the Special Issue Advances in Experimental Radiotherapy)

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31 pages, 1200 KiB

Open AccessEditor’s ChoiceReview

The CXCL12 Crossroads in Cancer Stem Cells and Their Niche

by Juan Carlos López-Gil, Laura Martin-Hijano, Patrick C. Hermann and Bruno Sainz, Jr.

Cancers 2021, 13(3), 469; https://doi.org/10.3390/cancers13030469 - 26 Jan 2021

Cited by 41 | Viewed by 7689

Abstract

Cancer stem cells (CSCs) are defined as a subpopulation of “stem”-like cells within the tumor with unique characteristics that allow them to maintain tumor growth, escape standard anti-tumor therapies and drive subsequent repopulation of the tumor. This is the result of their intrinsic [...] Read more.

Cancer stem cells (CSCs) are defined as a subpopulation of “stem”-like cells within the tumor with unique characteristics that allow them to maintain tumor growth, escape standard anti-tumor therapies and drive subsequent repopulation of the tumor. This is the result of their intrinsic “stem”-like features and the strong driving influence of the CSC niche, a subcompartment within the tumor microenvironment that includes a diverse group of cells focused on maintaining and supporting the CSC. CXCL12 is a chemokine that plays a crucial role in hematopoietic stem cell support and has been extensively reported to be involved in several cancer-related processes. In this review, we will provide the latest evidence about the interactions between CSC niche-derived CXCL12 and its receptors—CXCR4 and CXCR7—present on CSC populations across different tumor entities. The interactions facilitated by CXCL12/CXCR4/CXCR7 axes seem to be strongly linked to CSC “stem”-like features, tumor progression, and metastasis promotion. Altogether, this suggests a role for CXCL12 and its receptors in the maintenance of CSCs and the components of their niche. Moreover, we will also provide an update of the therapeutic options being currently tested to disrupt the CXCL12 axes in order to target, directly or indirectly, the CSC subpopulation. Full article

(This article belongs to the Special Issue Stem Cell in Cancer Therapy)

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