Cancers

13 pages, 2966 KiB

Open AccessEditor’s ChoiceReview

Active Targeting Strategies Using Biological Ligands for Nanoparticle Drug Delivery Systems

by Jihye Yoo, Changhee Park, Gawon Yi, Donghyun Lee and Heebeom Koo

Cancers 2019, 11(5), 640; https://doi.org/10.3390/cancers11050640 - 8 May 2019

Cited by 452 | Viewed by 17702

Targeting nanoparticle (NP) carriers to sites of disease is critical for their successful use as drug delivery systems. Along with optimization of physicochemical properties, researchers have focused on surface modification of NPs with biological ligands. Such ligands can bind specific receptors on the [...] Read more.

Targeting nanoparticle (NP) carriers to sites of disease is critical for their successful use as drug delivery systems. Along with optimization of physicochemical properties, researchers have focused on surface modification of NPs with biological ligands. Such ligands can bind specific receptors on the surface of target cells. Furthermore, biological ligands can facilitate uptake of modified NPs, which is referred to as ‘active targeting’ of NPs. In this review, we discuss recent applications of biological ligands including proteins, polysaccharides, aptamers, peptides, and small molecules for NP-mediated drug delivery. We prioritized studies that have demonstrated targeting in animals over in vitro studies. We expect that this review will assist biomedical researchers working with NPs for drug delivery and imaging. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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25 pages, 1935 KiB

Open AccessEditor’s ChoiceReview

Emerging Roles of the Endoplasmic Reticulum Associated Unfolded Protein Response in Cancer Cell Migration and Invasion

by Celia Maria Limia, Chloé Sauzay, Hery Urra, Claudio Hetz, Eric Chevet and Tony Avril

Cancers 2019, 11(5), 631; https://doi.org/10.3390/cancers11050631 - 6 May 2019

Cited by 64 | Viewed by 8361

Abstract

Endoplasmic reticulum (ER) proteostasis is often altered in tumor cells due to intrinsic (oncogene expression, aneuploidy) and extrinsic (environmental) challenges. ER stress triggers the activation of an adaptive response named the Unfolded Protein Response (UPR), leading to protein translation repression, and to the [...] Read more.

Endoplasmic reticulum (ER) proteostasis is often altered in tumor cells due to intrinsic (oncogene expression, aneuploidy) and extrinsic (environmental) challenges. ER stress triggers the activation of an adaptive response named the Unfolded Protein Response (UPR), leading to protein translation repression, and to the improvement of ER protein folding and clearance capacity. The UPR is emerging as a key player in malignant transformation and tumor growth, impacting on most hallmarks of cancer. As such, the UPR can influence cancer cells’ migration and invasion properties. In this review, we overview the involvement of the UPR in cancer progression. We discuss its cross-talks with the cell migration and invasion machinery. Specific aspects will be covered including extracellular matrix (ECM) remodeling, modification of cell adhesion, chemo-attraction, epithelial-mesenchymal transition (EMT), modulation of signaling pathways associated with cell mobility, and cytoskeleton remodeling. The therapeutic potential of targeting the UPR to treat cancer will also be considered with specific emphasis in the impact on metastasis and tissue invasion. Full article

(This article belongs to the Special Issue Cellular Stress in Cancer Progression, Drug Resistance and Treatment)

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23 pages, 1325 KiB

Open AccessEditor’s ChoiceReview

Focus on Formononetin: Anticancer Potential and Molecular Targets

by Samantha Kah Ling Ong, Muthu K. Shanmugam, Lu Fan, Sarah E. Fraser, Frank Arfuso, Kwang Seok Ahn, Gautam Sethi and Anupam Bishayee

Cancers 2019, 11(5), 611; https://doi.org/10.3390/cancers11050611 - 1 May 2019

Cited by 113 | Viewed by 9334

Abstract

Formononetin, an isoflavone, is extracted from various medicinal plants and herbs, including the red clover (Trifolium pratense) and Chinese medicinal plant Astragalus membranaceus. Formononetin’s antioxidant and neuroprotective effects underscore its therapeutic use against Alzheimer’s disease. Formononetin has been under intense investigation for [...] Read more.

Formononetin, an isoflavone, is extracted from various medicinal plants and herbs, including the red clover (Trifolium pratense) and Chinese medicinal plant Astragalus membranaceus. Formononetin’s antioxidant and neuroprotective effects underscore its therapeutic use against Alzheimer’s disease. Formononetin has been under intense investigation for the past decade as strong evidence on promoting apoptosis and against proliferation suggests for its use as an anticancer agent against diverse cancers. These anticancer properties are observed in multiple cancer cell models, including breast, colorectal, and prostate cancer. Formononetin also attenuates metastasis and tumor growth in various in vivo studies. The beneficial effects exuded by formononetin can be attributed to its antiproliferative and cell cycle arrest inducing properties. Formononetin regulates various transcription factors and growth-factor-mediated oncogenic pathways, consequently alleviating the possible causes of chronic inflammation that are linked to cancer survival of neoplastic cells and their resistance against chemotherapy. As such, this review summarizes and critically analyzes current evidence on the potential of formononetin for therapy of various malignancies with special emphasis on molecular targets. 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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20 pages, 1254 KiB

Open AccessEditor’s ChoiceReview

Tumor-Associated Neutrophils in Cancer: Going Pro

by Lingyun Wu, Sugandha Saxena, Mohammad Awaji and Rakesh K. Singh

Cancers 2019, 11(4), 564; https://doi.org/10.3390/cancers11040564 - 19 Apr 2019

Cited by 232 | Viewed by 11413

Abstract

The progression of cancer is not only about the tumor cell itself, but also about other involved players including cancer cell recruited immune cells, their released pro-inflammatory factors, and the extracellular matrix. These players constitute the tumor microenvironment and play vital roles in [...] Read more.

The progression of cancer is not only about the tumor cell itself, but also about other involved players including cancer cell recruited immune cells, their released pro-inflammatory factors, and the extracellular matrix. These players constitute the tumor microenvironment and play vital roles in the cancer progression. Neutrophils—the most abundant white blood cells in the circulation system—constitute a significant part of the tumor microenvironment. Neutrophils play major roles linking inflammation and cancer and are actively involved in progression and metastasis. Additionally, recent data suggest that neutrophils could be considered one of the emerging targets for multiple cancer types. This review summarizes the most recent updates regarding neutrophil recruitments and functions in the tumor microenvironment as well as potential development of neutrophils-targeted putative therapeutic strategies. Full article

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

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20 pages, 1185 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Next-Generation Hedgehog/GLI Pathway Inhibitors for Cancer Therapy

by Elisabeth Peer, Suzana Tesanovic and Fritz Aberger

Cancers 2019, 11(4), 538; https://doi.org/10.3390/cancers11040538 - 15 Apr 2019

Cited by 69 | Viewed by 7796

Abstract

The Hedgehog/Glioma-associated oncogene homolog (HH/GLI) signaling pathway regulates self-renewal of rare and highly malignant cancer stem cells (CSC), which have been shown to account for the initiation and maintenance of tumor growth as well as for drug resistance, metastatic spread and relapse. Efficacious [...] Read more.

