Cancers

19 pages, 1765 KB

Open AccessEditor’s ChoiceArticle

Extracellular Vesicle microRNAs Contribute to the Osteogenic Inhibition of Mesenchymal Stem Cells in Multiple Myeloma

by Stefania Raimondo, Ornella Urzì, Alice Conigliaro, Giosuè Lo Bosco, Sofia Parisi, Melania Carlisi, Sergio Siragusa, Lavinia Raimondi, Angela De Luca, Gianluca Giavaresi and Riccardo Alessandro

Cancers 2020, 12(2), 449; https://doi.org/10.3390/cancers12020449 - 14 Feb 2020

Cited by 59 | Viewed by 4728

Abstract

Osteolytic bone disease is the major complication associated with the progression of multiple myeloma (MM). Recently, extracellular vesicles (EVs) have emerged as mediators of MM-associated bone disease by inhibiting the osteogenic differentiation of human mesenchymal stem cells (hMSCs). Here, we investigated a correlation [...] Read more.

Osteolytic bone disease is the major complication associated with the progression of multiple myeloma (MM). Recently, extracellular vesicles (EVs) have emerged as mediators of MM-associated bone disease by inhibiting the osteogenic differentiation of human mesenchymal stem cells (hMSCs). Here, we investigated a correlation between the EV-mediated osteogenic inhibition and MM vesicle content, focusing on miRNAs. By the use of a MicroRNA Card, we identified a pool of miRNAs, highly expressed in EVs, from MM cell line (MM1.S EVs), expression of which was confirmed in EVs from bone marrow (BM) plasma of patients affected by smoldering myeloma (SMM) and MM. Notably,we found that miR-129-5p, which targets different osteoblast (OBs) differentiation markers, is enriched in MM-EVs compared to SMM-EVs, thus suggesting a selective packaging correlated with pathological grade. We found that miR-129-5p can be transported to hMSCs by MM-EVs and, by the use of miRNA mimics, we investigated its role in recipient cells. Our data demonstrated that the increase of miR-129-5p levels in hMSCs under osteoblastic differentiation stimuli inhibited the expression of the transcription factor Sp1, previously described as a positive modulator of osteoblastic differentiation, and of its target the Alkaline phosphatase (ALPL), thus identifying miR-129-5p among the players of vesicle-mediated bone disease. Full article

(This article belongs to the Special Issue Recent Advances on the Pathobiology and Treatment of Multiple Myeloma)

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32 pages, 1513 KB

Open AccessEditor’s ChoiceReview

Multiple Myeloma: Available Therapies and Causes of Drug Resistance

by Vanessa Pinto, Rui Bergantim, Hugo R. Caires, Hugo Seca, José E. Guimarães and M. Helena Vasconcelos

Cancers 2020, 12(2), 407; https://doi.org/10.3390/cancers12020407 - 10 Feb 2020

Cited by 175 | Viewed by 24893

Abstract

Multiple myeloma (MM) is the second most common blood cancer. Treatments for MM include corticosteroids, alkylating agents, anthracyclines, proteasome inhibitors, immunomodulatory drugs, histone deacetylase inhibitors and monoclonal antibodies. Survival outcomes have improved substantially due to the introduction of many of these drugs allied [...] Read more.

Multiple myeloma (MM) is the second most common blood cancer. Treatments for MM include corticosteroids, alkylating agents, anthracyclines, proteasome inhibitors, immunomodulatory drugs, histone deacetylase inhibitors and monoclonal antibodies. Survival outcomes have improved substantially due to the introduction of many of these drugs allied with their rational use. Nonetheless, MM patients successively relapse after one or more treatment regimens or become refractory, mostly due to drug resistance. This review focuses on the main drugs used in MM treatment and on causes of drug resistance, including cytogenetic, genetic and epigenetic alterations, abnormal drug transport and metabolism, dysregulation of apoptosis, autophagy activation and other intracellular signaling pathways, the presence of cancer stem cells, and the tumor microenvironment. Furthermore, we highlight the areas that need to be further clarified in an attempt to identify novel therapeutic targets to counteract drug resistance in MM patients. Full article

(This article belongs to the Special Issue Latest Development in Multiple Myeloma)

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14 pages, 8111 KB

Open AccessEditor’s ChoiceArticle

Expression of Tryptophan 2,3-Dioxygenase in Metastatic Uveal Melanoma

by Mizue Terai, Eric Londin, Ankit Rochani, Emma Link, Bao Lam, Gagan Kaushal, Alok Bhushan, Marlana Orloff and Takami Sato

Cancers 2020, 12(2), 405; https://doi.org/10.3390/cancers12020405 - 10 Feb 2020

Cited by 35 | Viewed by 4523

Abstract

Uveal melanoma (UM) is the most common primary eye malignancy in adults and up to 50% of patients subsequently develop systemic metastasis. Metastatic uveal melanoma (MUM) is highly resistant to immunotherapy. One of the mechanisms for resistance would be the immune-suppressive tumor microenvironment. [...] Read more.

Uveal melanoma (UM) is the most common primary eye malignancy in adults and up to 50% of patients subsequently develop systemic metastasis. Metastatic uveal melanoma (MUM) is highly resistant to immunotherapy. One of the mechanisms for resistance would be the immune-suppressive tumor microenvironment. Here, we have investigated the role of tryptophan 2,3-dioxygenase (TDO) in UM. Both TDO and indoleamine 2,3-dioxygenase (IDO) catalyze tryptophan and produce kynurenine, which could cause inhibition of T cell immune responses. We first studied the expression of TDO on tumor tissue specimens obtained from UM hepatic metastasis. High expression of TDO protein was confirmed in all hepatic metastasis. TDO was positive in both normal hepatocytes and the tumor cells with relatively higher expression in tumor cells. On the other hand, IDO protein remained undetectable in all of the MUM specimens. UM cell lines established from metastasis also expressed TDO protein and increasing kynurenine levels were detected in the supernatant of MUM cell culture. In TCGA database, higher TDO2 expression in primary UM significantly correlated to BAP1 mutation and monosomy 3. These results indicate that TDO might be one of the key mechanisms for resistance to immunotherapy in UM. Full article

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16 pages, 1717 KB

Open AccessEditor’s ChoiceReview

PARP Inhibitors as Therapeutics: Beyond Modulation of PARylation

by Ahrum Min and Seock-Ah Im

Cancers 2020, 12(2), 394; https://doi.org/10.3390/cancers12020394 - 8 Feb 2020

Cited by 112 | Viewed by 10900

Abstract

Poly (ADP-ribose) polymerase (PARP) 1 is an essential molecule in DNA damage response by sensing DNA damage and docking DNA repair proteins on the damaged DNA site through a type of posttranslational modification, poly (ADP-Ribosyl)ation (PARylation). PARP inhibitors, which inhibit PARylation through competitively [...] Read more.

Poly (ADP-ribose) polymerase (PARP) 1 is an essential molecule in DNA damage response by sensing DNA damage and docking DNA repair proteins on the damaged DNA site through a type of posttranslational modification, poly (ADP-Ribosyl)ation (PARylation). PARP inhibitors, which inhibit PARylation through competitively binding to NAD+ binding site of PARP1 and PARP2, have improved clinical benefits for BRCA mutated tumors, leading to their accelerated clinical application. However, the antitumor activities of PARP inhibitors in clinical development are different, due to PARP trapping activity beyond blocking PARylation reactions. In this review, we comprehensively address the current state of knowledge regarding the mechanisms of action of PARP inhibitors. We will also discuss the different effects of PARP inhibitors in combination with cytotoxic chemotherapeutic agents regarding the mechanism of regulating PARylation. Full article

(This article belongs to the Special Issue PARPs, PAR and NAD Metabolism and Their Inhibitors in Cancer)

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14 pages, 2618 KB

Open AccessEditor’s ChoiceArticle

Early Detection of Hyperprogressive Disease in Non-Small Cell Lung Cancer by Monitoring of Systemic T Cell Dynamics

by Hugo Arasanz, Miren Zuazo, Ana Bocanegra, María Gato, Maite Martínez-Aguillo, Idoia Morilla, Gonzalo Fernández, Berta Hernández, Paúl López, Nerea Alberdi, Carlos Hernández, Luisa Chocarro, Lucía Teijeira, Ruth Vera, Grazyna Kochan and David Escors

Cancers 2020, 12(2), 344; https://doi.org/10.3390/cancers12020344 - 4 Feb 2020

Cited by 64 | Viewed by 6504

Abstract

Hyperprogressive disease (HPD) is an adverse outcome of immunotherapy consisting of an acceleration of tumor growth associated with prompt clinical deterioration. The definitions based on radiological evaluation present important technical limitations. No biomarkers have been identified yet. In this study, 70 metastatic NSCLC [...] Read more.

Hyperprogressive disease (HPD) is an adverse outcome of immunotherapy consisting of an acceleration of tumor growth associated with prompt clinical deterioration. The definitions based on radiological evaluation present important technical limitations. No biomarkers have been identified yet. In this study, 70 metastatic NSCLC patients treated with anti-PD-1/PD-L1 immunotherapy after progression to platinum-based therapy were prospectively studied. Samples from peripheral blood were obtained before the first (baseline) and second cycles of treatment. Peripheral blood mononuclear cells (PBMCs) were isolated and differentiation stages of CD4 lymphocytes quantified by flow cytometry and correlated with HPD as identified with radiological criteria. A strong expansion of highly differentiated CD28⁻ CD4 T lymphocytes (CD4 THD) between the first and second cycle of therapy was observed in HPD patients. After normalizing, the proportion of posttreatment/pretreatment CD4 THD was significantly higher in HPD when compared with the rest of patients (median 1.525 vs. 0.990; p = 0.0007), and also when stratifying by HPD, non-HPD progressors, and responders (1.525, 1.000 and 0.9700 respectively; p = 0.0025). A cut-off value of 1.3 identified HPD with 82% specificity and 70% sensitivity. An increase of CD28⁻ CD4 T lymphocytes ≥ 1.3 (CD4 THD burst) was significantly associated with HPD (p = 0.008). The tumor growth ratio (TGR) was significantly higher in patients with expansion of CD4 THD burst compared to the rest of patients (median 2.67 vs. 0.86, p = 0.0049), and also when considering only progressors (median 2.67 vs. 1.03, p = 0.0126). A strong expansion of CD28⁻ CD4 lymphocytes in peripheral blood within the first cycle of therapy is an early differential feature of HPD in NSCLC treated with immune-checkpoint inhibitors. The monitoring of T cell dynamics allows the early detection of this adverse outcome in clinical practice and complements radiological evaluation. Full article

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32 pages, 3686 KB

Open AccessEditor’s ChoiceReview

Non-Coding RNAs as Regulators and Markers for Targeting of Breast Cancer and Cancer Stem Cells

by Kirti S. Prabhu, Afsheen Raza, Thasni Karedath, Syed Shadab Raza, Hamna Fathima, Eiman I. Ahmed, Shilpa Kuttikrishnan, Lubna Therachiyil, Michal Kulinski, Said Dermime, Kulsoom Junejo, Martin Steinhoff and Shahab Uddin

Cancers 2020, 12(2), 351; https://doi.org/10.3390/cancers12020351 - 4 Feb 2020

Cited by 39 | Viewed by 6108

Abstract

Breast cancer is regarded as a heterogeneous and complicated disease that remains the prime focus in the domain of public health concern. Next-generation sequencing technologies provided a new perspective dimension to non-coding RNAs, which were initially considered to be transcriptional noise or a [...] Read more.

Breast cancer is regarded as a heterogeneous and complicated disease that remains the prime focus in the domain of public health concern. Next-generation sequencing technologies provided a new perspective dimension to non-coding RNAs, which were initially considered to be transcriptional noise or a product generated from erroneous transcription. Even though understanding of biological and molecular functions of noncoding RNA remains enigmatic, researchers have established the pivotal role of these RNAs in governing a plethora of biological phenomena that includes cancer-associated cellular processes such as proliferation, invasion, migration, apoptosis, and stemness. In addition to this, the transmission of microRNAs and long non-coding RNAs was identified as a source of communication to breast cancer cells either locally or systemically. The present review provides in-depth information with an aim at discovering the fundamental potential of non-coding RNAs, by providing knowledge of biogenesis and functional roles of micro RNA and long non-coding RNAs in breast cancer and breast cancer stem cells, as either oncogenic drivers or tumor suppressors. Furthermore, non-coding RNAs and their potential role as diagnostic and therapeutic moieties have also been summarized. Full article

(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)

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24 pages, 1444 KB

Open AccessEditor’s ChoiceReview

The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias

by Alberto M. Martelli, Francesca Paganelli, Francesca Chiarini, Camilla Evangelisti and James A. McCubrey

Cancers 2020, 12(2), 333; https://doi.org/10.3390/cancers12020333 - 1 Feb 2020

Cited by 37 | Viewed by 7436

Abstract

The unfolded protein response (UPR) is an evolutionarily conserved adaptive response triggered by the stress of the endoplasmic reticulum (ER) due, among other causes, to altered cell protein homeostasis (proteostasis). UPR is mediated by three main sensors, protein kinase RNA-like endoplasmic reticulum kinase [...] Read more.

