Cancers

26 pages, 704 KiB

Open AccessEditor’s ChoiceReview

The Cancer Stem Cell in Hepatocellular Carcinoma

by Lucas-Alexander Schulte, Juan Carlos López-Gil, Bruno Sainz, Jr. and Patrick C. Hermann

Cancers 2020, 12(3), 684; https://doi.org/10.3390/cancers12030684 - 14 Mar 2020

Cited by 37 | Viewed by 6070

The recognition of intra-tumoral cellular heterogeneity has given way to the concept of the cancer stem cell (CSC). According to this concept, CSCs are able to self-renew and differentiate into all of the cancer cell lineages present within the tumor, placing the CSC [...] Read more.

The recognition of intra-tumoral cellular heterogeneity has given way to the concept of the cancer stem cell (CSC). According to this concept, CSCs are able to self-renew and differentiate into all of the cancer cell lineages present within the tumor, placing the CSC at the top of a hierarchical tree. The observation that these cells—in contrast to bulk tumor cells—are able to exclusively initiate new tumors, initiate metastatic spread and resist chemotherapy implies that CSCs are solely responsible for tumor recurrence and should be therapeutically targeted. Toward this end, dissecting and understanding the biology of CSCs should translate into new clinical therapeutic approaches. In this article, we review the CSC concept in cancer, with a special focus on hepatocellular carcinoma. Full article

(This article belongs to the Special Issue Liver Cancer and Potential Therapeutic Targets)

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13 pages, 1601 KiB

Open AccessEditor’s ChoiceReview

ATM-Deficient Cancers Provide New Opportunities for Precision Oncology

by Nicholas R. Jette, Mehul Kumar, Suraj Radhamani, Greydon Arthur, Siddhartha Goutam, Steven Yip, Michael Kolinsky, Gareth J. Williams, Pinaki Bose and Susan P. Lees-Miller

Cancers 2020, 12(3), 687; https://doi.org/10.3390/cancers12030687 - 14 Mar 2020

Cited by 75 | Viewed by 8019

Abstract

Poly-ADP ribose polymerase (PARP) inhibitors are currently used in the treatment of several cancers carrying mutations in the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2, with many more potential applications under study and in clinical trials. Here, we discuss the [...] Read more.

Poly-ADP ribose polymerase (PARP) inhibitors are currently used in the treatment of several cancers carrying mutations in the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2, with many more potential applications under study and in clinical trials. Here, we discuss the potential for extending PARP inhibitor therapies to tumours with deficiencies in the DNA damage-activated protein kinase, Ataxia-Telangiectasia Mutated (ATM). We highlight our recent findings that PARP inhibition alone is cytostatic but not cytotoxic in ATM-deficient cancer cells and that the combination of a PARP inhibitor with an ATR (ATM, Rad3-related) inhibitor is required to induce cell death. Full article

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

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16 pages, 1905 KiB

Open AccessEditor’s ChoiceArticle

Characterization of Human NK Cell-Derived Exosomes: Role of DNAM1 Receptor in Exosome-Mediated Cytotoxicity against Tumor

by Anna Laura Di Pace, Nicola Tumino, Francesca Besi, Claudia Alicata, Libenzio Adrian Conti, Enrico Munari, Enrico Maggi, Paola Vacca and Lorenzo Moretta

Cancers 2020, 12(3), 661; https://doi.org/10.3390/cancers12030661 - 12 Mar 2020

Cited by 98 | Viewed by 7677

Abstract

Despite the pivotal role of natural killer (NK) cells in defenses against tumors, their exploitation in cancer treatment is still limited due to their reduced ability to reaching tumor sites and the inhibitory effects of tumor microenvironment (TME) on their function. In this [...] Read more.

Despite the pivotal role of natural killer (NK) cells in defenses against tumors, their exploitation in cancer treatment is still limited due to their reduced ability to reaching tumor sites and the inhibitory effects of tumor microenvironment (TME) on their function. In this study, we have characterized the exosomes from IL2- or IL15-cultured human NK cells. Both cytokines induced comparable amounts of exosomes with similar cargo composition. Analysis of molecules contained within or exposed at the exosome surface, allowed the identification of molecules playing important roles in the NK cell function including IFN-γ, Lymphocyte Function-Associated Antigen (LFA-1), DNAX Accessory Molecule-1 (DNAM1) and Programmed Cell Death Protein (PD-1). Importantly, we show that DNAM1 is involved in exosome-mediated cytotoxicity as revealed by experiments using blocking antibodies to DNAM1 or DNAM1 ligands. In addition, antibody-mediated inhibition of exosome cytotoxicity results in a delay in target cell apoptosis. We also provide evidence that NK-exosomes may exert their cytolytic activity after short time interval and even at low concentrations. Regarding their possible use in immunotherapy, NK exosomes, detectable in peripheral blood, can diffuse into tissues and exert their cytolytic effect at tumor sites. This property offers a clue to integrate cancer treatments with NK exosomes. Full article