The Hedgehog/Glioma-associated oncogene homolog (HH/GLI) signaling pathway regulates self-renewal of rare and highly malignant cancer stem cells (CSC), which have been shown to account for the initiation and maintenance of tumor growth as well as for drug resistance, metastatic spread and relapse. Efficacious therapeutic approaches targeting CSC pathways, such as HH/GLI signaling in combination with chemo, radiation or immunotherapy are, therefore, of high medical need. Pharmacological inhibition of HH/GLI pathway activity represents a promising approach to eliminate malignant CSC. Clinically approved HH/GLI pathway inhibitors target the essential pathway effector Smoothened (SMO) with striking therapeutic efficacy in skin and brain cancer patients. However, multiple genetic and molecular mechanisms resulting in de novo and acquired resistance to SMO inhibitors pose major limitations to anti-HH/GLI therapies and, thus, the eradication of CSC. In this review, we summarize reasons for clinical failure of SMO inhibitors, including mechanisms caused by genetic alterations in HH pathway effectors or triggered by additional oncogenic signals activating GLI transcription factors in a noncanonical manner. We then discuss emerging novel and rationale-based approaches to overcome SMO-inhibitor resistance, focusing on pharmacological perturbations of enzymatic modifiers of GLI activity and on compounds either directly targeting oncogenic GLI factors or interfering with synergistic crosstalk signals known to boost the oncogenicity of HH/GLI signaling. Full article

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

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21 pages, 3175 KiB

Open AccessEditor’s ChoiceReview

Dendritic Cells and Cancer: From Biology to Therapeutic Intervention

by Ben Wylie, Christophe Macri, Justine D. Mintern and Jason Waithman

Cancers 2019, 11(4), 521; https://doi.org/10.3390/cancers11040521 - 11 Apr 2019

Cited by 101 | Viewed by 8779

Abstract

Inducing effective anti-tumor immunity has become a major therapeutic strategy against cancer. Dendritic cells (DC) are a heterogenous population of antigen presenting cells that infiltrate tumors. While DC play a critical role in the priming and maintenance of local immunity, their functions are [...] Read more.

Inducing effective anti-tumor immunity has become a major therapeutic strategy against cancer. Dendritic cells (DC) are a heterogenous population of antigen presenting cells that infiltrate tumors. While DC play a critical role in the priming and maintenance of local immunity, their functions are often diminished, or suppressed, by factors encountered in the tumor microenvironment. Furthermore, DC populations with immunosuppressive activities are also recruited to tumors, limiting T cell infiltration and promoting tumor growth. Anti-cancer therapies can impact the function of tumor-associated DC and/or alter their phenotype. Therefore, the design of effective anti-cancer therapies for clinical translation should consider how best to boost tumor-associated DC function to drive anti-tumor immunity. In this review, we discuss the different subsets of tumor-infiltrating DC and their role in anti-tumor immunity. Moreover, we describe strategies to enhance DC function within tumors and harness these cells for effective tumor immunotherapy. Full article

(This article belongs to the Special Issue Tumour Associated Dendritic Cells)

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15 pages, 1635 KiB

Open AccessEditor’s ChoiceArticle

Head and Body/Tail Pancreatic Carcinomas Are Not the Same Tumors

by David Jérémie Birnbaum, François Bertucci, Pascal Finetti, Daniel Birnbaum and Emilie Mamessier

Cancers 2019, 11(4), 497; https://doi.org/10.3390/cancers11040497 - 8 Apr 2019

Cited by 62 | Viewed by 8415

Abstract

The association between pancreatic ductal adenocarcinoma (PDAC) location (head vs. Body/Tail (B/T)) and clinical outcome remains controversial. We collected clinicopathological and gene expression data from 249 resected PDAC samples from public data sets, and we compared data between 208 head and 41 B/T [...] Read more.

The association between pancreatic ductal adenocarcinoma (PDAC) location (head vs. Body/Tail (B/T)) and clinical outcome remains controversial. We collected clinicopathological and gene expression data from 249 resected PDAC samples from public data sets, and we compared data between 208 head and 41 B/T samples. The 2-year overall survival (OS) was better for the head than for the B/T PDACs (44 vs. 27%, p = 0.043), especially when comparing tumors with similar TNM classification (T3/4N0M0: 67% vs. 17%, p = 0.002) or from the same molecular class (squamous subtype: 31% vs. 0%, p < 0.0001). Bailey’s molecular subtypes were differentially distributed within the two groups, with the immunogenic subtype being underrepresented in the “B/T” group (p = 0.005). Uni- and multivariate analyses indicated that PDAC anatomic location was an independent prognostic factor. Finally, the supervised analysis identified 334 genes differentially expressed. Genes upregulated in the “head” group suggested lymphocyte activation and pancreas exocrine functions. Genes upregulated in the “B/T” group were related to keratinocyte differentiation, in line with the enrichment for squamous phenotype. We identified a robust gene expression signature (GES) associated with B/T PDAC location, suggesting that head and B/T PDAC are different. This GES could serve as an indicator for differential therapeutic management based on PDAC location. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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29 pages, 1552 KiB

Open AccessEditor’s ChoiceReview

Natural Killer Cells as Key Players of Tumor Progression and Angiogenesis: Old and Novel Tools to Divert Their Pro-Tumor Activities into Potent Anti-Tumor Effects

by Barbara Bassani, Denisa Baci, Matteo Gallazzi, Alessandro Poggi, Antonino Bruno and Lorenzo Mortara

Cancers 2019, 11(4), 461; https://doi.org/10.3390/cancers11040461 - 1 Apr 2019

Cited by 114 | Viewed by 10521

Abstract

Immune cells, as a consequence of their plasticity, can acquire altered phenotype/functions within the tumor microenvironment (TME). Some of these aberrant functions include attenuation of targeting and killing of tumor cells, tolerogenic/immunosuppressive behavior and acquisition of pro-angiogenic activities. Natural killer (NK) cells are [...] Read more.

Immune cells, as a consequence of their plasticity, can acquire altered phenotype/functions within the tumor microenvironment (TME). Some of these aberrant functions include attenuation of targeting and killing of tumor cells, tolerogenic/immunosuppressive behavior and acquisition of pro-angiogenic activities. Natural killer (NK) cells are effector lymphocytes involved in tumor immunosurveillance. In solid malignancies, tumor-associated NK cells (TANK cells) in peripheral blood and tumor-infiltrating NK (TINK) cells show altered phenotypes and are characterized by either anergy or reduced cytotoxicity. Here, we aim at discussing how NK cells can support tumor progression and how induction of angiogenesis, due to TME stimuli, can be a relevant part on the NK cell-associated tumor supporting activities. We will review and discuss the contribution of the TME in shaping NK cell response favoring cancer progression. We will focus on TME-derived set of factors such as TGF-β, soluble HLA-G, prostaglandin E₂, adenosine, extracellular vesicles, and miRNAs, which can exhibit a dual function. On one hand, these factors can suppress NK cell-mediated activities but, on the other hand, they can induce a pro-angiogenic polarization in NK cells. Also, we will analyze the impact on cancer progression of the interaction of NK cells with several TME-associated cells, including macrophages, neutrophils, mast cells, cancer-associated fibroblasts, and endothelial cells. Then, we will discuss the most relevant therapeutic approaches aimed at potentiating/restoring NK cell activities against tumors. Finally, supported by the literature revision and our new findings on NK cell pro-angiogenic activities, we uphold NK cells to a key host cellular paradigm in controlling tumor progression and angiogenesis; thus, we should bear in mind NK cells like a TME-associated target for anti-tumor therapeutic approaches. Full article

(This article belongs to the Special Issue Natural Killer Cells and Cancer Therapy)

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22 pages, 13350 KiB

Open AccessFeature PaperEditor’s ChoiceReview

PTEN as a Prognostic/Predictive Biomarker in Cancer: An Unfulfilled Promise?

by Chiara Bazzichetto, Fabiana Conciatori, Matteo Pallocca, Italia Falcone, Maurizio Fanciulli, Francesco Cognetti, Michele Milella and Ludovica Ciuffreda

Cancers 2019, 11(4), 435; https://doi.org/10.3390/cancers11040435 - 28 Mar 2019

Cited by 91 | Viewed by 7930

Abstract

Identifying putative biomarkers of clinical outcomes in cancer is crucial for successful enrichment, and for the selection of patients who are the most likely to benefit from a specific therapeutic approach. Indeed, current research in personalized cancer therapy focuses on the possibility of [...] Read more.