The unfolded protein response (UPR) is an evolutionarily conserved adaptive response triggered by the stress of the endoplasmic reticulum (ER) due, among other causes, to altered cell protein homeostasis (proteostasis). UPR is mediated by three main sensors, protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor 6α (ATF6α), and inositol-requiring enzyme-1α (IRE1α). Given that proteostasis is frequently disregulated in cancer, UPR is emerging as a critical signaling network in controlling the survival, selection, and adaptation of a variety of neoplasias, including breast cancer, prostate cancer, colorectal cancer, and glioblastoma. Indeed, cancer cells can escape from the apoptotic pathways elicited by ER stress by switching UPR into a prosurvival mechanism instead of cell death. Although most of the studies on UPR focused on solid tumors, this intricate network plays a critical role in hematological malignancies, and especially in multiple myeloma (MM), where treatment with proteasome inhibitors induce the accumulation of unfolded proteins that severely perturb proteostasis, thereby leading to ER stress, and, eventually, to apoptosis. However, UPR is emerging as a key player also in acute leukemias, where recent evidence points to the likelihood that targeting UPR-driven prosurvival pathways could represent a novel therapeutic strategy. In this review, we focus on the oncogene-specific regulation of individual UPR signaling arms, and we provide an updated outline of the genetic, biochemical, and preclinical therapeutic findings that support UPR as a relevant, novel target in acute leukemias. Full article

(This article belongs to the Special Issue Therapeutic Targeting of the Unfolded Protein Response in Cancer)

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12 pages, 1915 KB

Open AccessEditor’s ChoiceArticle

Targeting CD47 as a Novel Immunotherapy for Multiple Myeloma

by Jennifer Sun, Barbara Muz, Kinan Alhallak, Matea Markovic, Shannon Gurley, Zhe Wang, Nicole Guenthner, Katherine Wasden, Mark Fiala, Justin King, Daniel Kohnen, Noha Nabil Salama, Ravi Vij and Abdel Kareem Azab

Cancers 2020, 12(2), 305; https://doi.org/10.3390/cancers12020305 - 28 Jan 2020

Cited by 68 | Viewed by 7473

Abstract

Multiple myeloma (MM) remains to be incurable despite recent therapeutic advances. CD47, an immune checkpoint known as the “don’t eat me” signal, is highly expressed on the surface of various cancers, allowing cancer cells to send inhibitory signals to macrophages and impede phagocytosis [...] Read more.

Multiple myeloma (MM) remains to be incurable despite recent therapeutic advances. CD47, an immune checkpoint known as the “don’t eat me” signal, is highly expressed on the surface of various cancers, allowing cancer cells to send inhibitory signals to macrophages and impede phagocytosis and immune response. In this study, we hypothesized that blocking the “don’t eat me” signaling using an anti-CD47 monoclonal antibody will induce killing of MM cells. We report that CD47 expression was directly correlated with stage of the disease, from normal to MGUS to MM. Moreover, MM cells had remarkably higher CD47 expression than other cell populations in the bone marrow. These findings indicate that CD47 is specifically expressed on MM and can be used as a potential therapeutic target. Further, blocking of CD47 using an anti-CD47 antibody induced immediate activation of macrophages, which resulted in induction of phagocytosis and killing of MM cells in the 3D-tissue engineered bone marrow model, as early as 4 hours. These results suggest that macrophage checkpoint immunotherapy by blocking the CD47 “don’t eat me” signal is a novel and promising strategy for the treatment of MM, providing a basis for additional studies to validate these effects in vivo and in patients. Full article

(This article belongs to the Special Issue Recent Advances on the Pathobiology and Treatment of Multiple Myeloma)

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36 pages, 3139 KB

Open AccessEditor’s ChoiceReview

A Comprehensive Picture of Extracellular Vesicles and Their Contents. Molecular Transfer to Cancer Cells

by Ancuta Jurj, Oana Zanoaga, Cornelia Braicu, Vladimir Lazar, Ciprian Tomuleasa, Alexandru Irimie and Ioana Berindan-Neagoe

Cancers 2020, 12(2), 298; https://doi.org/10.3390/cancers12020298 - 27 Jan 2020

Cited by 98 | Viewed by 9707

Abstract

Critical processes such as growth, invasion, and metastasis of cancer cells are sustained via bidirectional cell-to-cell communication in tissue complex environments. Such communication involves the secretion of soluble factors by stromal cells and/or cancer cells within the tumor microenvironment (TME). Both stromal and [...] Read more.

Critical processes such as growth, invasion, and metastasis of cancer cells are sustained via bidirectional cell-to-cell communication in tissue complex environments. Such communication involves the secretion of soluble factors by stromal cells and/or cancer cells within the tumor microenvironment (TME). Both stromal and cancer cells have been shown to export bilayer nanoparticles: encapsulated regulatory molecules that contribute to cell-to-cell communication. These nanoparticles are known as extracellular vesicles (EVs) being classified into exosomes, microvesicles, and apoptotic bodies. EVs carry a vast repertoire of molecules such as oncoproteins and oncopeptides, DNA fragments from parental to target cells, RNA species (mRNAs, microRNAs, and long non-coding RNA), and lipids, initiating phenotypic changes in TME. According to their specific cargo, EVs have crucial roles in several early and late processes associated with tumor development and metastasis. Emerging evidence suggests that EVs are being investigated for their implication in early cancer detection, monitoring cancer progression and chemotherapeutic response, and more relevant, the development of novel targeted therapeutics. In this study, we provide a comprehensive understanding of the biophysical properties and physiological functions of EVs, their implications in TME, and highlight the applicability of EVs for the development of cancer diagnostics and therapeutics. Full article

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21 pages, 2712 KB

Open AccessEditor’s ChoiceReview

A Comprehensive Review of Calcium Electroporation—A Novel Cancer Treatment Modality

by Stine K. Frandsen, Mille Vissing and Julie Gehl

Cancers 2020, 12(2), 290; https://doi.org/10.3390/cancers12020290 - 25 Jan 2020

Cited by 103 | Viewed by 8971

Abstract

Calcium electroporation is a potential novel anti-cancer treatment where high calcium concentrations are introduced into cells by electroporation, a method where short, high voltage pulses induce transient permeabilisation of the plasma membrane allowing passage of molecules into the cytosol. Calcium is a tightly [...] Read more.

Calcium electroporation is a potential novel anti-cancer treatment where high calcium concentrations are introduced into cells by electroporation, a method where short, high voltage pulses induce transient permeabilisation of the plasma membrane allowing passage of molecules into the cytosol. Calcium is a tightly regulated, ubiquitous second messenger involved in many cellular processes including cell death. Electroporation increases calcium uptake leading to acute and severe ATP depletion associated with cancer cell death. This comprehensive review describes published data about calcium electroporation applied in vitro, in vivo, and clinically from the first publication in 2012. Calcium electroporation has been shown to be a safe and efficient anti-cancer treatment in clinical studies with cutaneous metastases and recurrent head and neck cancer. Normal cells have been shown to be less affected by calcium electroporation than cancer cells and this difference might be partly induced by differences in membrane repair, expression of calcium transporters, and cellular structural changes. Interestingly, both clinical data and preclinical studies have indicated a systemic immune response induced by calcium electroporation. New cancer treatments are needed, and calcium electroporation represents an inexpensive and efficient treatment with few side effects, that could potentially be used worldwide and for different tumor types. Full article

(This article belongs to the Special Issue Electric Field Based Therapies in Cancer Treatment: a Selection of Studies Presented at the 3rd World Congress on Electroporation)

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19 pages, 734 KB

Open AccessEditor’s ChoiceReview

Proteasome Inhibitors for the Treatment of Multiple Myeloma

by Shigeki Ito

Cancers 2020, 12(2), 265; https://doi.org/10.3390/cancers12020265 - 22 Jan 2020

Cited by 144 | Viewed by 12702

Abstract

Use of proteasome inhibitors (PIs) has been the therapeutic backbone of myeloma treatment over the past decade. Many PIs are being developed and evaluated in the preclinical and clinical setting. The first-in-class PI, bortezomib, was approved by the US food and drug administration [...] Read more.

Use of proteasome inhibitors (PIs) has been the therapeutic backbone of myeloma treatment over the past decade. Many PIs are being developed and evaluated in the preclinical and clinical setting. The first-in-class PI, bortezomib, was approved by the US food and drug administration in 2003. Carfilzomib is a next-generation PI, which selectively and irreversibly inhibits proteasome enzymatic activities in a dose-dependent manner. Ixazomib was the first oral PI to be developed and has a robust efficacy and favorable safety profile in patients with multiple myeloma. These PIs, together with other agents, including alkylators, immunomodulatory drugs, and monoclonal antibodies, have been incorporated into several regimens. This review summarizes the biological effects and the results of clinical trials investigating PI-based combination regimens and novel investigational inhibitors and discusses the future perspective in the treatment of multiple myeloma. Full article

(This article belongs to the Special Issue Latest Development in Multiple Myeloma)

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19 pages, 2416 KB

Open AccessEditor’s ChoiceArticle

Cancer Stem Cell Marker DCLK1 Correlates with Tumorigenic Immune Infiltrates in the Colon and Gastric Adenocarcinoma Microenvironments

by Xiangyan Wu, Dongfeng Qu, Nathaniel Weygant, Jun Peng and Courtney W. Houchen

Cancers 2020, 12(2), 274; https://doi.org/10.3390/cancers12020274 - 22 Jan 2020

Cited by 64 | Viewed by 6876

Abstract

Immunotherapy that has proven efficacy in several solid cancers plays a partial role in improving clinical outcomes of advanced gastrointestinal (GI) cancers. There is an unmet need to find new immune-related therapeutic targets. Doublecortin-like kinase 1 (DCLK1) marks tuft cells which are recognized [...] Read more.

Immunotherapy that has proven efficacy in several solid cancers plays a partial role in improving clinical outcomes of advanced gastrointestinal (GI) cancers. There is an unmet need to find new immune-related therapeutic targets. Doublecortin-like kinase 1 (DCLK1) marks tuft cells which are recognized as cancer-initiating cells and regulators of the type II immune response, and has been studied for its role in many cancers including colon and gastric cancers, but its role in tumor immunity remains unexplored. In the current study, we analyzed colon and gastric cancer RNA sequencing data from 283 and 415 patients, respectively, from The Cancer Genome Atlas (TCGA). High DCLK1 expression predicted the worse clinical outcomes in colon and gastric cancer patients and correlated with increased immune and stromal components. Further analysis indicated that DCLK1 was strongly linked to infiltration of multiple immune cell types, especially TAMs and Treg, and strongly correlated with increased CD8+ T cell inhibitors TGFB1 and CXCL12 and their receptors, suggesting it may contribute to TAM-mediated inhibition of CD8+ T cells. Interestingly, we found that DCLK1 was a prognostic biomarker in left-sided colon cancer, which has worse outcomes and demonstrates a reduced response to existing immunotherapies. In conclusion, our results demonstrate that DCLK1 is linked with functional regulation of the tumor microenvironment and may have potential as a prognostic biomarker and adjuvant target to promote immunotherapy sensitivity in colon and gastric cancer patients. Full article

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

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23 pages, 1455 KB

Open AccessEditor’s ChoiceReview

Nano-Therapies for Glioblastoma Treatment

by Edouard Alphandéry

Cancers 2020, 12(1), 242; https://doi.org/10.3390/cancers12010242 - 19 Jan 2020

Cited by 94 | Viewed by 10518

Abstract

Traditional anti-cancer treatments are inefficient against glioblastoma, which remains one of the deadliest and most aggressive cancers. Nano-drugs could help to improve this situation by enabling: (i) an increase of anti-glioblastoma multiforme (GBM) activity of chemo/gene therapeutic drugs, notably by an improved diffusion [...] Read more.