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

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23 pages, 1368 KiB

Open AccessEditor’s ChoiceReview

Inflammatory Mechanisms of HCC Development

by Maria Grazia Refolo, Caterina Messa, Vito Guerra, Brian Irving Carr and Rosalba D’Alessandro

Cancers 2020, 12(3), 641; https://doi.org/10.3390/cancers12030641 - 10 Mar 2020

Cited by 107 | Viewed by 10272

Abstract

HCC (hepatocellular carcinoma) is the second leading cause of cancer deaths worldwide, with several etiologic causes, mostly inflammation-associated. Different inflammatory responses in the liver can be triggered by different etiological agents. The inflammatory process can be resolved or be persistent, depending on the [...] Read more.

HCC (hepatocellular carcinoma) is the second leading cause of cancer deaths worldwide, with several etiologic causes, mostly inflammation-associated. Different inflammatory responses in the liver can be triggered by different etiological agents. The inflammatory process can be resolved or be persistent, depending on the etiology and multiple other factors. Chronic inflammation, tissue remodeling, genetic alterations, and modifications in cellular signaling are considered to be key processes promoting immunosuppression. The progressive immunosuppression leads to the inactivation of anti-tumor immunity involved in HCC carcinogenesis and progression. Tumor cellular processes including DNA damage, necrosis, and ER (endoplasmic reticulum) stress can affect both immune-surveillance and cancer-promoting inflammation, supporting a mutual interdependence. Here, we review the current understanding of how chronic liver injury and inflammation is triggered and sustained, and how inflammation is linked to HCC. The identification of many hepatic microenvironmental inflammatory processes and their effector molecules, has resulted in extensive translational work and promising clinical trials of new immunomodulatory agents. Full article

(This article belongs to the Special Issue Liver Cancer and Potential Therapeutic Targets)

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19 pages, 782 KiB

Open AccessEditor’s ChoiceReview

The Application of Deep Learning in Cancer Prognosis Prediction

by Wan Zhu, Longxiang Xie, Jianye Han and Xiangqian Guo

Cancers 2020, 12(3), 603; https://doi.org/10.3390/cancers12030603 - 05 Mar 2020

Cited by 207 | Viewed by 22140

Abstract

Deep learning has been applied to many areas in health care, including imaging diagnosis, digital pathology, prediction of hospital admission, drug design, classification of cancer and stromal cells, doctor assistance, etc. Cancer prognosis is to estimate the fate of cancer, probabilities of cancer [...] Read more.

Deep learning has been applied to many areas in health care, including imaging diagnosis, digital pathology, prediction of hospital admission, drug design, classification of cancer and stromal cells, doctor assistance, etc. Cancer prognosis is to estimate the fate of cancer, probabilities of cancer recurrence and progression, and to provide survival estimation to the patients. The accuracy of cancer prognosis prediction will greatly benefit clinical management of cancer patients. The improvement of biomedical translational research and the application of advanced statistical analysis and machine learning methods are the driving forces to improve cancer prognosis prediction. Recent years, there is a significant increase of computational power and rapid advancement in the technology of artificial intelligence, particularly in deep learning. In addition, the cost reduction in large scale next-generation sequencing, and the availability of such data through open source databases (e.g., TCGA and GEO databases) offer us opportunities to possibly build more powerful and accurate models to predict cancer prognosis more accurately. In this review, we reviewed the most recent published works that used deep learning to build models for cancer prognosis prediction. Deep learning has been suggested to be a more generic model, requires less data engineering, and achieves more accurate prediction when working with large amounts of data. The application of deep learning in cancer prognosis has been shown to be equivalent or better than current approaches, such as Cox-PH. With the burst of multi-omics data, including genomics data, transcriptomics data and clinical information in cancer studies, we believe that deep learning would potentially improve cancer prognosis. Full article

(This article belongs to the Collection Application of Bioinformatics in Cancers)

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29 pages, 3529 KiB

Open AccessEditor’s ChoiceReview

Telomeres and Telomere Length: A General Overview

by Nalini Srinivas, Sivaramakrishna Rachakonda and Rajiv Kumar

Cancers 2020, 12(3), 558; https://doi.org/10.3390/cancers12030558 - 28 Feb 2020

Cited by 138 | Viewed by 17520

Abstract

Telomeres are highly conserved tandem nucleotide repeats that include proximal double-stranded and distal single-stranded regions that in complex with shelterin proteins afford protection at chromosomal ends to maintain genomic integrity. Due to the inherent limitations of DNA replication and telomerase suppression in most [...] Read more.