Identifying putative biomarkers of clinical outcomes in cancer is crucial for successful enrichment, and for the selection of patients who are the most likely to benefit from a specific therapeutic approach. Indeed, current research in personalized cancer therapy focuses on the possibility of identifying biomarkers that predict prognosis, sensitivity or resistance to therapies. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor gene that regulates several crucial cell functions such as proliferation, survival, genomic stability and cell motility through both enzymatic and non-enzymatic activities and phosphatidylinositol 3-kinase (PI3K)-dependent and -independent mechanisms. Despite its undisputed role as a tumor suppressor, assessment of PTEN status in sporadic human tumors has yet to provide clinically robust prognostic, predictive or therapeutic information. This is possibly due to the exceptionally complex regulation of PTEN function, which involves genetic, transcriptional, post-transcriptional and post-translational events. This review shows a brief summary of the regulation and function of PTEN and discusses its controversial aspects as a prognostic/predictive biomarker. Full article

(This article belongs to the Special Issue PTEN: A Multifaceted Tumor Suppressor)

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22 pages, 1286 KiB

Open AccessEditor’s ChoiceReview

The Contributions of Prostate Cancer Stem Cells in Prostate Cancer Initiation and Metastasis

by Wenjuan Mei, Xiaozeng Lin, Anil Kapoor, Yan Gu, Kuncheng Zhao and Damu Tang

Cancers 2019, 11(4), 434; https://doi.org/10.3390/cancers11040434 - 27 Mar 2019

Cited by 69 | Viewed by 6540

Abstract

Research in the last decade has clearly revealed a critical role of prostate cancer stem cells (PCSCs) in prostate cancer (PC). Prostate stem cells (PSCs) reside in both basal and luminal layers, and are the target cells of oncogenic transformation, suggesting a role [...] Read more.

Research in the last decade has clearly revealed a critical role of prostate cancer stem cells (PCSCs) in prostate cancer (PC). Prostate stem cells (PSCs) reside in both basal and luminal layers, and are the target cells of oncogenic transformation, suggesting a role of PCSCs in PC initiation. Mutations in PTEN, TP53, and RB1 commonly occur in PC, particularly in metastasis and castration-resistant PC. The loss of PTEN together with Ras activation induces partial epithelial–mesenchymal transition (EMT), which is a major mechanism that confers plasticity to cancer stem cells (CSCs) and PCSCs, which contributes to metastasis. While PTEN inactivation leads to PC, it is not sufficient for metastasis, the loss of PTEN concurrently with the inactivation of both TP53 and RB1 empower lineage plasticity in PC cells, which substantially promotes PC metastasis and the conversion to PC adenocarcinoma to neuroendocrine PC (NEPC), demonstrating the essential function of TP53 and RB1 in the suppression of PCSCs. TP53 and RB1 suppress lineage plasticity through the inhibition of SOX2 expression. In this review, we will discuss the current evidence supporting a major role of PCSCs in PC initiation and metastasis, as well as the underlying mechanisms regulating PCSCs. These discussions will be developed along with the cancer stem cell (CSC) knowledge in other cancer types. Full article

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

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18 pages, 3871 KiB

Open AccessEditor’s ChoiceArticle

The Flavonoid Metabolite 2,4,6-Trihydroxybenzoic Acid Is a CDK Inhibitor and an Anti-Proliferative Agent: A Potential Role in Cancer Prevention

by Ranjini Sankaranarayanan, Chaitanya K. Valiveti, D. Ramesh Kumar, Severine Van slambrouck, Siddharth S. Kesharwani, Teresa Seefeldt, Joy Scaria, Hemachand Tummala and G. Jayarama Bhat

Cancers 2019, 11(3), 427; https://doi.org/10.3390/cancers11030427 - 26 Mar 2019

Cited by 40 | Viewed by 14982

Abstract

Flavonoids have emerged as promising compounds capable of preventing colorectal cancer (CRC) due to their anti-oxidant and anti-inflammatory properties. It is hypothesized that the metabolites of flavonoids are primarily responsible for the observed anti-cancer effects owing to the unstable nature of the parent [...] Read more.

Flavonoids have emerged as promising compounds capable of preventing colorectal cancer (CRC) due to their anti-oxidant and anti-inflammatory properties. It is hypothesized that the metabolites of flavonoids are primarily responsible for the observed anti-cancer effects owing to the unstable nature of the parent compounds and their degradation by colonic microflora. In this study, we investigated the ability of one metabolite, 2,4,6-trihydroxybenzoic acid (2,4,6-THBA) to inhibit Cyclin Dependent Kinase (CDK) activity and cancer cell proliferation. Using in vitro kinase assays, we demonstrated that 2,4,6-THBA dose-dependently inhibited CDKs 1, 2 and 4 and in silico studies identified key amino acids involved in these interactions. Interestingly, no significant CDK inhibition was observed with the structurally related compounds 3,4,5-trihydroxybenzoic acid (3,4,5-THBA) and phloroglucinol, suggesting that orientation of the functional groups and specific amino acid interactions may play a role in inhibition. We showed that cellular uptake of 2,4,6-THBA required the expression of functional SLC5A8, a monocarboxylic acid transporter. Consistent with this, in cells expressing functional SLC5A8, 2,4,6-THBA induced CDK inhibitory proteins p21^Cip1 and p27^Kip1 and inhibited cell proliferation. These findings, for the first time, suggest that the flavonoid metabolite 2,4,6-THBA may mediate its effects through a CDK- and SLC5A8-dependent pathway contributing to the prevention of CRC. Full article

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17 pages, 1027 KiB

Open AccessEditor’s ChoiceReview

Acquired Resistance to Antibody-Drug Conjugates

by Denis M. Collins, Birgit Bossenmaier, Gwendlyn Kollmorgen and Gerhard Niederfellner

Cancers 2019, 11(3), 394; https://doi.org/10.3390/cancers11030394 - 20 Mar 2019

Cited by 85 | Viewed by 8962

Abstract

Antibody-drug conjugates (ADCs) combine the tumor selectivity of antibodies with the potency of cytotoxic small molecules thereby constituting antibody-mediated chemotherapy. As this inherently limits the adverse effects of the chemotherapeutic, such approaches are heavily pursued by pharma and biotech companies and have resulted [...] Read more.