Traditional anti-cancer treatments are inefficient against glioblastoma, which remains one of the deadliest and most aggressive cancers. Nano-drugs could help to improve this situation by enabling: (i) an increase of anti-glioblastoma multiforme (GBM) activity of chemo/gene therapeutic drugs, notably by an improved diffusion of these drugs through the blood brain barrier (BBB), (ii) the sensibilization of radio-resistant GBM tumor cells to radiotherapy, (iii) the removal by surgery of infiltrating GBM tumor cells, (iv) the restoration of an apoptotic mechanism of GBM cellular death, (v) the destruction of angiogenic blood vessels, (vi) the stimulation of anti-tumor immune cells, e.g., T cells, NK cells, and the neutralization of pro-tumoral immune cells, e.g., T_reg cells, (vii) the local production of heat or radical oxygen species (ROS), and (viii) the controlled release/activation of anti-GBM drugs following the application of a stimulus. This review covers these different aspects. Full article

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48 pages, 2713 KB

Open AccessEditor’s ChoiceReview

Pharmacological Inhibition of Oncogenic STAT3 and STAT5 Signaling in Hematopoietic Cancers

by Marie Brachet-Botineau, Marion Polomski, Heidi A. Neubauer, Ludovic Juen, Damien Hédou, Marie-Claude Viaud-Massuard, Gildas Prié and Fabrice Gouilleux

Cancers 2020, 12(1), 240; https://doi.org/10.3390/cancers12010240 - 18 Jan 2020

Cited by 60 | Viewed by 10114

Abstract

Signal Transducer and Activator of Transcription (STAT) 3 and 5 are important effectors of cellular transformation, and aberrant STAT3 and STAT5 signaling have been demonstrated in hematopoietic cancers. STAT3 and STAT5 are common targets for different tyrosine kinase oncogenes (TKOs). In addition, STAT3 [...] Read more.

Signal Transducer and Activator of Transcription (STAT) 3 and 5 are important effectors of cellular transformation, and aberrant STAT3 and STAT5 signaling have been demonstrated in hematopoietic cancers. STAT3 and STAT5 are common targets for different tyrosine kinase oncogenes (TKOs). In addition, STAT3 and STAT5 proteins were shown to contain activating mutations in some rare but aggressive leukemias/lymphomas. Both proteins also contribute to drug resistance in hematopoietic malignancies and are now well recognized as major targets in cancer treatment. The development of inhibitors targeting STAT3 and STAT5 has been the subject of intense investigations during the last decade. This review summarizes the current knowledge of oncogenic STAT3 and STAT5 functions in hematopoietic cancers as well as advances in preclinical and clinical development of pharmacological inhibitors. Full article

(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)

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29 pages, 1155 KB

Open AccessEditor’s ChoiceArticle

Metformin as Potential Therapy for High-Grade Glioma

by Marek Mazurek, Jakub Litak, Piotr Kamieniak, Bartłomiej Kulesza, Katarzyna Jonak, Jacek Baj and Cezary Grochowski

Cancers 2020, 12(1), 210; https://doi.org/10.3390/cancers12010210 - 15 Jan 2020

Cited by 73 | Viewed by 10384

Abstract

Metformin (MET), 1,1-dimethylbiguanide hydrochloride, is a biguanide drug used as the first-line medication in the treatment of type 2 diabetes. The recent years have brought many observations showing metformin in its new role. The drug, commonly used in the therapy of diabetes, may [...] Read more.

Metformin (MET), 1,1-dimethylbiguanide hydrochloride, is a biguanide drug used as the first-line medication in the treatment of type 2 diabetes. The recent years have brought many observations showing metformin in its new role. The drug, commonly used in the therapy of diabetes, may also find application in the therapy of a vast variety of tumors. Its effectiveness has been demonstrated in colon, breast, prostate, pancreatic cancer, leukemia, melanoma, lung and endometrial carcinoma, as well as in gliomas. This is especially important in light of the poor options offered to patients in the case of high-grade gliomas, which include glioblastoma (GBM). A thorough understanding of the mechanism of action of metformin can make it possible to discover new drugs that could be used in neoplasm therapy. Full article

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

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25 pages, 2583 KB

Open AccessEditor’s ChoiceReview

Interplay among SNAIL Transcription Factor, MicroRNAs, Long Non-Coding RNAs, and Circular RNAs in the Regulation of Tumor Growth and Metastasis

by Klaudia Skrzypek and Marcin Majka

Cancers 2020, 12(1), 209; https://doi.org/10.3390/cancers12010209 - 14 Jan 2020

Cited by 49 | Viewed by 5380

Abstract

SNAIL (SNAI1) is a zinc finger transcription factor that binds to E-box sequences and regulates the expression of genes. It usually acts as a gene repressor, but it may also activate the expression of genes. SNAIL plays a key role in the regulation [...] Read more.

SNAIL (SNAI1) is a zinc finger transcription factor that binds to E-box sequences and regulates the expression of genes. It usually acts as a gene repressor, but it may also activate the expression of genes. SNAIL plays a key role in the regulation of epithelial to mesenchymal transition, which is the main mechanism responsible for the progression and metastasis of epithelial tumors. Nevertheless, it also regulates different processes that are responsible for tumor growth, such as the activity of cancer stem cells, the control of cell metabolism, and the regulation of differentiation. Different proteins and microRNAs may regulate the SNAIL level, and SNAIL may be an important regulator of microRNA expression as well. The interplay among SNAIL, microRNAs, long non-coding RNAs, and circular RNAs is a key event in the regulation of tumor growth and metastasis. This review for the first time discusses different types of regulation between SNAIL and non-coding RNAs with a focus on feedback loops and the role of competitive RNA. Understanding these mechanisms may help develop novel therapeutic strategies against cancer based on microRNAs. Full article

(This article belongs to the Special Issue Role of miRNAs in Cancer—Analysis of Their Targetome)

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27 pages, 27850 KB

Open AccessEditor’s ChoiceArticle

Polyphyllin VI Induces Caspase-1-Mediated Pyroptosis via the Induction of ROS/NF-κB/NLRP3/GSDMD Signal Axis in Non-Small Cell Lung Cancer

by Jin-Feng Teng, Qi-Bing Mei, Xiao-Gang Zhou, Yong Tang, Rui Xiong, Wen-Qiao Qiu, Rong Pan, Betty Yuen-Kwan Law, Vincent Kam-Wai Wong, Chong-Lin Yu, Han-An Long, Xiu-Li Xiao, Feng Zhang, Jian-Ming Wu, Da-Lian Qin and An-Guo Wu

Cancers 2020, 12(1), 193; https://doi.org/10.3390/cancers12010193 - 13 Jan 2020

Cited by 293 | Viewed by 16267

Abstract

Trillium tschonoskii Maxim (TTM), a traditional Chinese medicine, has been demonstrated to have a potent anti-tumor effect. Recently, polyphyllin VI (PPVI), a main saponin isolated from TTM, was reported by us to significantly suppress the proliferation of non-small cell lung cancer (NSCLC) via [...] Read more.

Trillium tschonoskii Maxim (TTM), a traditional Chinese medicine, has been demonstrated to have a potent anti-tumor effect. Recently, polyphyllin VI (PPVI), a main saponin isolated from TTM, was reported by us to significantly suppress the proliferation of non-small cell lung cancer (NSCLC) via the induction of apoptosis and autophagy in vitro and in vivo. In this study, we further found that the NLRP3 inflammasome was activated in PPVI administrated A549-bearing athymic nude mice. As is known to us, pyroptosis is an inflammatory form of caspase-1-dependent programmed cell death that plays an important role in cancer. By using A549 and H1299 cells, the in vitro effect and action mechanism by which PPVI induces activation of the NLRP3 inflammasome in NSCLC were investigated. The anti-proliferative effect of PPVI in A549 and H1299 cells was firstly measured and validated by MTT assay. The activation of the NLRP3 inflammasome was detected by using Hoechst33324/PI staining, flow cytometry analysis and real-time live cell imaging methods. We found that PPVI significantly increased the percentage of cells with PI signal in A549 and H1299, and the dynamic change in cell morphology and the process of cell death of A549 cells indicated that PPVI induced an apoptosis-to-pyroptosis switch, and, ultimately, lytic cell death. In addition, belnacasan (VX-765), an inhibitor of caspase-1, could remarkably decrease the pyroptotic cell death of PPVI-treated A549 and H1299 cells. Moreover, by detecting the expression of NLRP3, ASC, caspase-1, IL-1β, IL-18 and GSDMD in A549 and h1299 cells using Western blotting, immunofluorescence imaging and flow cytometric analysis, measuring the caspase-1 activity using colorimetric assay, and quantifying the cytokines level of IL-1β and IL-18 using ELISA, the NLRP3 inflammasome was found to be activated in a dose manner, while VX-765 and necrosulfonamide (NSA), an inhibitor of GSDMD, could inhibit PPVI-induced activation of the NLRP3 inflammasome. Furthermore, the mechanism study found that PPVI could activate the NF-κB signaling pathway via increasing reactive oxygen species (ROS) levels in A549 and H1299 cells, and N-acetyl-L-cysteine (NAC), a scavenger of ROS, remarkably inhibited the cell death, and the activation of NF-κB and the NLRP3 inflammasome in PPVI-treated A549 and H1299 cells. Taken together, these data suggested that PPVI-induced, caspase-1-mediated pyroptosis via the induction of the ROS/NF-κB/NLRP3/GSDMD signal axis in NSCLC, which further clarified the mechanism of PPVI in the inhibition of NSCLC, and thereby provided a possibility for PPVI to serve as a novel therapeutic agent for NSCLC in the future. Full article

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15 pages, 3094 KB

Open AccessEditor’s ChoiceArticle

Tivantinib, A c-Met Inhibitor in Clinical Trials, Is Susceptible to ABCG2-Mediated Drug Resistance

by Zhuo-Xun Wu, Yuqi Yang, Qiu-Xu Teng, Jing-Quan Wang, Zi-Ning Lei, Jing-Qiu Wang, Sabrina Lusvarghi, Suresh V. Ambudkar, Dong-Hua Yang and Zhe-Sheng Chen

Cancers 2020, 12(1), 186; https://doi.org/10.3390/cancers12010186 - 12 Jan 2020

Cited by 42 | Viewed by 5829

Abstract

Tivantinib, also known as ARQ-197, is a potent non-ATP competitive selective c-Met inhibitor currently under phase 3 clinical trial evaluation for liver and lung cancers. In this study, we explored factors that may lead to tivantinib resistance, especially in regards to its interaction [...] Read more.

Tivantinib, also known as ARQ-197, is a potent non-ATP competitive selective c-Met inhibitor currently under phase 3 clinical trial evaluation for liver and lung cancers. In this study, we explored factors that may lead to tivantinib resistance, especially in regards to its interaction with ATP-binding cassette super-family G member 2 (ABCG2). ABCG2 is one of the most important members of the ATP-binding cassette (ABC) transporter family, a group of membrane proteins that play a critical role in mediating multidrug resistance (MDR) in a variety of cancers, including those of the liver and lung. Tivantinib received a high score in docking analysis, indicating a strong interaction between tivantinib and ABCG2, and an ATPase assay indicated that tivantinib stimulated ABCG2 ATPase activity in a concentration-dependent manner. An MTT assay showed that ABCG2 overexpression significantly desensitized both the cancer cells and ABCG2 transfected-HEK293 cells to tivantinib and that this drug resistance can be reversed by ABCG2 inhibitors. Furthermore, tivantinib upregulated the protein expression of ABCG2 without altering the cell surface localization of ABCG2, leading to increased resistance to substrate drugs, such as mitoxantrone. Altogether, these data demonstrate that tivantinib is a substrate of ABCG2, and, therefore, ABCG2 overexpression may decrease its therapeutic effect. Our study provides evidence that the overexpression of ABCG2 should be monitored in clinical settings as an important risk factor for tivantinib drug resistance. Full article

(This article belongs to the Special Issue The Role of Drug Resistance-Associated Proteins in Cancer: from Conventional Anticancer Drugs to Targeting Drugs)

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14 pages, 1777 KB

Open AccessEditor’s ChoiceArticle

Predictors of Response and Survival in Immune Checkpoint Inhibitor-Treated Unresectable Hepatocellular Carcinoma

by Pei-Chang Lee, Yee Chao, Ming-Huang Chen, Keng-Hsin Lan, Chieh-Ju Lee, I-Cheng Lee, San-Chi Chen, Ming-Chih Hou and Yi-Hsiang Huang

Cancers 2020, 12(1), 182; https://doi.org/10.3390/cancers12010182 - 11 Jan 2020

Cited by 91 | Viewed by 7410

Abstract

Immune checkpoint inhibitors (ICIs) with nivolumab and pembrolizumab are promising agents for advanced hepatocellular carcinoma (HCC) but lack of effective biomarkers. We aimed to investigate the potential predictors of response and factors associated with overall survival (OS) for ICI treatment in unresectable HCC [...] Read more.