Telomeres are highly conserved tandem nucleotide repeats that include proximal double-stranded and distal single-stranded regions that in complex with shelterin proteins afford protection at chromosomal ends to maintain genomic integrity. Due to the inherent limitations of DNA replication and telomerase suppression in most somatic cells, telomeres undergo age-dependent incremental attrition. Short or dysfunctional telomeres are recognized as DNA double-stranded breaks, triggering cells to undergo replicative senescence. Telomere shortening, therefore, acts as a counting mechanism that drives replicative senescence by limiting the mitotic potential of cells. Telomere length, a complex hereditary trait, is associated with aging and age-related diseases. Epidemiological data, in general, support an association with varying magnitudes between constitutive telomere length and several disorders, including cancers. Telomere attrition is also influenced by oxidative damage and replicative stress caused by genetic, epigenetic, and environmental factors. Several single nucleotide polymorphisms at different loci, identified through genome-wide association studies, influence inter-individual variation in telomere length. In addition to genetic factors, environmental factors also influence telomere length during growth and development. Telomeres hold potential as biomarkers that reflect the genetic predisposition together with the impact of environmental conditions and as targets for anti-cancer therapies. Full article

(This article belongs to the Special Issue The Role of Telomeres and Telomerase in Cancer)

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11 pages, 1668 KiB

Open AccessEditor’s ChoiceReview

Association of Steroids Use with Survival in Patients Treated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis

by Fausto Petrelli, Diego Signorelli, Michele Ghidini, Antonio Ghidini, Elio Gregory Pizzutilo, Lorenzo Ruggieri, Mary Cabiddu, Karen Borgonovo, Giuseppina Dognini, Matteo Brighenti, Alessandro De Toma, Erika Rijavec, Marina Chiara Garassino, Francesco Grossi and Gianluca Tomasello

Cancers 2020, 12(3), 546; https://doi.org/10.3390/cancers12030546 - 27 Feb 2020

Cited by 176 | Viewed by 8307

Abstract

Immune checkpoint inhibitors (ICIs) can elicit toxicities by inhibiting negative regulators of adaptive immunity. Sometimes, management of toxicities may require systemic glucocorticoids. We performed a systematic review and meta-analysis of published studies to evaluate the correlation between steroids use, overall survival (OS), and [...] Read more.

Immune checkpoint inhibitors (ICIs) can elicit toxicities by inhibiting negative regulators of adaptive immunity. Sometimes, management of toxicities may require systemic glucocorticoids. We performed a systematic review and meta-analysis of published studies to evaluate the correlation between steroids use, overall survival (OS), and progression-free survival (PFS) in cancer patients treated with ICIs. Publications that compared steroids with non-steroid users in cancer patients treated with ICIs from inception to June 2019 were identified by searching the EMBASE, PubMed, SCOPUS, Web of Science, and Cochrane Library databases. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Patients (studies, n = 16; patients, n = 4045) taking steroids were at increased risk of death and progression compared to those not taking steroids (HR = 1.54, 95% CI: 1.24–1.91; p = 0.01 and HR = 1.34, 95% CI: 1.02–1.76; p = 0.03, respectively). The main negative effect on OS was associated with patients taking steroids for supportive care (HR = 2.5, 95% CI 1.41–4.43; p < 0.01) or brain metastases (HR = 1.51, 95% CI 1.22–1.87; p < 0.01). In contrast, steroids used to mitigate adverse events did not negatively affect OS. In conclusion, caution is needed when steroids are used for symptom control. In these patients, a negative impact of steroid use was observed for both OS and PFS. Full article

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

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44 pages, 1351 KiB

Open AccessEditor’s ChoiceReview

Current Advances in the Treatment of BRAF-Mutant Melanoma

by Hima Patel, Nour Yacoub, Rosalin Mishra, Aaron White, Long Yuan, Samar Alanazi and Joan T. Garrett

Cancers 2020, 12(2), 482; https://doi.org/10.3390/cancers12020482 - 19 Feb 2020

Cited by 112 | Viewed by 12322

Abstract

Melanoma is the most lethal form of skin cancer. Melanoma is usually curable with surgery if detected early, however, treatment options for patients with metastatic melanoma are limited and the five-year survival rate for metastatic melanoma had been 15–20% before the advent of [...] Read more.