Antibody-drug conjugates (ADCs) combine the tumor selectivity of antibodies with the potency of cytotoxic small molecules thereby constituting antibody-mediated chemotherapy. As this inherently limits the adverse effects of the chemotherapeutic, such approaches are heavily pursued by pharma and biotech companies and have resulted in four FDA (Food and Drug Administration)-approved ADCs. However, as with other cancer therapies, durable responses are limited by the fact that under cell stress exerted by these drugs, tumors can acquire mechanisms of escape. Resistance can develop against the antibody component of ADCs by down-regulation/mutation of the targeted cell surface antigen or against payload toxicity by up-regulation of drug efflux transporters. Unique resistance mechanisms specific for the mode of action of ADCs have also emerged, like altered internalization or cell surface recycling of the targeted tumor antigen, changes in the intracellular routing or processing of ADCs, and impaired release of the toxic payload into the cytosol. These evasive changes are tailored to the specific nature and interplay of the three ADC constituents: the antibody, the linker, and the payload. Hence, they do not necessarily endow broad resistance to ADC therapy. This review summarizes preclinical and clinical findings that shed light on the mechanisms of acquired resistance to ADC therapies. Full article

(This article belongs to the Special Issue Cellular Stress in Cancer Progression, Drug Resistance and Treatment)

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24 pages, 18990 KiB

Open AccessEditor’s ChoiceReview

Contribution of Anoctamins to Cell Survival and Cell Death

by Karl Kunzelmann, Jiraporn Ousingsawat, Roberta Benedetto, Ines Cabrita and Rainer Schreiber

Cancers 2019, 11(3), 382; https://doi.org/10.3390/cancers11030382 - 19 Mar 2019

Cited by 59 | Viewed by 8006

Abstract

Before anoctamins (TMEM16 proteins) were identified as a family of Ca²⁺-activated chloride channels and phospholipid scramblases, the founding member anoctamin 1 (ANO1, TMEM16A) was known as DOG1, a marker protein for gastrointestinal stromal tumors (GIST). Meanwhile, ANO1 has been examined in [...] Read more.

Before anoctamins (TMEM16 proteins) were identified as a family of Ca²⁺-activated chloride channels and phospholipid scramblases, the founding member anoctamin 1 (ANO1, TMEM16A) was known as DOG1, a marker protein for gastrointestinal stromal tumors (GIST). Meanwhile, ANO1 has been examined in more detail, and the role of ANO1 in cell proliferation and the development of different types of malignomas is now well established. While ANO5, ANO7, and ANO9 may also be relevant for growth of cancers, evidence has been provided for a role of ANO6 (TMEM16F) in regulated cell death. The cellular mechanisms by which anoctamins control cell proliferation and cell death, respectively, are just emerging; however, the pronounced effects of anoctamins on intracellular Ca²⁺ levels are likely to play a significant role. Recent results suggest that some anoctamins control membrane exocytosis by setting Ca²⁺_i levels near the plasma membrane, and/or by controlling the intracellular Cl⁻ concentration. Exocytosis and increased membrane trafficking induced by ANO1 and ANO6 may enhance membrane expression of other chloride channels, such as CFTR and volume activated chloride channels (VRAC). Notably, ANO6-induced phospholipid scrambling with exposure of phosphatidylserine is pivotal for the sheddase function of disintegrin and metalloproteinase (ADAM). This may support cell death and tumorigenic activity of IL-6 by inducing IL-6 trans-signaling. The reported anticancer effects of the anthelminthic drug niclosamide are probably related to the potent inhibitory effect on ANO1, apart from inducing cell cycle arrest through the Let-7d/CDC34 axis. On the contrary, pronounced activation of ANO6 due to a large increase in intracellular calcium, activation of phospholipase A2 or lipid peroxidation, can lead to ferroptotic death of cancer cells. It therefore appears reasonable to search for both inhibitors and potent activators of TMEM16 in order to interfere with cancer growth and metastasis. Full article

(This article belongs to the Special Issue Ion Channels in Cancer)

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14 pages, 1230 KiB

Open AccessEditor’s ChoiceReview

Newer-Generation EGFR Inhibitors in Lung Cancer: How Are They Best Used?

by Tri Le and David E. Gerber

Cancers 2019, 11(3), 366; https://doi.org/10.3390/cancers11030366 - 15 Mar 2019

Cited by 50 | Viewed by 7878

Abstract

The FLAURA trial established osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), as a viable first-line therapy in non-small cell lung cancer (NSCLC) with sensitizing EGFR mutations, namely exon 19 deletion and L858R. In this phase 3 randomized, controlled, [...] Read more.

The FLAURA trial established osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), as a viable first-line therapy in non-small cell lung cancer (NSCLC) with sensitizing EGFR mutations, namely exon 19 deletion and L858R. In this phase 3 randomized, controlled, double-blind trial of treatment-naïve patients with EGFR mutant NSCLC, osimertinib was compared to standard-of-care EGFR TKIs (i.e., erlotinib or gefinitib) in the first-line setting. Osimertinib demonstrated improvement in median progression-free survival (18.9 months vs. 10.2 months; hazard ratio 0.46; 95% CI, 0.37 to 0.57; p < 0.001) and a more favorable toxicity profile due to its lower affinity for wild-type EGFR. Furthermore, similar to later-generation anaplastic lymphoma kinase (ALK) inhibitors, osimertinib has improved efficacy against brain metastases. Despite this impressive effect, the optimal sequencing of osimertinib, whether in the first line or as subsequent therapy after the failure of earlier-generation EGFR TKIs, is not clear. Because up-front use of later-generation TKIs may result in the inability to use earlier-generation TKIs, this treatment paradigm must be evaluated carefully. For EGFR mutant NSCLC, considerations include the incidence of T790M resistance mutations, quality of life, whether there is a potential role for earlier-generation TKIs after osimertinib failure, and overall survival. This review explores these issues for EGFR inhibitors and other molecularly targeted therapies. Full article

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

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27 pages, 11879 KiB

Open AccessEditor’s ChoiceArticle

The Small Molecule Ephrin Receptor Inhibitor, GLPG1790, Reduces Renewal Capabilities of Cancer Stem Cells, Showing Anti-Tumour Efficacy on Preclinical Glioblastoma Models

by Giovanni Luca Gravina, Andrea Mancini, Alessandro Colapietro, Simona Delle Monache, Roberta Sferra, Flora Vitale, Loredana Cristiano, Stefano Martellucci, Francesco Marampon, Vincenzo Mattei, Filip Beirinckx, Philippe Pujuguet, Laurent Saniere, Giocondo Lorenzon, Ellen van der Aar and Claudio Festuccia

Cancers 2019, 11(3), 359; https://doi.org/10.3390/cancers11030359 - 13 Mar 2019

Cited by 40 | Viewed by 5909

Abstract

Therapies against glioblastoma (GBM) show a high percentage of failure associated with the survival of glioma stem cells (GSCs) that repopulate treated tumours. Forced differentiation of GSCs is a promising new approach in cancer treatment. Erythropoietin-producing hepatocellular (Eph) receptors drive tumourigenicity and stemness [...] Read more.