Immune checkpoint inhibitors (ICIs) with nivolumab and pembrolizumab are promising agents for advanced hepatocellular carcinoma (HCC) but lack of effective biomarkers. We aimed to investigate the potential predictors of response and factors associated with overall survival (OS) for ICI treatment in unresectable HCC patients. Ninety-five patients who received nivolumab or pembrolizumab for unresectable HCC were enrolled for analyses. Radiologic evaluation was based on RECIST v1.1. Factors associated with outcomes were analyzed. Of 90 patients with evaluable images, the objective response rate (ORR) was 24.4%. Patients at Child–Pugh A or received combination treatment had higher ORR. Early alpha-fetoprotein (AFP) >10% reduction (within 4 weeks) was the only independent predictor of best objective response (odds ratio: 7.259, p = 0.001). For patients with baseline AFP ≥10 ng/mL, significantly higher ORR (63.6% vs. 10.2%, p < 0.001) and disease control rate (81.8% vs. 14.3%, p < 0.001) were observed in those with early AFP reduction than those without. In addition, early AFP reduction and albumin-bilirubin (ALBI) grade or Child–Pugh class were independent factors associated with OS in different models. In conclusion, a 10-10 rule of early AFP response can predict objective response and survival to ICI treatment in unresectable HCC. ALBI grade and Child–Pugh class determines survival by ICI treatment. Full article

(This article belongs to the Special Issue Immunotherapy in Hepatocellular Carcinoma)

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20 pages, 993 KB

Open AccessEditor’s ChoiceReview

Vimentin Intermediate Filaments as Potential Target for Cancer Treatment

by Katerina Strouhalova, Magdalena Přechová, Aneta Gandalovičová, Jan Brábek, Martin Gregor and Daniel Rosel

Cancers 2020, 12(1), 184; https://doi.org/10.3390/cancers12010184 - 11 Jan 2020

Cited by 183 | Viewed by 16475

Abstract

Intermediate filaments constitute the third component of the cellular skeleton. Unlike actin and microtubule cytoskeletons, the intermediate filaments are composed of a wide variety of structurally related proteins showing distinct expression patterns in tissues and cell types. Changes in the expression patterns of [...] Read more.

Intermediate filaments constitute the third component of the cellular skeleton. Unlike actin and microtubule cytoskeletons, the intermediate filaments are composed of a wide variety of structurally related proteins showing distinct expression patterns in tissues and cell types. Changes in the expression patterns of intermediate filaments are often associated with cancer progression; in particular with phenotypes leading to increased cellular migration and invasion. In this review we will describe the role of vimentin intermediate filaments in cancer cell migration, cell adhesion structures, and metastasis formation. The potential for targeting vimentin in cancer treatment and the development of drugs targeting vimentin will be reviewed. Full article

(This article belongs to the Collection Targeting Solid Tumors)

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19 pages, 1331 KB

Open AccessEditor’s ChoiceReview

Extracellular Vesicles and Cancer: A Focus on Metabolism, Cytokines, and Immunity

by Donatella Lucchetti, Claudio Ricciardi Tenore, Filomena Colella and Alessandro Sgambato

Cancers 2020, 12(1), 171; https://doi.org/10.3390/cancers12010171 - 10 Jan 2020

Cited by 47 | Viewed by 7013

Abstract

A better understanding of the mechanisms of cell communication between cancer cells and the tumor microenvironment is crucial to develop personalized therapies. It has been known for a while that cancer cells are metabolically distinct from other non-transformed cells. This metabolic phenotype is [...] Read more.

A better understanding of the mechanisms of cell communication between cancer cells and the tumor microenvironment is crucial to develop personalized therapies. It has been known for a while that cancer cells are metabolically distinct from other non-transformed cells. This metabolic phenotype is not peculiar to cancer cells but reflects the characteristics of the tumor microenvironment. Recently, it has been shown that extracellular vesicles are involved in the metabolic switch occurring in cancer and tumor-stroma cells. Moreover, in an immune system, the metabolic programs of different cell subsets are distinctly associated with their immunological function, and extracellular vesicles could be a key factor in the shift of cell fate modulating cancer immunity. Indeed, during tumor progression, tumor-associated immune cells and fibroblasts acquire a tumor-supportive and anti-inflammatory phenotype due to their interaction with tumor cells and several findings suggest a role of extracellular vesicles in this phenomenon. This review aims to collect all the available evidence so far obtained on the role of extracellular vesicles in the modulation of cell metabolism and immunity. Moreover, we discuss the possibility for extracellular vesicles of being involved in drug resistance mechanisms, cancer progression and metastasis by inducing immune-metabolic effects on surrounding cells. Full article

(This article belongs to the Special Issue Extracellular Vesicles in Cancer Progression and Drug Resistance)

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24 pages, 1129 KB

Open AccessEditor’s ChoiceReview

Ferroptosis in Cancer Cell Biology

by Christina M. Bebber, Fabienne Müller, Laura Prieto Clemente, Josephine Weber and Silvia von Karstedt

Cancers 2020, 12(1), 164; https://doi.org/10.3390/cancers12010164 - 9 Jan 2020

Cited by 287 | Viewed by 23341

Abstract

A major hallmark of cancer is successful evasion of regulated forms of cell death. Ferroptosis is a recently discovered type of regulated necrosis which, unlike apoptosis or necroptosis, is independent of caspase activity and receptor-interacting protein 1 (RIPK1) kinase activity. Instead, ferroptotic cells [...] Read more.

A major hallmark of cancer is successful evasion of regulated forms of cell death. Ferroptosis is a recently discovered type of regulated necrosis which, unlike apoptosis or necroptosis, is independent of caspase activity and receptor-interacting protein 1 (RIPK1) kinase activity. Instead, ferroptotic cells die following iron-dependent lipid peroxidation, a process which is antagonised by glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1). Importantly, tumour cells escaping other forms of cell death have been suggested to maintain or acquire sensitivity to ferroptosis. Therefore, therapeutic exploitation of ferroptosis in cancer has received increasing attention. Here, we systematically review current literature on ferroptosis signalling, cross-signalling to cellular metabolism in cancer and a potential role for ferroptosis in tumour suppression and tumour immunology. By summarising current findings on cell biology relevant to ferroptosis in cancer, we aim to point out new conceptual avenues for utilising ferroptosis in systemic treatment approaches for cancer. Full article

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

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38 pages, 497 KB

Open AccessEditor’s ChoiceReview

Targeting Glucose Transporters for Breast Cancer Therapy: The Effect of Natural and Synthetic Compounds

by Ana M. Barbosa and Fátima Martel

Cancers 2020, 12(1), 154; https://doi.org/10.3390/cancers12010154 - 8 Jan 2020

Cited by 114 | Viewed by 10444

Abstract

Reprogramming of cellular energy metabolism is widely accepted to be a cancer hallmark. The deviant energetic metabolism of cancer cells-known as the Warburg effect-consists in much higher rates of glucose uptake and glycolytic oxidation coupled with the production of lactic acid, even in [...] Read more.

Reprogramming of cellular energy metabolism is widely accepted to be a cancer hallmark. The deviant energetic metabolism of cancer cells-known as the Warburg effect-consists in much higher rates of glucose uptake and glycolytic oxidation coupled with the production of lactic acid, even in the presence of oxygen. Consequently, cancer cells have higher glucose needs and thus display a higher sensitivity to glucose deprivation-induced death than normal cells. So, inhibitors of glucose uptake are potential therapeutic targets in cancer. Breast cancer is the most commonly diagnosed cancer and a leading cause of cancer death in women worldwide. Overexpression of facilitative glucose transporters (GLUT), mainly GLUT1, in breast cancer cells is firmly established, and the consequences of GLUT inhibition and/or knockout are under investigation. Herein we review the compounds, both of natural and synthetic origin, found to interfere with uptake of glucose by breast cancer cells, and the consequences of interference with that mechanism on breast cancer cell biology. We will also present data where the interaction with GLUT is exploited in order to increase the efficiency or selectivity of anticancer agents, in breast cancer cells. Full article

(This article belongs to the Special Issue Role of Natural Bioactive Compounds in the Rise and Fall of Cancers)

17 pages, 743 KB

Open AccessEditor’s ChoiceReview

Shaping the Innate Immune Response by Dietary Glucans: Any Role in the Control of Cancer?

by Manuela Del Cornò, Sandra Gessani and Lucia Conti

Cancers 2020, 12(1), 155; https://doi.org/10.3390/cancers12010155 - 8 Jan 2020

Cited by 68 | Viewed by 10459

Abstract

β-glucans represent a heterogeneous group of naturally occurring and biologically active polysaccharides found in many kinds of edible mushrooms, baker’s yeast, cereals and seaweeds, whose health-promoting effects have been known since ancient times. These compounds can be taken orally as food supplements or [...] Read more.

β-glucans represent a heterogeneous group of naturally occurring and biologically active polysaccharides found in many kinds of edible mushrooms, baker’s yeast, cereals and seaweeds, whose health-promoting effects have been known since ancient times. These compounds can be taken orally as food supplements or as part of daily diets, and are safe to use, nonimmunogenic and well tolerated. A main feature of β-glucans is their capacity to function as biological response modifiers, exerting regulatory effects on inflammation and shaping the effector functions of different innate and adaptive immunity cell populations. The potential to interfere with processes involved in the development or control of cancer makes β-glucans interesting candidates as adjuvants in antitumor therapies as well as in cancer prevention strategies. Here, the regulatory effects of dietary β-glucans on human innate immunity cells are reviewed and their potential role in cancer control is discussed. Full article

(This article belongs to the Special Issue Role of Natural Bioactive Compounds in the Rise and Fall of Cancers)

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13 pages, 498 KB

Open AccessEditor’s ChoiceReview

The Future of Immunotherapy-Based Combination Therapy in Metastatic Renal Cell Carcinoma

by Rohan Garje, Josiah An, Austin Greco, Raju Kumar Vaddepally and Yousef Zakharia

Cancers 2020, 12(1), 143; https://doi.org/10.3390/cancers12010143 - 7 Jan 2020

Cited by 47 | Viewed by 6443

Abstract

In the past two decades, there has been a significant improvement in the understanding of the molecular pathogenesis of Renal Cell Carcinoma (RCC). These insights in the biological pathways have resulted in the development of multiple agents targeting vascular endothelial growth factor (VEGF), [...] Read more.

In the past two decades, there has been a significant improvement in the understanding of the molecular pathogenesis of Renal Cell Carcinoma (RCC). These insights in the biological pathways have resulted in the development of multiple agents targeting vascular endothelial growth factor (VEGF), as well as inhibitors of the mammalian target of the rapamycin (mTOR) pathway. Most recently, checkpoint inhibitors were shown to have excellent clinical efficacy. Although the patients are living longer, durable complete responses are rarely seen. Historically, high dose interleukin 2 (IL2) therapy has produced durable complete responses in 5% to 8% highly selected patients—albeit with significant toxicity. A durable complete response is a surrogate for a long-term response in the modern era of targeted therapy and checkpoint immunotherapy. Numerous clinical trials are currently exploring the combination of immunotherapy with various targeted therapeutic agents to develop therapies with a higher complete response rate with acceptable toxicity. in this study, we provide a comprehensive review of multiple reported and ongoing clinical trials evaluating the combination of PD-1/PD-L1 inhibitors with either ipilimumab (a cytotoxic T-lymphocyte-associated protein 4, CTLA-4 inhibitor) or with anti-VEGF targeted therapy. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma)

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16 pages, 4045 KB

Open AccessEditor’s ChoiceArticle

The Role of Transient Receptor Potential Melastatin 7 (TRPM7) in Cell Viability: A Potential Target to Suppress Breast Cancer Cell Cycle

by Hengrui Liu, James P. Dilger and Jun Lin

Cancers 2020, 12(1), 131; https://doi.org/10.3390/cancers12010131 - 4 Jan 2020

Cited by 69 | Viewed by 5593

Abstract

The divalent cation-selective channel transient receptor potential melastatin 7 (TRPM7) channel was shown to affect the proliferation of some types of cancer cell. However, the function of TRPM7 in the viability of breast cancer cells remains unclear. Here we show that TRPM inhibitors [...] Read more.