Melanoma is the most lethal form of skin cancer. Melanoma is usually curable with surgery if detected early, however, treatment options for patients with metastatic melanoma are limited and the five-year survival rate for metastatic melanoma had been 15–20% before the advent of immunotherapy. Treatment with immune checkpoint inhibitors has increased long-term survival outcomes in patients with advanced melanoma to as high as 50% although individual response can vary greatly. A mutation within the MAPK pathway leads to uncontrollable growth and ultimately develops into cancer. The most common driver mutation that leads to this characteristic overactivation in the MAPK pathway is the B-RAF mutation. Current combinations of BRAF and MEK inhibitors that have demonstrated improved patient outcomes include dabrafenib with trametinib, vemurafenib with cobimetinib or encorafenib with binimetinib. Treatment with BRAF and MEK inhibitors has met challenges as patient responses began to drop due to the development of resistance to these inhibitors which paved the way for development of immunotherapies and other small molecule inhibitor approaches to address this. Resistance to these inhibitors continues to push the need to expand our understanding of novel mechanisms of resistance associated with treatment therapies. This review focuses on the current landscape of how resistance occurs with the chronic use of BRAF and MEK inhibitors in BRAF-mutant melanoma and progress made in the fields of immunotherapies and other small molecules when used alone or in combination with BRAF and MEK inhibitors to delay or circumvent the onset of resistance for patients with stage III/IV BRAF mutant melanoma. Full article

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18 pages, 2015 KiB

Open AccessEditor’s ChoiceArticle

Predictive Value of Soluble PD-1, PD-L1, VEGFA, CD40 Ligand and CD44 for Nivolumab Therapy in Advanced Non-Small Cell Lung Cancer: A Case-Control Study

by Manuela Tiako Meyo, Anne Jouinot, Etienne Giroux-Leprieur, Elizabeth Fabre, Marie Wislez, Marco Alifano, Karen Leroy, Pascaline Boudou-Rouquette, Camille Tlemsani, Nihel Khoudour, Jennifer Arrondeau, Audrey Thomas-Schoemann, Hélène Blons, Audrey Mansuet-Lupo, Diane Damotte, Michel Vidal, François Goldwasser, Jérôme Alexandre and Benoit Blanchet

Cancers 2020, 12(2), 473; https://doi.org/10.3390/cancers12020473 - 18 Feb 2020

Cited by 75 | Viewed by 4840

Abstract

A large interindividual variability has been observed in anti Programmed cell Death 1 (anti-PD1) therapies efficacy. The aim of this study is to assess the correlation of soluble PD-1 (sPD-1), soluble Programmed cell Death Ligand 1 (sPD-L1), Vascular Endothelial Growth Factor A (VEGFA), [...] Read more.

A large interindividual variability has been observed in anti Programmed cell Death 1 (anti-PD1) therapies efficacy. The aim of this study is to assess the correlation of soluble PD-1 (sPD-1), soluble Programmed cell Death Ligand 1 (sPD-L1), Vascular Endothelial Growth Factor A (VEGFA), soluble CD40 ligand (sCD40L) and soluble CD44 (sCD44), with survival in nivolumab-treated metastatic non-small cell lung cancer (NSCLC) patients. Plasma biomarkers were assayed at baseline and after two cycles of nivolumab. A cut-off of positivity for sPD-1, sPD-L1 and sCD40L expressions was defined as a plasma level above the lower limit of quantification. Baseline sPD-1 and sPD-L1 levels were subsequently analyzed in a control group of EGFR-mutated (Epidermal Growth Factor Receptor) NSCLC patients. Association between survival and biomarkers was investigated using Cox proportional hazard regression model. Eighty-seven patients were included (51 nivolumab-treated patients, 36 in EGFR-mutated group). In nivolumab group, baseline sPD-1, sPD-L1 and sCD40L were positive for 15(29.4%), 27(52.9%) and 18(50%) patients, respectively. We defined a composite criteria (sCombo) corresponding to sPD-1 and/or sPD-L1 positivity for each patient. In nivolumab group, baseline sCombo positivity was associated with shorter median progression-free survival (PFS) (78 days 95%CI (55–109) vs. 658 days (222-not reached); HR: 4.12 (1.95–8.71), p = 0.0002) and OS (HR: 3.99(1.63–9.80), p = 0.003). In multivariate analysis, baseline sCombo independently correlated with PFS (HR: 2.66 (1.17–6.08), p = 0.02) but not OS. In EGFR-mutated group, all patients were baseline sCombo positive; therefore this factor was not associated with survival. After two cycles of nivolumab, an increased or stable sPD-1 level independently correlated with longer PFS (HR: 0.49, 95%CI (0.30–0.80), p = 0.004) and OS (HR: 0.39, 95%CI (0.21–0.71), p = 0.002). VEGFA, sCD40L and sCD44 did not correlate with survival. We propose a composite biomarker using sPD-1and sPDL-1 to predict nivolumab efficacy in NSCLC patients. A larger validation study is warranted. Full article