Therapies against glioblastoma (GBM) show a high percentage of failure associated with the survival of glioma stem cells (GSCs) that repopulate treated tumours. Forced differentiation of GSCs is a promising new approach in cancer treatment. Erythropoietin-producing hepatocellular (Eph) receptors drive tumourigenicity and stemness in GBM. We tested GLPG1790, a first small molecule with inhibition activity versus inhibitor of various Eph receptor kinases, in preclinical GBM models using in vitro and in vivo assays. GLPG1790 rapidly and persistently inhibited Ephrin-A1-mediated phosphorylation of Tyr⁵⁸⁸ and Ser⁸⁹⁷, completely blocking EphA2 receptor signalling. Similarly, this compound blocks the ephrin B2-mediated EphA3 and EphB4 tyrosine phosphorylation. This resulted in anti-glioma effects. GLPG1790 down-modulated the expression of mesenchymal markers CD44, Sox2, nestin, octamer-binding transcription factor 3/4 (Oct3/4), Nanog, CD90, and CD105, and up-regulated that of glial fibrillary acidic protein (GFAP) and pro-neural/neuronal markers, βIII tubulin, and neurofilaments. GLPG1790 reduced tumour growth in vivo. These effects were larger compared to radiation therapy (RT; U251 and T98G xenografts) and smaller than those of temozolomide (TMZ; U251 and U87MG cell models). By contrast, GLPG1790 showed effects that were higher than Radiotherapy (RT) and similar to Temozolomide (TMZ) in orthotopic U87MG and CSCs-5 models in terms of disease-free survival (DFS) and overall survival (OS). Further experiments were necessary to study possible interactions with radio- and chemotherapy. GLPG1790 demonstrated anti-tumor effects regulating both the differentiative status of Glioma Initiating Cells (GICs) and the quality of tumor microenvironment, translating into efficacy in aggressive GBM mouse models. Significant common molecular targets to radio and chemo therapy supported the combination use of GLPG1790 in ameliorative antiglioma therapy. Full article

(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)

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19 pages, 5894 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Conversion of Stem Cells to Cancer Stem Cells: Undercurrent of Cancer Initiation

by Said M. Afify and Masaharu Seno

Cancers 2019, 11(3), 345; https://doi.org/10.3390/cancers11030345 - 11 Mar 2019

Cited by 129 | Viewed by 16892

Abstract

Cancer stem cells (CSCs) also known as cancer-initiating cells (CIC), are responsible for the sustained and uncontrolled growth of malignant tumors and are proposed to play significant roles in metastasis and recurrence. Several hypotheses have proposed that the events in either stem and/or [...] Read more.

Cancer stem cells (CSCs) also known as cancer-initiating cells (CIC), are responsible for the sustained and uncontrolled growth of malignant tumors and are proposed to play significant roles in metastasis and recurrence. Several hypotheses have proposed that the events in either stem and/or differentiated cells, such as genomic instability, inflammatory microenvironment, cell fusion, and lateral gene transfer, should be considered as the possible origin of CSCs. However, until now, the exact origin of CSC has been obscure. The development of induced pluripotent stem cells (iPSCs) in 2007, by Yamanaka’s group, has been met with much fervency and hailed as a breakthrough discovery by the scientific and research communities, especially in regeneration therapy. The studies on the development of CSC from iPSCs should also open a new page of cancer research, which will help in designing new therapies applicable to CSCs. Currently most reviews have focused on CSCs and CSC niches. However, the insight into the niche before the CSC niche should also be of keen interest. This review introduces the novel concept of cancer initiation introducing the conversion of iPSCs to CSCs and proposes a relationship between the inflammatory microenvironment and cancer initiation as the key concept of the cancer-inducing niche responsible for the development of CSC. Full article

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

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17 pages, 2027 KiB

Open AccessEditor’s ChoiceArticle

CAFs and TGF-β Signaling Activation by Mast Cells Contribute to Resistance to Gemcitabine/Nabpaclitaxel in Pancreatic Cancer

by Letizia Porcelli, Rosa Maria Iacobazzi, Roberta Di Fonte, Simona Serratì, Angelica Intini, Antonio Giovanni Solimando, Oronzo Brunetti, Angela Calabrese, Francesco Leonetti, Amalia Azzariti and Nicola Silvestris

Cancers 2019, 11(3), 330; https://doi.org/10.3390/cancers11030330 - 7 Mar 2019

Cited by 72 | Viewed by 6405

Abstract

Tumor–stroma interactions are of key importance for pancreatic ductal adenocarcinoma (PDAC) progression. Our aim was to investigate whether cancer associated fibroblasts (CAFs) and mast cells (MC) affected the sensitivity of PDAC cells to gemcitabine/nabpaclitaxel (GEM/NAB). For this purpose, the combination cytotoxicity and the [...] Read more.

Tumor–stroma interactions are of key importance for pancreatic ductal adenocarcinoma (PDAC) progression. Our aim was to investigate whether cancer associated fibroblasts (CAFs) and mast cells (MC) affected the sensitivity of PDAC cells to gemcitabine/nabpaclitaxel (GEM/NAB). For this purpose, the combination cytotoxicity and the effect on tumor invasion and angiogenesis were evaluated with or without a conditioned medium from the mast cell line HMC-1 (human mast cell line-1 cells) and CAFs. Beside the clinical outcome of a homogenous population of PDAC patients, receiving GEM/NAB, was correlated to the circulating levels of mast cell tryptase and to a panel of inflammatory and immunosuppressive cytokines. CAFs neither affected drugs’ cytotoxicity nor the inhibition of angiogenesis, but promoted tumor cell invasion. The MC instead, caused resistance to drugs by reducing apoptosis, by activating the TGF-β signalling and by promoting tumor invasion. Indeed, the inhibition of TβRI serine/threonine kinase activity by galunisertib restored drugs cytotoxicity. Moreover, MC induced the release of TGF-β1, and increased expression of PAR-2, ERK1/2 and Akt activation. Accordingly, TGF-β1, tryptase and other pro-inflammatory and immunosuppressive cytokines increased in the unresponsive patients. In conclusion, MC play a pivotal role in the resistance to GEM/NAB. A correlation between high level of circulating pro-inflammatory/ immunosuppressive cytokines and unresponsiveness was found in PDAC patients. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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23 pages, 1321 KiB

Open AccessEditor’s ChoiceReview

Role of miRNAs in Melanoma Metastasis

by Anna Gajos-Michniewicz and Malgorzata Czyz

Cancers 2019, 11(3), 326; https://doi.org/10.3390/cancers11030326 - 7 Mar 2019

Cited by 61 | Viewed by 6846

Abstract

Tumour metastasis is a multistep process. Melanoma is a highly aggressive cancer and metastasis accounts for the majority of patient deaths. microRNAs (miRNAs) are non-coding RNAs that affect the expression of their target genes. When aberrantly expressed they contribute to the development of [...] Read more.

Tumour metastasis is a multistep process. Melanoma is a highly aggressive cancer and metastasis accounts for the majority of patient deaths. microRNAs (miRNAs) are non-coding RNAs that affect the expression of their target genes. When aberrantly expressed they contribute to the development of melanoma. While miRNAs can act locally in the cell where they are synthesized, they can also influence the phenotype of neighboring melanoma cells or execute their function in the direct tumour microenvironment by modulating ECM (extracellular matrix) and the activity of fibroblasts, endothelial cells, and immune cells. miRNAs are involved in all stages of melanoma metastasis, including intravasation into the lumina of vessels, survival during circulation in cardiovascular or lymphatic systems, extravasation, and formation of the pre-metastatic niche in distant organs. miRNAs contribute to metabolic alterations that provide a selective advantage during melanoma progression. They play an important role in the development of drug resistance, including resistance to targeted therapies and immunotherapies. Distinct profiles of miRNA expression are detected at each step of melanoma development. Since miRNAs can be detected in liquid biopsies, they are considered biomarkers of early disease stages or response to treatment. This review summarizes recent findings regarding the role of miRNAs in melanoma metastasis. Full article

(This article belongs to the Special Issue MicroRNA-Associated Cancer Metastasis)

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9 pages, 476 KiB

Open AccessEditor’s ChoiceBrief Report

Breast Cancer Prognosis Using a Machine Learning Approach

by Patrizia Ferroni, Fabio M. Zanzotto, Silvia Riondino, Noemi Scarpato, Fiorella Guadagni and Mario Roselli

Cancers 2019, 11(3), 328; https://doi.org/10.3390/cancers11030328 - 7 Mar 2019

Cited by 104 | Viewed by 9921

Abstract

Machine learning (ML) has been recently introduced to develop prognostic classification models that can be used to predict outcomes in individual cancer patients. Here, we report the significance of an ML-based decision support system (DSS), combined with random optimization (RO), to extract prognostic [...] Read more.