The divalent cation-selective channel transient receptor potential melastatin 7 (TRPM7) channel was shown to affect the proliferation of some types of cancer cell. However, the function of TRPM7 in the viability of breast cancer cells remains unclear. Here we show that TRPM inhibitors suppressed the viability of TRPM7-expressing breast cancer cells. We first demonstrated that the TRPM7 inhibitors 2-aminoethyl diphenylborinate (2-APB), ginsenoside Rd (Gin Rd), and waixenicin A preferentially suppressed the viability of human embryonic kidney HEK293 overexpressing TRPM7 (HEK-M7) cells over wildtype HEK293 (WT-HEK). Next, we confirmed the effects of 2-APB on the TRPM7 channel functions by whole-cell currents and divalent cation influx. The inhibition of the viability of HEK-M7 cells by 2-APB was not mediated by the increase in cell death but by the interruption of the cell cycle. Similar to HEK-M7 cells, the viability of TRPM7-expressing human breast cancer MDA-MB-231, AU565, and T47D cells were also suppressed by 2-APB by arresting the cell cycle in the S phase. Furthermore, in a novel TRPM7 knock-out MDA-MB-231 (KO-231) cell line, decreased divalent influx and reduced proliferation were observed compared to the wildtype MDA-MB-231 cells. 2-APB and Gin Rd preferentially suppressed the viability of wildtype MDA-MB-231 cells over KO-231 by affecting the cell cycle in wildtype but not KO-231 cells. Our results suggest that TRPM7 regulates the cell cycle of breast cancers and is a potential therapeutic target. Full article

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17 pages, 2440 KB

Open AccessEditor’s ChoiceArticle

High-Throughput Label-Free Isolation of Heterogeneous Circulating Tumor Cells and CTC Clusters from Non-Small-Cell Lung Cancer Patients

by Mina Zeinali, Maggie Lee, Arthi Nadhan, Anvya Mathur, Casey Hedman, Eric Lin, Ramdane Harouaka, Max S. Wicha, Lili Zhao, Nallasivam Palanisamy, Mathias Hafner, Rishindra Reddy, Gregory P. Kalemkerian, Bryan J. Schneider, Khaled A. Hassan, Nithya Ramnath and Sunitha Nagrath

Cancers 2020, 12(1), 127; https://doi.org/10.3390/cancers12010127 - 3 Jan 2020

Cited by 77 | Viewed by 9456

Abstract

(1) Background: Circulating tumor cell (CTC) clusters are emerging as clinically significant harbingers of metastases in solid organ cancers. Prior to engaging these CTC clusters in animal models of metastases, it is imperative for technology to identify them with high sensitivity. These clusters [...] Read more.

(1) Background: Circulating tumor cell (CTC) clusters are emerging as clinically significant harbingers of metastases in solid organ cancers. Prior to engaging these CTC clusters in animal models of metastases, it is imperative for technology to identify them with high sensitivity. These clusters often present heterogeneous surface markers and current methods for isolation of clusters may fall short. (2) Methods: We applied an inertial microfluidic Labyrinth device for high-throughput, biomarker-independent, size-based isolation of CTCs/CTC clusters from patients with metastatic non-small-cell lung cancer (NSCLC). (3) Results: Using Labyrinth, CTCs (PanCK+/DAPI+/CD45−) were isolated from patients (n = 25). Heterogeneous CTC populations, including CTCs expressing epithelial (EpCAM), mesenchymal (Vimentin) or both markers were detected. CTCs were isolated from 100% of patients (417 ± 1023 CTCs/mL). EpCAM− CTCs were significantly greater than EpCAM+ CTCs. Cell clusters of ≥2 CTCs were observed in 96% of patients—of which, 75% were EpCAM−. CTCs revealed identical genetic aberrations as the primary tumor for RET, ROS1, and ALK genes using fluorescence in situ hybridization (FISH) analysis. (4) Conclusions: The Labyrinth device recovered heterogeneous CTCs in 100% and CTC clusters in 96% of patients with metastatic NSCLC. The majority of recovered CTCs/clusters were EpCAM−, suggesting that these would have been missed using traditional antibody-based capture methods. Full article

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19 pages, 715 KB

Open AccessEditor’s ChoiceReview

Fourier Transform Infrared Spectroscopy as a Cancer Screening and Diagnostic Tool: A Review and Prospects

by Kar-Yan Su and Wai-Leng Lee

Cancers 2020, 12(1), 115; https://doi.org/10.3390/cancers12010115 - 1 Jan 2020

Cited by 153 | Viewed by 13546

Abstract

Infrared spectroscopy has long been used to characterize chemical compounds, but the applicability of this technique to the analysis of biological materials containing highly complex chemical components is arguable. However, recent advances in the development of infrared spectroscopy have significantly enhanced the capacity [...] Read more.

Infrared spectroscopy has long been used to characterize chemical compounds, but the applicability of this technique to the analysis of biological materials containing highly complex chemical components is arguable. However, recent advances in the development of infrared spectroscopy have significantly enhanced the capacity of this technique in analyzing various types of biological specimens. Consequently, there is an increased number of studies investigating the application of infrared spectroscopy in screening and diagnosis of various diseases. The lack of highly sensitive and specific methods for early detection of cancer has warranted the search for novel approaches. Being more simple, rapid, accurate, inexpensive, non-destructive and suitable for automation compared to existing screening, diagnosis, management and monitoring methods, Fourier transform infrared spectroscopy can potentially improve clinical decision-making and patient outcomes by detecting biochemical changes in cancer patients at the molecular level. Besides the commonly analyzed blood and tissue samples, extracellular vesicle-based method has been gaining popularity as a non-invasive approach. Therefore, infrared spectroscopic analysis of extracellular vesicles could be a useful technique in the future for biomedical applications. In this review, we discuss the potential clinical applications of Fourier transform infrared spectroscopic analysis using various types of biological materials for cancer. Additionally, the rationale and advantages of using extracellular vesicles in the spectroscopic analysis for cancer diagnostics are discussed. Furthermore, we highlight the challenges and future directions of clinical translation of the technique for cancer. Full article

(This article belongs to the Special Issue Non-Invasive Early Detection of Cancers)

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26 pages, 1098 KB

Open AccessEditor’s ChoiceReview

Activation of STAT3 and STAT5 Signaling in Epithelial Ovarian Cancer Progression: Mechanism and Therapeutic Opportunity

by Chin-Jui Wu, Vignesh Sundararajan, Bor-Ching Sheu, Ruby Yun-Ju Huang and Lin-Hung Wei

Cancers 2020, 12(1), 24; https://doi.org/10.3390/cancers12010024 - 19 Dec 2019

Cited by 63 | Viewed by 9300

Abstract

Epithelial ovarian cancer (EOC) is the most lethal of all gynecologic malignancies. Despite advances in surgical and chemotherapeutic options, most patients with advanced EOC have a relapse within three years of diagnosis. Unfortunately, recurrent disease is generally not curable. Recent advances in maintenance [...] Read more.

Epithelial ovarian cancer (EOC) is the most lethal of all gynecologic malignancies. Despite advances in surgical and chemotherapeutic options, most patients with advanced EOC have a relapse within three years of diagnosis. Unfortunately, recurrent disease is generally not curable. Recent advances in maintenance therapy with anti-angiogenic agents or Poly ADP-ribose polymerase (PARP) inhibitors provided a substantial benefit concerning progression-free survival among certain women with advanced EOC. However, effective treatment options remain limited in most recurrent cases. Therefore, validated novel molecular therapeutic targets remain urgently needed in the management of EOC. Signal transducer and activator of transcription-3 (STAT3) and STAT5 are aberrantly activated through tyrosine phosphorylation in a wide variety of cancer types, including EOC. Extrinsic tumor microenvironmental factors in EOC, such as inflammatory cytokines, growth factors, hormones, and oxidative stress, can activate STAT3 and STAT5 through different mechanisms. Persistently activated STAT3 and, to some extent, STAT5 increase EOC tumor cell proliferation, survival, self-renewal, angiogenesis, metastasis, and chemoresistance while suppressing anti-tumor immunity. By doing so, the STAT3 and STAT5 activation in EOC controls properties of both tumor cells and their microenvironment, driving multiple distinct functions during EOC progression. Clinically, increasing evidence indicates that the activation of the STAT3/STAT5 pathway has significant correlation with reduced survival of recurrent EOC, suggesting the importance of STAT3/STAT5 as potential therapeutic targets for cancer therapy. This review summarizes the distinct role of STAT3 and STAT5 activities in the progression of EOC and discusses the emerging therapies specifically targeting STAT3 and STAT5 signaling in this disease setting. Full article

(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)

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26 pages, 1413 KB

Open AccessEditor’s ChoiceReview

JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression

by Katie L. Owen, Natasha K. Brockwell and Belinda S. Parker

Cancers 2019, 11(12), 2002; https://doi.org/10.3390/cancers11122002 - 12 Dec 2019

Cited by 495 | Viewed by 31902

Abstract

Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling mediates almost all immune regulatory processes, including those that are involved in tumor cell recognition and tumor-driven immune escape. Antitumor immune responses are largely driven by STAT1 and STAT2 induction of type I and [...] Read more.

Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling mediates almost all immune regulatory processes, including those that are involved in tumor cell recognition and tumor-driven immune escape. Antitumor immune responses are largely driven by STAT1 and STAT2 induction of type I and II interferons (IFNs) and the downstream programs IFNs potentiate. Conversely, STAT3 has been widely linked to cancer cell survival, immunosuppression, and sustained inflammation in the tumor microenvironment. The discovery of JAK-STAT cross-regulatory mechanisms, post-translational control, and non-canonical signal transduction has added a new level of complexity to JAK-STAT governance over tumor initiation and progression. Endeavors to better understand the vast effects of JAK-STAT signaling on antitumor immunity have unearthed a wide range of targets, including oncogenes, miRNAs, and other co-regulatory factors, which direct specific phenotypical outcomes subsequent to JAK-STAT stimulation. Yet, the rapidly expanding field of therapeutic developments aimed to resolve JAK-STAT aberrations commonly reported in a multitude of cancers has been marred by off-target effects. Here, we discuss JAK-STAT biology in the context of immunity and cancer, the consequences of pathway perturbations and current therapeutic interventions, to provide insight and consideration for future targeting innovations. Full article

(This article belongs to the Special Issue JAK-STAT Signalling Pathway in Cancer)

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11 pages, 2129 KB

Open AccessFeature PaperEditor’s ChoiceArticle

Switching to Immune Checkpoint Inhibitors upon Response to Targeted Therapy; The Road to Long-Term Survival in Advanced Melanoma Patients with Highly Elevated Serum LDH?

by Maartje G. Schouwenburg, Karijn P.M. Suijkerbuijk, Rutger H.T. Koornstra, Anouk Jochems, Michiel C.T. van Zeijl, Alfons J.M. van den Eertwegh, John B.A.G. Haanen, Maureen J.B. Aarts, Alexander C.J. van Akkooi, Franchette W.P.J. van den Berkmortel, Jan Willem B. de Groot, Geke A.P. Hospers, Ellen Kapiteijn, Wim H. Kruit, Djura Piersma, Rozemarijn S. van Rijn, Albert J. ten Tije, Gerard Vreugdenhil, Jacobus J.M. van der Hoeven and Michel W.J.M. Wouters

Cancers 2019, 11(12), 1940; https://doi.org/10.3390/cancers11121940 - 4 Dec 2019

Cited by 32 | Viewed by 4287

Abstract

The prognosis of patients with advanced melanoma has improved dramatically. However, the clinical outcomes of patients with highly elevated serum lactate dehydrogenase (LDH) remain very poor. The aim of this study was to explore whether patients with normalized LDH after targeted therapy could [...] Read more.

The prognosis of patients with advanced melanoma has improved dramatically. However, the clinical outcomes of patients with highly elevated serum lactate dehydrogenase (LDH) remain very poor. The aim of this study was to explore whether patients with normalized LDH after targeted therapy could benefit from subsequent treatment with immune checkpoint inhibitors (ICI). Data from all patients with BRAF-mutant metastatic melanoma with a highly elevated serum LDH at baseline (≥2× upper limit of normal) receiving first-line targeted therapy between 2012 and 2019 in the Netherlands were collected. Patients were stratified according to response status to targeted therapy and change in LDH at start of subsequent treatment with ICI. Differences in overall survival (OS) between the subgroups were compared using log-rank tests. After a median follow-up of 35.1 months, median OS of the total study population (n = 360) was 4.9 months (95% CI 4.4–5.4). Of all patients receiving subsequent treatment with ICI (n = 113), survival from start of subsequent treatment was significantly longer in patients who had normalized LDH and were still responding to targeted therapy compared to those with LDH that remained elevated (median OS 24.7 vs. 1.1 months). Our study suggests that introducing ICI upon response to targeted therapy with normalization of LDH could be an effective strategy in obtaining long-term survival in advanced melanoma patients with initial highly elevated serum LDH. Full article

(This article belongs to the Special Issue Advanced Melanoma)

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14 pages, 1727 KB

Open AccessEditor’s ChoiceReview

ER Stress and Unfolded Protein Response in Cancer Cachexia

by Anirban Roy and Ashok Kumar

Cancers 2019, 11(12), 1929; https://doi.org/10.3390/cancers11121929 - 3 Dec 2019

Cited by 50 | Viewed by 7643

Abstract

Cancer cachexia is a devastating syndrome characterized by unintentional weight loss attributed to extensive skeletal muscle wasting. The pathogenesis of cachexia is multifactorial because of complex interactions of tumor and host factors. The irreversible wasting syndrome has been ascribed to systemic inflammation, insulin [...] Read more.