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18 pages, 6010 KiB

Open AccessEditor’s ChoiceArticle

Venetoclax, a BCL-2 Inhibitor, Enhances the Efficacy of Chemotherapeutic Agents in Wild-Type ABCG2-Overexpression-Mediated MDR Cancer Cells

by Jing-Quan Wang, Jonathan Y. Li, Qiu-Xu Teng, Zi-Ning Lei, Ning Ji, Qingbin Cui, Leli Zeng, Yihang Pan, Dong-Hua Yang and Zhe-Sheng Chen

Cancers 2020, 12(2), 466; https://doi.org/10.3390/cancers12020466 - 18 Feb 2020

Cited by 43 | Viewed by 5174

Abstract

Previous studies have shown that small-molecule BCL-2 inhibitors can have a synergistic interaction with ABCG2 substrates in chemotherapy. Venetoclax is a potent and selective BCL-2 inhibitor, approved by the FDA in 2016 for the treatment of patients with chronic lymphocytic leukemia (CLL). This [...] Read more.

Previous studies have shown that small-molecule BCL-2 inhibitors can have a synergistic interaction with ABCG2 substrates in chemotherapy. Venetoclax is a potent and selective BCL-2 inhibitor, approved by the FDA in 2016 for the treatment of patients with chronic lymphocytic leukemia (CLL). This study showed that, at a non-toxic concentration, venetoclax at 10 µM significantly reversed multidrug resistance (MDR) mediated by wild-type ABCG2, without significantly affecting MDR mediated by mutated ABCG2 (R482G and R482T) and ABCB1, while moderate or no reversal effects were observed at lower concentrations (0.5 to 1 µM). The results showed that venetoclax increased the intracellular accumulation of chemotherapeutic agents, which was the result of directly blocking the wild-type ABCG2 efflux function and inhibiting the ATPase activity of ABCG2. Our study demonstrated that venetoclax potentiates the efficacy of wild-type ABCG2 substrate drugs. These findings may provide useful guidance in combination therapy against wild-type ABCG2-mediated MDR cancer in clinical practice. Full article

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

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13 pages, 1333 KiB

Open AccessEditor’s ChoiceArticle

Multicenter External Validation of the Liverpool Uveal Melanoma Prognosticator Online: An OOG Collaborative Study

by Alda Cunha Rola, Azzam Taktak, Antonio Eleuteri, Helen Kalirai, Heinrich Heimann, Rumana Hussain, Laura J. Bonnett, Christopher J. Hill, Matthew Traynor, Martine J. Jager, Marina Marinkovic, Gregorius P.M. Luyten, Mehmet Dogrusöz, Emine Kilic, Annelies de Klein, Kyra Smit, Natasha M van Poppelen, Bertil E. Damato, Armin Afshar, Rudolf F. Guthoff, Björn O. Scheef, Vinodh Kakkassery, Svetlana Saakyan, Alexander Tsygankov, Carlo Mosci, Paolo Ligorio, Silvia Viaggi, Claudia H.D. Le Guin, Norbert Bornfeld, Nikolaos E. Bechrakis and Sarah E. Coupland Show full author list Hide full author list

Cancers 2020, 12(2), 477; https://doi.org/10.3390/cancers12020477 - 18 Feb 2020

Cited by 31 | Viewed by 4098

Abstract

Uveal melanoma (UM) is fatal in ~50% of patients as a result of disseminated disease. This study aims to externally validate the Liverpool Uveal Melanoma Prognosticator Online V3 (LUMPO3) to determine its reliability in predicting survival after treatment for choroidal melanoma when utilizing [...] Read more.