Machine learning (ML) has been recently introduced to develop prognostic classification models that can be used to predict outcomes in individual cancer patients. Here, we report the significance of an ML-based decision support system (DSS), combined with random optimization (RO), to extract prognostic information from routinely collected demographic, clinical and biochemical data of breast cancer (BC) patients. A DSS model was developed in a training set (n = 318), whose performance analysis in the testing set (n = 136) resulted in a C-index for progression-free survival of 0.84, with an accuracy of 86%. Furthermore, the model was capable of stratifying the testing set into two groups of patients with low- or high-risk of progression with a hazard ratio (HR) of 10.9 (p < 0.0001). Validation in multicenter prospective studies and appropriate management of privacy issues in relation to digital electronic health records (EHR) data are presently needed. Nonetheless, we may conclude that the implementation of ML algorithms and RO models into EHR data might help to achieve prognostic information, and has the potential to revolutionize the practice of personalized medicine. Full article

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

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24 pages, 2556 KiB

Open AccessEditor’s ChoiceReview

Tumor Energy Metabolism and Potential of 3-Bromopyruvate as an Inhibitor of Aerobic Glycolysis: Implications in Tumor Treatment

by Tengjiao Fan, Guohui Sun, Xiaodong Sun, Lijiao Zhao, Rugang Zhong and Yongzhen Peng

Cancers 2019, 11(3), 317; https://doi.org/10.3390/cancers11030317 - 6 Mar 2019

Cited by 119 | Viewed by 14641

Abstract

Tumor formation and growth depend on various biological metabolism processes that are distinctly different with normal tissues. Abnormal energy metabolism is one of the typical characteristics of tumors. It has been proven that most tumor cells highly rely on aerobic glycolysis to obtain [...] Read more.

Tumor formation and growth depend on various biological metabolism processes that are distinctly different with normal tissues. Abnormal energy metabolism is one of the typical characteristics of tumors. It has been proven that most tumor cells highly rely on aerobic glycolysis to obtain energy rather than mitochondrial oxidative phosphorylation (OXPHOS) even in the presence of oxygen, a phenomenon called “Warburg effect”. Thus, inhibition of aerobic glycolysis becomes an attractive strategy to specifically kill tumor cells, while normal cells remain unaffected. In recent years, a small molecule alkylating agent, 3-bromopyruvate (3-BrPA), being an effective glycolytic inhibitor, has shown great potential as a promising antitumor drug. Not only it targets glycolysis process, but also inhibits mitochondrial OXPHOS in tumor cells. Excellent antitumor effects of 3-BrPA were observed in cultured cells and tumor-bearing animal models. In this review, we described the energy metabolic pathways of tumor cells, mechanism of action and cellular targets of 3-BrPA, antitumor effects, and the underlying mechanism of 3-BrPA alone or in combination with other antitumor drugs (e.g., cisplatin, doxorubicin, daunorubicin, 5-fluorouracil, etc.) in vitro and in vivo. In addition, few human case studies of 3-BrPA were also involved. Finally, the novel chemotherapeutic strategies of 3-BrPA, including wafer, liposomal nanoparticle, aerosol, and conjugate formulations, were also discussed for future clinical application. Full article

(This article belongs to the Collection Targeting Solid Tumors)

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21 pages, 1159 KiB

Open AccessEditor’s ChoiceReview

EMT Regulation by Autophagy: A New Perspective in Glioblastoma Biology

by Barbara Colella, Fiorella Faienza and Sabrina Di Bartolomeo

Cancers 2019, 11(3), 312; https://doi.org/10.3390/cancers11030312 - 6 Mar 2019

Cited by 94 | Viewed by 8025

Abstract

Epithelial-to-mesenchymal transition (EMT) and its reverse process MET naturally occur during development and in tissue repair in vertebrates. EMT is also recognized as the crucial event by which cancer cells acquire an invasive phenotype through the activation of specific transcription factors and signalling [...] Read more.

Epithelial-to-mesenchymal transition (EMT) and its reverse process MET naturally occur during development and in tissue repair in vertebrates. EMT is also recognized as the crucial event by which cancer cells acquire an invasive phenotype through the activation of specific transcription factors and signalling pathways. Even though glial cells have a mesenchymal phenotype, an EMT-like process tends to exacerbate it during gliomagenesis and progression to more aggressive stages of the disease. Autophagy is an evolutionary conserved degradative process that cells use in order to maintain a proper homeostasis, and defects in autophagy have been associated to several pathologies including cancer. Besides modulating cell resistance or sensitivity to therapy, autophagy also affects the migration and invasion capabilities of tumor cells. Despite this evidence, few papers are present in literature about the involvement of autophagy in EMT-like processes in glioblastoma (GBM) so far. This review summarizes the current understanding of the interplay between autophagy and EMT in cancer, with special regard to GBM model. As the invasive behaviour is a hallmark of GBM aggressiveness, defining a new link between autophagy and EMT can open a novel scenario for targeting these processes in future therapeutical approaches. Full article

(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)

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14 pages, 1201 KiB

Open AccessEditor’s ChoiceReview

Recent Advances in Cancer Stem Cell-Targeted Immunotherapy

by Narayanasamy Badrinath and So Young Yoo

Cancers 2019, 11(3), 310; https://doi.org/10.3390/cancers11030310 - 5 Mar 2019

Cited by 55 | Viewed by 7382

Abstract

Cancer stem cells (CSCs) are one of the reasons for the relapse of cancer cells and metastasis. They have drug resistance against most chemotherapeutic agents. CSCs are also responsible for tumor cell heterogeneity and cause minimal residual disease. In order to achieve complete [...] Read more.