Cancer cachexia is a devastating syndrome characterized by unintentional weight loss attributed to extensive skeletal muscle wasting. The pathogenesis of cachexia is multifactorial because of complex interactions of tumor and host factors. The irreversible wasting syndrome has been ascribed to systemic inflammation, insulin resistance, dysfunctional mitochondria, oxidative stress, and heightened activation of ubiquitin-proteasome system and macroautophagy. Accumulating evidence suggests that deviant regulation of an array of signaling pathways engenders cancer cachexia where the human body is sustained in an incessant self-consuming catabolic state. Recent studies have further suggested that several components of endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) are activated in skeletal muscle of animal models and muscle biopsies of cachectic cancer patients. However, the exact role of ER stress and the individual arms of the UPR in the regulation of skeletal muscle mass in various catabolic states including cancer has just begun to be elucidated. This review provides a succinct overview of emerging roles of ER stress and the UPR in cancer-induced skeletal muscle wasting. Full article

(This article belongs to the Special Issue Cancer Cachexia)

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14 pages, 2214 KB

Open AccessEditor’s ChoiceReview

Retinoic Acid Receptors in Acute Myeloid Leukemia Therapy

by Orsola di Martino and John S. Welch

Cancers 2019, 11(12), 1915; https://doi.org/10.3390/cancers11121915 - 1 Dec 2019

Cited by 57 | Viewed by 7806

Abstract

Retinoic acid (RA) signaling pathways regulate fundamental biological processes, such as cell proliferation, development, differentiation, and apoptosis. Retinoid receptors (RARs and RXRs) are ligand-dependent transcription factors. All-trans retinoic acid (ATRA) is the principal endogenous ligand for the retinoic acid receptor alpha (RARA) and [...] Read more.

Retinoic acid (RA) signaling pathways regulate fundamental biological processes, such as cell proliferation, development, differentiation, and apoptosis. Retinoid receptors (RARs and RXRs) are ligand-dependent transcription factors. All-trans retinoic acid (ATRA) is the principal endogenous ligand for the retinoic acid receptor alpha (RARA) and is produced by the enzymatic oxidation of dietary vitamin A, whose deficiency is associated with several pathological conditions. Differentiation therapy using ATRA revolutionized the outcome of acute promyelocytic leukemia (APL), although attempts to replicate these results in other cancer types have been met with more modest results. A better knowledge of RA signaling in different leukemia contexts is required to improve initial designs. Here, we will review the RA signaling pathway in normal and malignant hematopoiesis, and will discuss the advantages and the limitations related to retinoid therapy in acute myeloid leukemia. Full article

(This article belongs to the Special Issue Acute Myeloid Leukemia)

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21 pages, 1238 KB

Open AccessEditor’s ChoiceReview

Thirty Years of Cancer Nanomedicine: Success, Frustration, and Hope

by Lucia Salvioni, Maria Antonietta Rizzuto, Jessica Armida Bertolini, Laura Pandolfi, Miriam Colombo and Davide Prosperi

Cancers 2019, 11(12), 1855; https://doi.org/10.3390/cancers11121855 - 25 Nov 2019

Cited by 170 | Viewed by 15220

Abstract

Starting with the enhanced permeability and retention (EPR) effect discovery, nanomedicine has gained a crucial role in cancer treatment. The advances in the field have led to the approval of nanodrugs with improved safety profile and still inspire the ongoing investigations. However, several [...] Read more.

Starting with the enhanced permeability and retention (EPR) effect discovery, nanomedicine has gained a crucial role in cancer treatment. The advances in the field have led to the approval of nanodrugs with improved safety profile and still inspire the ongoing investigations. However, several restrictions, such as high manufacturing costs, technical challenges, and effectiveness below expectations, raised skeptical opinions within the scientific community about the clinical relevance of nanomedicine. In this review, we aim to give an overall vision of the current hurdles encountered by nanotherapeutics along with their design, development, and translation, and we offer a prospective view on possible strategies to overcome such limitations. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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17 pages, 253 KB

Open AccessFeature PaperEditor’s ChoiceReview

Cachexia and Sarcopenia in Older Adults with Cancer: A Comprehensive Review

by Richard F. Dunne, Kah Poh Loh, Grant R. Williams, Aminah Jatoi, Karen M. Mustian and Supriya G. Mohile

Cancers 2019, 11(12), 1861; https://doi.org/10.3390/cancers11121861 - 25 Nov 2019

Cited by 150 | Viewed by 10647

Abstract

Cancer cachexia is a syndrome characterized by weight loss with accompanying loss of muscle and/or fat mass and leads to impaired patient function and physical performance and is associated with a poor prognosis. It is prevalent in older adults with cancer; age-associated physiologic [...] Read more.

Cancer cachexia is a syndrome characterized by weight loss with accompanying loss of muscle and/or fat mass and leads to impaired patient function and physical performance and is associated with a poor prognosis. It is prevalent in older adults with cancer; age-associated physiologic muscle wasting and weakness, also known as sarcopenia, can compound deficits associated with cancer cachexia in older adults and makes studying this condition more complex in this population. Multiple measurement options are available to assess the older patient with cancer and cachexia and/or sarcopenia including anthropometric measures, imaging modalities such as Dual X-ray absorptiometry (DEXA) and Computed Tomography (CT), muscular strength and physical performance testing, and patient-reported outcomes (PROs). A geriatric assessment (GA) is a useful tool when studying the older patient with cachexia given its comprehensive ability to capture aging-sensitive PROs. Interventions focused on nutrition and increasing physical activity may improve outcomes in older adults with cachexia. Efforts to develop targeted pharmacologic therapies with cachexia have not been successful thus far. Formal treatment guidelines, an updated consensus definition for cancer cachexia and the development of a widely adapted assessment tool, much like the GA utilized in geriatric oncology, could help advance the field of cancer cachexia over the next decade. Full article

(This article belongs to the Special Issue Cancer Cachexia)

19 pages, 1476 KB

Open AccessEditor’s ChoiceReview

Molecular Targeting Therapy against EGFR Family in Breast Cancer: Progress and Future Potentials

by Amaia Eleonora Maennling, Mehmet Kemal Tur, Marcus Niebert, Torsten Klockenbring, Felix Zeppernick, Stefan Gattenlöhner, Ivo Meinhold-Heerlein and Ahmad Fawzi Hussain

Cancers 2019, 11(12), 1826; https://doi.org/10.3390/cancers11121826 - 20 Nov 2019

Cited by 179 | Viewed by 14871

Abstract

The epidermal growth factor receptor (EGFR) family contains four transmembrane tyrosine kinases (EGFR1/ErbB1, Her2/ErbB2, Her3/ErbB3 and Her4/ErbB4) and 13 secreted polypeptide ligands. EGFRs are overexpressed in many solid tumors, including breast, pancreas, head-and-neck, prostate, ovarian, renal, colon, and non-small-cell lung cancer. Such overexpression [...] Read more.

The epidermal growth factor receptor (EGFR) family contains four transmembrane tyrosine kinases (EGFR1/ErbB1, Her2/ErbB2, Her3/ErbB3 and Her4/ErbB4) and 13 secreted polypeptide ligands. EGFRs are overexpressed in many solid tumors, including breast, pancreas, head-and-neck, prostate, ovarian, renal, colon, and non-small-cell lung cancer. Such overexpression produces strong stimulation of downstream signaling pathways, which induce cell growth, cell differentiation, cell cycle progression, angiogenesis, cell motility and blocking of apoptosis.The high expression and/or functional activation of EGFRs correlates with the pathogenesis and progression of several cancers, which make them attractive targets for both diagnosis and therapy. Several approaches have been developed to target these receptors and/or the EGFR modulated effects in cancer cells. Most approaches include the development of anti-EGFRs antibodies and/or small-molecule EGFR inhibitors. This review presents the state-of-the-art and future prospects of targeting EGFRs to treat breast cancer. Full article

(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling in Cancer)

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18 pages, 955 KB

Open AccessEditor’s ChoiceArticle

Hyperprogressive Disease during Anti-PD-1 (PDCD1) / PD-L1 (CD274) Therapy: A Systematic Review and Meta-Analysis

by Jong Yeob Kim, Keum Hwa Lee, Jeonghyun Kang, Edith Borcoman, Esma Saada-Bouzid, Andreas Kronbichler, Sung Hwi Hong, Leandro Fórnias Machado de Rezende, Shuji Ogino, Nana Keum, Mingyang Song, Claudio Luchini, Hans J. van der Vliet, Jae Il Shin and Gabriele Gamerith

Cancers 2019, 11(11), 1699; https://doi.org/10.3390/cancers11111699 - 1 Nov 2019

Cited by 88 | Viewed by 7594

Abstract

Hyperprogressive disease (HPD) is a recently acknowledged pattern of rapid tumor progression after the initiation of immune checkpoint inhibitors. HPD has been observed across various types of tumors and has been associated with poor survival. We performed a meta-analysis to identify baseline (i.e., [...] Read more.

Hyperprogressive disease (HPD) is a recently acknowledged pattern of rapid tumor progression after the initiation of immune checkpoint inhibitors. HPD has been observed across various types of tumors and has been associated with poor survival. We performed a meta-analysis to identify baseline (i.e., prior to programmed cell death 1 [PD-1, PDCD1] / programmed cell death 1 ligand 1 [PD-L1, CD274] inhibitor therapy) patient factors associated with risks of developing HPD during PD-1/PD-L1 inhibitor therapy. We searched eight databases until 6 June 2019. We calculated the summary odds ratio (OR) and its 95% confidence interval (CI) using the random-effects model and explored between-study heterogeneity and small-study effects. A total of nine articles was eligible (217 HPD cases, 1519 cancer patients) for meta-analysis. There was no standard definition of HPD, and the incidence of HPD ranged from 1 to 30%. We identified twenty-three baseline patient factors, of which five factors were statistically significantly associated with HPD. These were serum lactate dehydrogenase (LDH) above the upper normal limit (OR = 1.89, 95% CI = 1.02–3.49, p = 0.043), more than two metastatic sites (OR = 1.86, 1.34–2.57, p < 0.001), liver metastases (OR = 3.33, 2.07–5.34, p < 0.001), Royal Marsden Hospital prognostic score of 2 or above (OR = 3.33, 1.96–5.66, p < 0.001), and positive PD-L1 expression status that was inversely correlated with HPD (OR = 0.60, 0.36–0.99, p = 0.044). Between-study heterogeneity was low. Evidence of small-study effect was found in one association (PD-L1 expression). Subset analyses of patients with non-small cell lung cancer showed similar results. Future studies are warranted to identify underlying molecular mechanisms and to test their roles as predictive biomarkers of HPD. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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24 pages, 1065 KB

Open AccessEditor’s ChoiceReview

Long Noncoding RNAs in Acute Myeloid Leukemia: Functional Characterization and Clinical Relevance

by Morgane Gourvest, Pierre Brousset and Marina Bousquet

Cancers 2019, 11(11), 1638; https://doi.org/10.3390/cancers11111638 - 24 Oct 2019

Cited by 72 | Viewed by 7141

Abstract

Acute Myeloid Leukemia (AML) is the most common form of leukemia in adults with an incidence of 4.3 per 100,000 cases per year. Historically, the identification of genetic alterations in AML focused on protein-coding genes to provide biomarkers and to understand the molecular [...] Read more.