Uveal melanoma (UM) is fatal in ~50% of patients as a result of disseminated disease. This study aims to externally validate the Liverpool Uveal Melanoma Prognosticator Online V3 (LUMPO3) to determine its reliability in predicting survival after treatment for choroidal melanoma when utilizing external data from other ocular oncology centers. Anonymized data of 1836 UM patients from seven international ocular oncology centers were analyzed with LUMPO3 to predict the 10-year survival for each patient in each external dataset. The analysts were masked to the patient outcomes. Model predictions were sent to an independent statistician to evaluate LUMPO3’s performance using discrimination and calibration methods. LUMPO3’s ability to discriminate between UM patients who died of metastatic UM and those who were still alive was fair-to-good, with C-statistics ranging from 0.64 to 0.85 at year 1. The pooled estimate for all external centers was 0.72 (95% confidence interval: 0.68 to 0.75). Agreement between observed and predicted survival probabilities was generally good given differences in case mix and survival rates between different centers. Despite the differences between the international cohorts of patients with primary UM, LUMPO3 is a valuable tool for predicting all-cause mortality in this disease when using data from external centers. Full article

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19 pages, 1765 KiB

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 51 | Viewed by 3878

Abstract

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

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

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

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32 pages, 1513 KiB

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 131 | Viewed by 19463

Abstract

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

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

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

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14 pages, 8111 KiB

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 29 | Viewed by 3673

Abstract

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

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

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16 pages, 1717 KiB

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 - 08 Feb 2020

Cited by 87 | Viewed by 8568

Abstract

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

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

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

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32 pages, 3686 KiB

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 - 04 Feb 2020

Cited by 35 | Viewed by 5052

Abstract

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

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

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

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14 pages, 2618 KiB

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 - 04 Feb 2020

Cited by 56 | Viewed by 5497

Abstract

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

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

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24 pages, 1444 KiB

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 - 01 Feb 2020

Cited by 25 | Viewed by 6040

Abstract

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

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

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

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12 pages, 1915 KiB

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 57 | Viewed by 6133

Abstract

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

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

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

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36 pages, 3139 KiB

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 82 | Viewed by 7758

Abstract

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

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

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21 pages, 2712 KiB

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 75 | Viewed by 6657

Abstract

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

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

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

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19 pages, 2416 KiB

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 51 | Viewed by 5199

Abstract

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

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

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

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19 pages, 734 KiB

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 107 | Viewed by 9973

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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23 pages, 1455 KiB

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 70 | Viewed by 8125

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 KiB

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 48 | Viewed by 7932

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 KiB

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 52 | Viewed by 8725

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 KiB

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 40 | Viewed by 4166

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 KiB

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 206 | Viewed by 12673

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 KiB

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 35 | Viewed by 4464

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 KiB

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 79 | Viewed by 6159

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 KiB

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 140 | Viewed by 12740

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 KiB

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 40 | Viewed by 5585

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 KiB

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 - 09 Jan 2020

Cited by 212 | Viewed by 18922

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 KiB

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 - 08 Jan 2020

Cited by 80 | Viewed by 7644

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 KiB

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 - 08 Jan 2020

Cited by 53 | Viewed by 7743

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 KiB

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 - 07 Jan 2020

Cited by 38 | Viewed by 5356

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 KiB

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 - 04 Jan 2020

Cited by 44 | Viewed by 4413

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 KiB

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 - 03 Jan 2020

Cited by 57 | Viewed by 7716

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 KiB

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 - 01 Jan 2020

Cited by 105 | Viewed by 10047

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 KiB

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 50 | Viewed by 7499

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 KiB

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 347 | Viewed by 24870

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 KiB

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 - 04 Dec 2019

Cited by 29 | Viewed by 3357

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 KiB

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 - 03 Dec 2019

Cited by 43 | Viewed by 6223

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 KiB

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 - 01 Dec 2019

Cited by 44 | Viewed by 6175

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 KiB

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 140 | Viewed by 12644

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 KiB

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 127 | Viewed by 7316

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 KiB

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 127 | Viewed by 11150

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 KiB

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 - 01 Nov 2019

Cited by 76 | Viewed by 6112

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 KiB

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 53 | Viewed by 5868

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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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 503 | Viewed by 24728

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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