Cancer stem cells (CSCs) are one of the reasons for the relapse of cancer cells and metastasis. They have drug resistance against most chemotherapeutic agents. CSCs are also responsible for tumor cell heterogeneity and cause minimal residual disease. In order to achieve complete regression of tumors, CSCs have to be targeted. Recent advances in immunotherapies have shown promising outcomes in curing cancer, which are also applicable to target CSCs. CSCs express immune markers and exhibit specific immune characteristics in various cancers, which can be used in immunotherapies to target CSCs in the tumor microenvironment. Recently, various strategies have been used to target CSCs. Adaptive T-cells, dendritic cell (DC)-based vaccines, oncolytic viruses, immune checkpoint inhibitors, and combination therapies are now being used to target CSCs. Here, we discuss the feasibility of these immunological approaches and the recent trends in immunotherapies to target CSCs. Full article

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

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17 pages, 1277 KiB

Open AccessEditor’s ChoiceReview

Immunotherapy Associated Pulmonary Toxicity: Biology Behind Clinical and Radiological Features

by Michele Porcu, Pushpamali De Silva, Cinzia Solinas, Angelo Battaglia, Marina Schena, Mario Scartozzi, Dominique Bron, Jasjit S. Suri, Karen Willard-Gallo, Dario Sangiolo and Luca Saba

Cancers 2019, 11(3), 305; https://doi.org/10.3390/cancers11030305 - 5 Mar 2019

Cited by 53 | Viewed by 6235

Abstract

The broader use of immune checkpoint blockade in clinical routine challenges clinicians in the diagnosis and management of side effects which are caused by inflammation generated by the activation of the immune response. Nearly all organs can be affected by immune-related toxicities. However, [...] Read more.

The broader use of immune checkpoint blockade in clinical routine challenges clinicians in the diagnosis and management of side effects which are caused by inflammation generated by the activation of the immune response. Nearly all organs can be affected by immune-related toxicities. However, the most frequently reported are: fatigue, rash, pruritus, diarrhea, nausea/vomiting, arthralgia, decreased appetite and abdominal pain. Although these adverse events are usually mild, reversible and not frequent, an early diagnosis is crucial. Immune-related pulmonary toxicity was most frequently observed in trials of lung cancer and of melanoma patients treated with the combination of the anti-cytotoxic T lymphocyte antigen (CTLA)-4 and the anti-programmed cell death-1 (PD-1) antibodies. The most frequent immune-related adverse event in the lung is represented by pneumonitis due to the development of infiltrates in the interstitium and in the alveoli. Clinical symptoms and radiological patterns are the key elements to be considered for an early diagnosis, rendering the differential diagnosis crucial. Diagnosis of immune-related pneumonitis may imply the temporary or definitive suspension of immunotherapy, along with the start of immuno-suppressive treatments. The aim of this work is to summarize the biological bases, clinical and radiological findings of lung toxicity under immune checkpoint blockade, underlining the importance of multidisciplinary teams for an optimal early diagnosis of this side effect, with the aim to reach an improved patient care. Full article

(This article belongs to the Special Issue Signaling Pathways and Immune Checkpoint Regulation in Cancer)

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22 pages, 2251 KiB

Open AccessEditor’s ChoiceArticle

Pan-Cancer Analyses Reveal Genomic Features of FOXM1 Overexpression in Cancer

by Carter J Barger, Connor Branick, Linda Chee and Adam R. Karpf

Cancers 2019, 11(2), 251; https://doi.org/10.3390/cancers11020251 - 21 Feb 2019

Cited by 124 | Viewed by 13254

Abstract

FOXM1 is frequently overexpressed in cancer, but this has not been studied in a comprehensive manner. We utilized genotype-tissue expression (GTEx) normal and The Cancer Genome Atlas (TCGA) tumor data to define FOXM1 expression, including its isoforms, and to determine the genetic alterations [...] Read more.

FOXM1 is frequently overexpressed in cancer, but this has not been studied in a comprehensive manner. We utilized genotype-tissue expression (GTEx) normal and The Cancer Genome Atlas (TCGA) tumor data to define FOXM1 expression, including its isoforms, and to determine the genetic alterations that promote FOXM1 expression in cancer. Additionally, we used human fallopian tube epithelial (FTE) cells to dissect the role of Retinoblastoma (Rb)-E2F and Cyclin E1 in FOXM1 regulation, and a novel human embryonic kidney cell (HEK293T) CRISPR FOXM1 knockout model to define isoform-specific transcriptional programs. FOXM1 expression, at the mRNA and protein level, was significantly elevated in tumors with FOXM1 amplification, p53 inactivation, and Rb-E2F deregulation. FOXM1 expression was remarkably high in testicular germ cell tumors (TGCT), high-grade serous ovarian cancer (HGSC), and basal breast cancer (BBC). FOXM1 expression in cancer was associated with genomic instability, as measured using aneuploidy signatures. FTE models confirmed a role for Rb-E2F signaling in FOXM1 regulation and in particular identified Cyclin E1 as a novel inducer of FOXM1 expression. Among the three FOXM1 isoforms, FOXM1c showed the highest expression in normal and tumor tissues and cancer cell lines. The CRISPR knockout model demonstrated that FOXM1b and FOXM1c are transcriptionally active, while FOXM1a is not. Finally, we were unable to confirm the existence of a FOXM1 auto-regulatory loop. This study provides significant and novel information regarding the frequency, causes, and consequences of elevated FOXM1 expression in human cancer. Full article

(This article belongs to the Special Issue Fox Proteins and Cancers: Old Proteins with Emerging New Tales)

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23 pages, 15676 KiB

Open AccessEditor’s ChoiceReview

State-of-the-Art of Profiling Immune Contexture in the Era of Multiplexed Staining and Digital Analysis to Study Paraffin Tumor Tissues

by Edwin Roger Parra, Alejandro Francisco-Cruz and Ignacio Ivan Wistuba

Cancers 2019, 11(2), 247; https://doi.org/10.3390/cancers11020247 - 20 Feb 2019

Cited by 85 | Viewed by 10072

Abstract

Multiplexed platforms for multiple epitope detection have emerged in the last years as very powerful tools to study tumor tissues. These revolutionary technologies provide important visual techniques for tumor examination in formalin-fixed paraffin-embedded specimens to improve the understanding of the tumor microenvironment, promote [...] Read more.

Multiplexed platforms for multiple epitope detection have emerged in the last years as very powerful tools to study tumor tissues. These revolutionary technologies provide important visual techniques for tumor examination in formalin-fixed paraffin-embedded specimens to improve the understanding of the tumor microenvironment, promote new treatment discoveries, aid in cancer prevention, as well as allowing translational studies to be carried out. The aim of this review is to highlight the more recent methodologies that use multiplexed staining to study simultaneous protein identification in formalin-fixed paraffin-embedded tumor tissues for immune profiling, clinical research, and potential translational analysis. New multiplexed methodologies, which permit the identification of several proteins at the same time in one single tissue section, have been developed in recent years with the ability to study different cell populations, cells by cells, and their spatial distribution in different tumor specimens including whole sections, core needle biopsies, and tissue microarrays. Multiplexed technologies associated with image analysis software can be performed with a high-quality throughput assay to study cancer specimens and are important tools for new discoveries. The different multiplexed technologies described in this review have shown their utility in the study of cancer tissues and their advantages for translational research studies and application in cancer prevention and treatments. Full article

(This article belongs to the Special Issue Towards New Promising Discoveries for Lung Cancer Patients: A Selection of Papers from the First Joint Meeting on Lung Cancer of the FHU OncoAge (Nice, France) and the MD Anderson Cancer Center (Houston, TX, USA))

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19 pages, 884 KiB

Open AccessEditor’s ChoiceReview

The Role of Platelets in the Tumor-Microenvironment and the Drug Resistance of Cancer Cells

by Phung Thanh Huong, Lap Thi Nguyen, Xuan-Bac Nguyen, Sang Kook Lee and Duc-Hiep Bach

Cancers 2019, 11(2), 240; https://doi.org/10.3390/cancers11020240 - 19 Feb 2019

Cited by 91 | Viewed by 7028

Abstract

Besides the critical functions in hemostasis, thrombosis and the wounding process, platelets have been increasingly identified as active players in various processes in tumorigenesis, including angiogenesis and metastasis. Once activated, platelets can release bioactive contents such as lipids, microRNAs, and growth factors into [...] Read more.