Acute Myeloid Leukemia (AML) is the most common form of leukemia in adults with an incidence of 4.3 per 100,000 cases per year. Historically, the identification of genetic alterations in AML focused on protein-coding genes to provide biomarkers and to understand the molecular complexity of AML. Despite these findings and because of the heterogeneity of this disease, questions as to the molecular mechanisms underlying AML development and progression remained unsolved. Recently, transcriptome-wide profiling approaches have uncovered a large family of long noncoding RNAs (lncRNAs). Larger than 200 nucleotides and with no apparent protein coding potential, lncRNAs could unveil a new set of players in AML development. Originally considered as dark matter, lncRNAs have critical roles to play in the different steps of gene expression and thus affect cellular homeostasis including proliferation, survival, differentiation, migration or genomic stability. Consequently, lncRNAs are found to be differentially expressed in tumors, notably in AML, and linked to the transformation of healthy cells into leukemic cells. In this review, we aim to summarize the knowledge concerning lncRNAs functions and implications in AML, with a particular emphasis on their prognostic and therapeutic potential. Full article

(This article belongs to the Special Issue Acute Myeloid Leukemia)

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25 pages, 1616 KB

Open AccessEditor’s ChoiceReview

A Comprehensive Review on MAPK: A Promising Therapeutic Target in Cancer

by Cornelia Braicu, Mihail Buse, Constantin Busuioc, Rares Drula, Diana Gulei, Lajos Raduly, Alexandru Rusu, Alexandru Irimie, Atanas G. Atanasov, Ondrej Slaby, Calin Ionescu and Ioana Berindan-Neagoe

Cancers 2019, 11(10), 1618; https://doi.org/10.3390/cancers11101618 - 22 Oct 2019

Cited by 730 | Viewed by 34199

Abstract

The mitogen-activated protein kinase (MAPK) pathway is an important bridge in the switch from extracellular signals to intracellular responses. Alterations of signaling cascades are found in various diseases, including cancer, as a result of genetic and epigenetic changes. Numerous studies focused on both [...] Read more.

The mitogen-activated protein kinase (MAPK) pathway is an important bridge in the switch from extracellular signals to intracellular responses. Alterations of signaling cascades are found in various diseases, including cancer, as a result of genetic and epigenetic changes. Numerous studies focused on both the homeostatic and the pathologic conduct of MAPK signaling; however, there is still much to be deciphered in terms of regulation and action models in both preclinical and clinical research. MAPK has implications in the response to cancer therapy, particularly the activation of the compensatory pathways in response to experimental MAPK inhibition. The present paper discusses new insights into MAPK as a complex cell signaling pathway with roles in the sustenance of cellular normal conduit, response to cancer therapy, and activation of compensatory pathways. Unfortunately, most MAPK inhibitors trigger resistance due to the activation of compensatory feed-back loops in tumor cells and tumor microenvironment components. Therefore, novel combinatorial therapies have to be implemented for cancer management in order to restrict the possibility of alternative pathway activation, as a perspective for developing novel therapies based on integration in translational studies. Full article

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47 pages, 9681 KB

Open AccessEditor’s ChoiceReview

Targeting Autophagy for Cancer Treatment and Tumor Chemosensitization

by Marta Pérez-Hernández, Alain Arias, David Martínez-García, Ricardo Pérez-Tomás, Roberto Quesada and Vanessa Soto-Cerrato

Cancers 2019, 11(10), 1599; https://doi.org/10.3390/cancers11101599 - 19 Oct 2019

Cited by 123 | Viewed by 8857

Abstract

Autophagy is a tightly regulated catabolic process that facilitates nutrient recycling from damaged organelles and other cellular components through lysosomal degradation. Deregulation of this process has been associated with the development of several pathophysiological processes, such as cancer and neurodegenerative diseases. In cancer, [...] Read more.

Autophagy is a tightly regulated catabolic process that facilitates nutrient recycling from damaged organelles and other cellular components through lysosomal degradation. Deregulation of this process has been associated with the development of several pathophysiological processes, such as cancer and neurodegenerative diseases. In cancer, autophagy has opposing roles, being either cytoprotective or cytotoxic. Thus, deciphering the role of autophagy in each tumor context is crucial. Moreover, autophagy has been shown to contribute to chemoresistance in some patients. In this regard, autophagy modulation has recently emerged as a promising therapeutic strategy for the treatment and chemosensitization of tumors, and has already demonstrated positive clinical results in patients. In this review, the dual role of autophagy during carcinogenesis is discussed and current therapeutic strategies aimed at targeting autophagy for the treatment of cancer, both under preclinical and clinical development, are presented. The use of autophagy modulators in combination therapies, in order to overcome drug resistance during cancer treatment, is also discussed as well as the potential challenges and limitations for the use of these novel therapeutic strategies in the clinic. Full article

(This article belongs to the Special Issue The Role of Autophagy in Cancer Progression and Drug Resistance)

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21 pages, 1419 KB

Open AccessEditor’s ChoiceReview

Acute Promyelocytic Leukemia: Update on the Mechanisms of Leukemogenesis, Resistance and on Innovative Treatment Strategies

by N. I. Noguera, G. Catalano, C. Banella, M. Divona, I. Faraoni, T. Ottone, W. Arcese and M. T. Voso

Cancers 2019, 11(10), 1591; https://doi.org/10.3390/cancers11101591 - 18 Oct 2019

Cited by 88 | Viewed by 11494

Abstract

This review highlights new findings that have deepened our understanding of the mechanisms of leukemogenesis, therapy and resistance in acute promyelocytic leukemia (APL). Promyelocytic leukemia-retinoic acid receptor α (PML-RARa) sets the cellular landscape of acute promyelocytic leukemia (APL) by repressing the transcription of [...] Read more.

This review highlights new findings that have deepened our understanding of the mechanisms of leukemogenesis, therapy and resistance in acute promyelocytic leukemia (APL). Promyelocytic leukemia-retinoic acid receptor α (PML-RARa) sets the cellular landscape of acute promyelocytic leukemia (APL) by repressing the transcription of RARa target genes and disrupting PML-NBs. The RAR receptors control the homeostasis of tissue growth, modeling and regeneration, and PML-NBs are involved in self-renewal of normal and cancer stem cells, DNA damage response, senescence and stress response. The additional somatic mutations in APL mainly involve FLT3, WT1, NRAS, KRAS, ARID1B and ARID1A genes. The treatment outcomes in patients with newly diagnosed APL improved dramatically since the advent of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). ATRA activates the transcription of blocked genes and degrades PML-RARα, while ATO degrades PML-RARa by promoting apoptosis and has a pro-oxidant effect. The resistance to ATRA and ATO may derive from the mutations in the RARa ligand binding domain (LBD) and in the PML-B2 domain of PML-RARa, but such mutations cannot explain the majority of resistances experienced in the clinic, globally accounting for 5–10% of cases. Several studies are ongoing to unravel clonal evolution and resistance, suggesting the therapeutic potential of new retinoid molecules and combinatorial treatments of ATRA or ATO with different drugs acting through alternative mechanisms of action, which may lead to synergistic effects on growth control or the induction of apoptosis in APL cells. Full article

(This article belongs to the Special Issue Acute Myeloid Leukemia)

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26 pages, 1099 KB

Open AccessEditor’s ChoiceReview

Breast Cancer Stem Cells as Drivers of Tumor Chemoresistance, Dormancy and Relapse: New Challenges and Therapeutic Opportunities

by Maria Laura De Angelis, Federica Francescangeli and Ann Zeuner

Cancers 2019, 11(10), 1569; https://doi.org/10.3390/cancers11101569 - 15 Oct 2019

Cited by 141 | Viewed by 10086

Abstract

Breast cancer is the most frequent cancer among women worldwide. Therapeutic strategies to prevent or treat metastatic disease are still inadequate although great progress has been made in treating early-stage breast cancer. Cancer stem-like cells (CSCs) that are endowed with high plasticity and [...] Read more.

Breast cancer is the most frequent cancer among women worldwide. Therapeutic strategies to prevent or treat metastatic disease are still inadequate although great progress has been made in treating early-stage breast cancer. Cancer stem-like cells (CSCs) that are endowed with high plasticity and self-renewal properties have been shown to play a key role in breast cancer development, progression, and metastasis. A subpopulation of CSCs that combines tumor-initiating capacity and a dormant/quiescent/slow cycling status is present throughout the clinical history of breast cancer patients. Dormant/quiescent/slow cycling CSCs are a key component of tumor heterogeneity and they are responsible for chemoresistance, tumor migration, and metastatic dormancy, defined as the ability of CSCs to survive in target organs and generate metastasis up to two decades after diagnosis. Understanding the strategies that are used by CSCs to resist conventional and targeted therapies, to interact with their niche, to escape immune surveillance, and finally to awaken from dormancy is of key importance to prevent and treat metastatic cancer. This review summarizes the current understanding of mechanisms involved in CSCs chemoresistance, dissemination, and metastasis in breast cancer, with a particular focus on dormant cells. Finally, we discuss how advancements in the detection, molecular understanding, and targeting of dormant CSCs will likely open new therapeutic avenues for breast cancer treatment. Full article

(This article belongs to the Special Issue Breast Cancer Stem Cells: Therapy Resistance and Novel Therapeutic Targets)

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13 pages, 1298 KB

Open AccessEditor’s ChoiceArticle

Comprehensive Metabolomic Search for Biomarkers to Differentiate Early Stage Hepatocellular Carcinoma from Cirrhosis

by Da Jung Kim, Eun Ju Cho, Kyung-Sang Yu, In-Jin Jang, Jung-Hwan Yoon, Taesung Park and Joo-Youn Cho

Cancers 2019, 11(10), 1497; https://doi.org/10.3390/cancers11101497 - 6 Oct 2019

Cited by 66 | Viewed by 5959

Abstract

The established biomarker for hepatocellular carcinoma (HCC), serum α-fetoprotein (AFP), has suboptimal performance in early disease stages. This study aimed to develop a metabolite panel to differentiate early-stage HCC from cirrhosis. Cross-sectional metabolomic analyses of serum samples were performed for 53 and 47 [...] Read more.

The established biomarker for hepatocellular carcinoma (HCC), serum α-fetoprotein (AFP), has suboptimal performance in early disease stages. This study aimed to develop a metabolite panel to differentiate early-stage HCC from cirrhosis. Cross-sectional metabolomic analyses of serum samples were performed for 53 and 47 patients with early HCC and cirrhosis, respectively, and 50 matched healthy controls. Results were validated in 82 and 80 patients with early HCC and cirrhosis, respectively. To retain a broad spectrum of metabolites, technically distinct analyses (global metabolomic profiling using gas chromatography time-of-flight mass spectrometry and targeted analyses using liquid chromatography with tandem mass spectrometry) were employed. Multivariate analyses classified distinct metabolites; logistic regression was employed to construct a prediction model for HCC diagnosis. Five metabolites (methionine, proline, ornithine, pimelylcarnitine, and octanoylcarnitine) were selected in a panel. The panel distinguished HCC from cirrhosis and normal controls, with an area under the receiver operating curve (AUC) of 0.82; this was significantly better than that of AFP (AUC: 0.75). During validation, the panel demonstrated significantly better predictability (AUC: 0.94) than did AFP (AUC: 0.78). Defects in ammonia recycling, the urea cycle, and amino acid metabolism, demonstrated on enrichment pathway analysis, may reliably distinguish HCC from cirrhosis. Compared with AFP alone, the metabolite panel substantially improved early-stage HCC detection. Full article

(This article belongs to the Special Issue Human Hepatocellular Carcinoma (HCC))

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20 pages, 4485 KB

Open AccessEditor’s ChoiceArticle

STAT3 Activity Promotes Programmed-Death Ligand 1 Expression and Suppresses Immune Responses in Breast Cancer

by Ioannis Zerdes, Majken Wallerius, Emmanouil G. Sifakis, Tatjana Wallmann, Stina Betts, Margarita Bartish, Nikolaos Tsesmetzis, Nicholas P. Tobin, Christos Coucoravas, Jonas Bergh, George Z. Rassidakis, Charlotte Rolny and Theodoros Foukakis

Cancers 2019, 11(10), 1479; https://doi.org/10.3390/cancers11101479 - 1 Oct 2019

Cited by 78 | Viewed by 7651

Abstract

Signal transducer and activator of transcription 3 (STAT3) is an oncogene and multifaceted transcription factor involved in multiple cellular functions. Its role in modifying anti-tumor immunity has been recently recognized. In this study, the biologic effects of STAT3 on immune checkpoint expression and [...] Read more.

Signal transducer and activator of transcription 3 (STAT3) is an oncogene and multifaceted transcription factor involved in multiple cellular functions. Its role in modifying anti-tumor immunity has been recently recognized. In this study, the biologic effects of STAT3 on immune checkpoint expression and anti-tumor responses were investigated in breast cancer (BC). A transcriptional signature of phosphorylated STAT3 was positively correlated with PD-L1 expression in two independent cohorts of early BC. Pharmacologic inhibition and gene silencing of STAT3 led to decreased Programmed Death Ligand 1 (PD-L1) expression levels in vitro, and resulted as well in reduction of tumor growth and decreased metastatic dissemination in a mammary carcinoma mouse model. The hampering of tumor progression was correlated to an anti-tumoral macrophage phenotype and accumulation of natural-killer cells, but also in reduced accrual of cytotoxic lymphocytes. In human BC, pro-tumoral macrophages correlated to PD-L1 expression, proliferation status and higher grade of malignancy, indicating a subset of patients with immunosuppressive properties. In conclusion, this study provides evidence for STAT3-mediated regulation of PD-L1 and modulation of immune microenvironment in BC. Full article

(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)

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38 pages, 1835 KB

Open AccessEditor’s ChoiceReview

Current Perspectives in Cancer Immunotherapy

by Theodoulakis Christofi, Stavroula Baritaki, Luca Falzone, Massimo Libra and Apostolos Zaravinos

Cancers 2019, 11(10), 1472; https://doi.org/10.3390/cancers11101472 - 30 Sep 2019

Cited by 181 | Viewed by 18217

Abstract

Different immunotherapeutic approaches have proved to be of significant clinical value to many patients with different types of advanced cancer. However, we need more precise immunotherapies and predictive biomarkers to increase the successful response rates. The advent of next generation sequencing technologies and [...] Read more.

Different immunotherapeutic approaches have proved to be of significant clinical value to many patients with different types of advanced cancer. However, we need more precise immunotherapies and predictive biomarkers to increase the successful response rates. The advent of next generation sequencing technologies and their applications in immuno-oncology has helped us tremendously towards this aim. We are now moving towards the realization of personalized medicine, thus, significantly increasing our expectations for a more successful management of the disease. Here, we discuss the current immunotherapeutic approaches against cancer, including immune checkpoint blockade with an emphasis on anti-PD-L1 and anti-CTLA-4 monoclonal antibodies. We also analyze a growing list of other co-inhibitory and co-stimulatory markers and emphasize the mechanism of action of the principal pathway for each of these, as well as on drugs that either have been FDA-approved or are under clinical investigation. We further discuss recent advances in other immunotherapies, including cytokine therapy, adoptive cell transfer therapy and therapeutic vaccines. We finally discuss the modulation of gut microbiota composition and response to immunotherapy, as well as how tumor-intrinsic factors and immunological processes influence the mutational and epigenetic landscape of progressing tumors and response to immunotherapy but also how immunotherapeutic intervention influences the landscape of cancer neoepitopes and tumor immunoediting. Full article

(This article belongs to the Special Issue New Insights into Cancer Vaccines and Immunotherapy)

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11 pages, 1749 KB

Open AccessEditor’s ChoiceArticle

Increased Plasmatic Levels of PSA-Expressing Exosomes Distinguish Prostate Cancer Patients from Benign Prostatic Hyperplasia: A Prospective Study

by Mariantonia Logozzi, Daniela F. Angelini, Alessandro Giuliani, Davide Mizzoni, Rossella Di Raimo, Martina Maggi, Alessandro Gentilucci, Vittorio Marzio, Stefano Salciccia, Giovanna Borsellino, Luca Battistini, Alessandro Sciarra and Stefano Fais

Cancers 2019, 11(10), 1449; https://doi.org/10.3390/cancers11101449 - 27 Sep 2019

Cited by 86 | Viewed by 8923

Abstract

Prostate Specific Antigen (PSA) fails to discriminate between benign prostatic hyperplasia (BPH) and Prostate Cancer (PCa), resulting in large numbers of unnecessary biopsies and missed cancer diagnoses. Nanovesicles called exosomes are directly detectable in patient plasma and here we explore the potential use [...] Read more.

Prostate Specific Antigen (PSA) fails to discriminate between benign prostatic hyperplasia (BPH) and Prostate Cancer (PCa), resulting in large numbers of unnecessary biopsies and missed cancer diagnoses. Nanovesicles called exosomes are directly detectable in patient plasma and here we explore the potential use of plasmatic exosomes expressing PSA (Exo-PSA) in distinguishing healthy individuals, BPH, and PCa. Exosomes were obtained from plasma samples of 80 PCa, 80 BPH, and 80 healthy donors (CTR). Nanoparticle Tracking Analysis (NTA), immunocapture-based ELISA (IC-ELISA), and nanoscale flow-cytometry (NSFC), were exploited to detect and characterize plasmatic exosomes. Statistical analysis showed that plasmatic exosomes expressing both CD81 and PSA were significantly higher in PCa as compared to both BPH and CTR, reaching 100% specificity and sensitivity in distinguishing PCa patients from healthy individuals. IC-ELISA, NSFC, and Exo-PSA consensus score (EXOMIX) showed 98% to 100% specificity and sensitivity for BPH-PCa discrimination. This study outperforms the conventional PSA test with a minimally invasive widely exploitable approach. Full article

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15 pages, 1085 KB

Open AccessEditor’s ChoiceReview

Tumour Microenvironment and Immune Evasion in EGFR Addicted NSCLC: Hurdles and Possibilities

by Antonio Santaniello, Fabiana Napolitano, Alberto Servetto, Pietro De Placido, Nicola Silvestris, Cataldo Bianco, Luigi Formisano and Roberto Bianco

Cancers 2019, 11(10), 1419; https://doi.org/10.3390/cancers11101419 - 24 Sep 2019

Cited by 54 | Viewed by 7589

Abstract

In the last few years, the treatment strategy in Non-Small Cell Lung Cancer (NSCLC) patients has been heavily modified by the introduction of the immune-checkpoint inhibitors. Anti-programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) therapy has improved both progression-free and the overall [...] Read more.

In the last few years, the treatment strategy in Non-Small Cell Lung Cancer (NSCLC) patients has been heavily modified by the introduction of the immune-checkpoint inhibitors. Anti-programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) therapy has improved both progression-free and the overall survival in almost all subgroups of patients, with or without PDL1 expression, with different degrees of responses. However, there are patients that are not benefitting from this treatment. A defined group of immune-checkpoint inhibitors non-responder tumours carry EGFR (epidermal growth factor receptor) mutations: nowadays, anti-PD-1/PD-L1 clinical trials often do not involve this type of patient and the use of immune-checkpoint inhibitors are under evaluation in this setting. Our review aims to elucidate the mechanisms underlying this resistance: we focused on evaluating the role of the tumour microenvironment, including infiltrating cells, cytokines, secreted factors, and angiogenesis, and its interaction with the tumour tissue. Finally, we analysed the possible role of immunotherapy in EGFR mutated tumours. Full article

(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling in Cancer)

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13 pages, 5407 KB

Open AccessEditor’s ChoiceArticle

CD8+ and Regulatory T cells Differentiate Tumor Immune Phenotypes and Predict Survival in Locally Advanced Head and Neck Cancer

by Alessia Echarti, Markus Hecht, Maike Büttner-Herold, Marlen Haderlein, Arndt Hartmann, Rainer Fietkau and Luitpold Distel

Cancers 2019, 11(9), 1398; https://doi.org/10.3390/cancers11091398 - 19 Sep 2019

Cited by 69 | Viewed by 5241

Abstract

Background: The tumor immune status “inflamed”, “immune excluded”, and “desert” might serve as a predictive parameter. We studied these three cancer immune phenotypes while using a simple immunohistochemical algorithm. Methods: Pre-treatment tissue samples of 280 patients with locally advanced HNSCC treated with radiochemotherapy [...] Read more.

Background: The tumor immune status “inflamed”, “immune excluded”, and “desert” might serve as a predictive parameter. We studied these three cancer immune phenotypes while using a simple immunohistochemical algorithm. Methods: Pre-treatment tissue samples of 280 patients with locally advanced HNSCC treated with radiochemotherapy were analyzed. A double staining of CD8+ cytotoxic T cells (CTL) and FoxP3+ (Treg) was performed and the cell density was evaluated in the intraepithelial and stromal compartment of the tumor. Results: The classification of tumors as “immune desert” when stromal CTL were ≤ 50 cells/mm², “inflamed” when intraepithelial CTL were > 500 cells/mm², and as “excluded” when neither of these definitions met these cut off values allowed the best discrimination regarding overall survival. These groups had median OS periods of 37, 61, and 85 months, respectively. In “immune desert” and “immune excluded” tumors high Treg tended to worsen OS, but in “inflamed” tumors high Treg clearly improved OS. Conclusions: We propose that, in locally advanced HNSCC, the tumor immune state “inflamed”, “immune excluded”, and “immune desert” can be defined by intraepithelial and stromal CTL. Tregs can further subdivide these groups. The opposing effects of Tregs in the different groups might be the reason for the inconsistency of Tregs prognostic values published earlier. Full article

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23 pages, 1979 KB

Open AccessEditor’s ChoiceReview

Hyperglycemia Associated Metabolic and Molecular Alterations in Cancer Risk, Progression, Treatment, and Mortality

by Pranay Ramteke, Ankita Deb, Varsha Shepal and Manoj Kumar Bhat

Cancers 2019, 11(9), 1402; https://doi.org/10.3390/cancers11091402 - 19 Sep 2019

Cited by 111 | Viewed by 16546

Abstract

Cancer and diabetes are amongst the leading causes of deaths worldwide. There is an alarming rise in cancer incidences and mortality, with approximately 18.1 million new cases and 9.6 million deaths in 2018. A major contributory but neglected factor for risk of neoplastic [...] Read more.

Cancer and diabetes are amongst the leading causes of deaths worldwide. There is an alarming rise in cancer incidences and mortality, with approximately 18.1 million new cases and 9.6 million deaths in 2018. A major contributory but neglected factor for risk of neoplastic transformation is hyperglycemia. Epidemiologically too, lifestyle patterns resulting in high blood glucose level, with or without the role of insulin, are more often correlated with cancer risk, progression, and mortality. The two conditions recurrently exist in comorbidity, and their interplay has rendered treatment regimens more challenging by restricting the choice of drugs, affecting surgical consequences, and having associated fatal complications. Limited comprehensive literature is available on their correlation, and a lack of clarity in understanding in such comorbid conditions contributes to higher mortality rates. Hence, a critical analysis of the elements responsible for enhanced mortality due to hyperglycemia-cancer concomitance is warranted. Given the lifestyle changes in the human population, increasing metabolic disorders, and glucose addiction of cancer cells, hyperglycemia related complications in cancer underline the necessity for further in-depth investigations. This review, therefore, attempts to shed light upon hyperglycemia associated factors in the risk, progression, mortality, and treatment of cancer to highlight important mechanisms and potential therapeutic targets. Full article

(This article belongs to the Special Issue Metabolic Reprogramming and Vulnerabilities in Cancer)

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Open AccessEditor’s ChoiceReview

Current Treatment Options for Metastatic Hormone-Sensitive Prostate Cancer

by Carlo Cattrini, Elena Castro, Rebeca Lozano, Elisa Zanardi, Alessandra Rubagotti, Francesco Boccardo and David Olmos

Cancers 2019, 11(9), 1355; https://doi.org/10.3390/cancers11091355 - 12 Sep 2019

Cited by 62 | Viewed by 10997

Abstract

The possible treatments options for metastatic hormone-sensitive prostate cancer (mHSPC) have dramatically increased during the last years. The old backbone, which androgen-deprivation therapy (ADT) is the exclusive approach for hormone-naïve patients, has been disrupted. Despite the fact that several high-quality, randomized, controlled phase [...] Read more.

The possible treatments options for metastatic hormone-sensitive prostate cancer (mHSPC) have dramatically increased during the last years. The old backbone, which androgen-deprivation therapy (ADT) is the exclusive approach for hormone-naïve patients, has been disrupted. Despite the fact that several high-quality, randomized, controlled phase 3 trials have been conducted in this setting, no direct comparison is currently available among the different strategies. Inadequate power, absence of preplanning and small sample size frequently affect the subgroup analyses according to disease volume or patient’s risk. The choice between ADT alone and ADT combined with docetaxel, abiraterone acetate, enzalutamide, apalutamide or radiotherapy to the primary tumor remains challenging. Factors that are related to the tumor, patient or drug side effects, currently guide these clinical decisions. This comprehensive review aims to indirectly compare the phase 3 trials in the mHSPC setting, in order to extrapolate data useful for treatment selection, providing also perspectives on future biomarkers. Full article

(This article belongs to the Special Issue Prostate Cancer: Past, Present, and Future)

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