Besides the critical functions in hemostasis, thrombosis and the wounding process, platelets have been increasingly identified as active players in various processes in tumorigenesis, including angiogenesis and metastasis. Once activated, platelets can release bioactive contents such as lipids, microRNAs, and growth factors into the bloodstream, subsequently enhancing the platelet–cancer interaction and stimulating cancer metastasis and angiogenesis. The mechanisms of treatment failure of chemotherapeutic drugs have been investigated to be associated with platelets. Therefore, understanding how platelets contribute to the tumor microenvironment may potentially identify strategies to suppress cancer angiogenesis, metastasis, and drug resistance. Herein, we present a review of recent investigations on the role of platelets in the tumor-microenvironment including angiogenesis, and metastasis, as well as targeting platelets for cancer treatment, especially in drug resistance. Full article

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31 pages, 6116 KiB

Open AccessEditor’s ChoiceReview

Histone Deacetylase Inhibitors and Phenotypical Transformation of Cancer Cells

by Anna Wawruszak, Joanna Kalafut, Estera Okon, Jakub Czapinski, Marta Halasa, Alicja Przybyszewska, Paulina Miziak, Karolina Okla, Adolfo Rivero-Muller and Andrzej Stepulak

Cancers 2019, 11(2), 148; https://doi.org/10.3390/cancers11020148 - 27 Jan 2019

Cited by 73 | Viewed by 6466

Abstract

Histone deacetylase inhibitors (HDIs) are a group of potent epigenetic drugs which have been investigated for their therapeutic potential in various clinical disorders, including hematological malignancies and solid tumors. Currently, several HDIs are already in clinical use and many more are on clinical [...] Read more.

Histone deacetylase inhibitors (HDIs) are a group of potent epigenetic drugs which have been investigated for their therapeutic potential in various clinical disorders, including hematological malignancies and solid tumors. Currently, several HDIs are already in clinical use and many more are on clinical trials. HDIs have shown efficacy to inhibit initiation and progression of cancer cells. Nevertheless, both pro-invasive and anti-invasive activities of HDIs have been reported, questioning their impact in carcinogenesis. The aim of this review is to compile and discuss the most recent findings on the effect of HDIs on the epithelial-mesenchymal transition (EMT) process in human cancers. We have summarized the impact of HDIs on epithelial (E-cadherin, β-catenin) and mesenchymal (N-cadherin, vimentin) markers, EMT activators (TWIST, SNAIL, SLUG, SMAD, ZEB), as well as morphology, migration and invasion potential of cancer cells. We further discuss the use of HDIs as monotherapy or in combination with existing or novel anti-neoplastic drugs in relation to changes in EMT. Full article

(This article belongs to the Special Issue Histone Modification in Cancer)

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15 pages, 630 KiB

Open AccessEditor’s ChoiceReview

Platinum Resistance in Ovarian Cancer: Role of DNA Repair

by Giovanna Damia and Massimo Broggini

Cancers 2019, 11(1), 119; https://doi.org/10.3390/cancers11010119 - 20 Jan 2019

Cited by 195 | Viewed by 12691

Abstract

Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer. It is initially responsive to cisplatin and carboplatin, two DNA damaging agents used in first line therapy. However, almost invariably, patients relapse with a tumor resistant to subsequent treatment with platinum containing drugs. [...] Read more.

Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer. It is initially responsive to cisplatin and carboplatin, two DNA damaging agents used in first line therapy. However, almost invariably, patients relapse with a tumor resistant to subsequent treatment with platinum containing drugs. Several mechanisms associated with the development of acquired drug resistance have been reported. Here we focused our attention on DNA repair mechanisms, which are fundamental for recognition and removal of platinum adducts and hence for the ability of these drugs to exert their activity. We analyzed the major DNA repair pathways potentially involved in drug resistance, detailing gene mutation, duplication or deletion as well as polymorphisms as potential biomarkers for drug resistance development. We dissected potential ways to overcome DNA repair-associated drug resistance thanks to the development of new combinations and/or drugs directly targeting DNA repair proteins or taking advantage of the vulnerability arising from DNA repair defects in EOCs. Full article

(This article belongs to the Special Issue Cancer Chemoresistance)

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15 pages, 1387 KiB

Open AccessEditor’s ChoiceReview

Connexins and Integrins in Exosomes

by Motomu Shimaoka, Eiji Kawamoto, Arong Gaowa, Takayuki Okamoto and Eun Jeong Park

Cancers 2019, 11(1), 106; https://doi.org/10.3390/cancers11010106 - 17 Jan 2019

Cited by 59 | Viewed by 6964

Abstract

Connexins and integrins, the two structurally and functionally distinct families of transmembrane proteins, have been shown to be inter-connected by various modes of cross-talk in cells, such as direct physical coupling via lateral contact, indirect physical coupling via actin and actin-binding proteins, and [...] Read more.

Connexins and integrins, the two structurally and functionally distinct families of transmembrane proteins, have been shown to be inter-connected by various modes of cross-talk in cells, such as direct physical coupling via lateral contact, indirect physical coupling via actin and actin-binding proteins, and functional coupling via signaling cascades. This connexin-integrin cross-talk exemplifies a biologically important collaboration between channels and adhesion receptors in cells. Exosomes are biological lipid-bilayer nanoparticles secreted from virtually all cells via endosomal pathways into the extracellular space, thereby mediating intercellular communications across a broad range of health and diseases, including cancer progression and metastasis, infection and inflammation, and metabolic deregulation. Connexins and integrins are embedded in the exosomal membranes and have emerged as critical regulators of intercellular communication. This concise review article will explain and discuss recent progress in better understanding the roles of connexins, integrins, and their cross-talk in cells and exosomes. Full article

(This article belongs to the Special Issue Gap Junctions and Connexins in Cancer Formation, Progression, and Therapy)

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11 pages, 2438 KiB

Open AccessEditor’s ChoiceArticle

Capture of Circulating Tumour Cell Clusters Using Straight Microfluidic Chips

by Arutha Kulasinghe, Jian Zhou, Liz Kenny, Ian Papautsky and Chamindie Punyadeera

Cancers 2019, 11(1), 89; https://doi.org/10.3390/cancers11010089 - 14 Jan 2019

Cited by 75 | Viewed by 6764

Abstract

Circulating tumour cells (CTCs) are the metastatic precursors to distant disease in head and neck cancers (HNCs). Whilst the prognostic and predictive value of single CTCs have been well documented, the role of CTC clusters, which potentially have a higher metastatic capacity are [...] Read more.

Circulating tumour cells (CTCs) are the metastatic precursors to distant disease in head and neck cancers (HNCs). Whilst the prognostic and predictive value of single CTCs have been well documented, the role of CTC clusters, which potentially have a higher metastatic capacity are limited. In this study, the authors used a novel straight microfluidic chip to focus and capture CTCs. The chip offers high cell recoveries with clinically relevant numbers (10–500 cells/mL) without the need for further purification. Single CTCs were identified in 10/21 patient samples (range 2–24 CTCs/mL), CTC clusters in 9/21 patient samples (range 1–6 CTC clusters/mL) and circulating tumour microemboli (CTM) in 2/21 samples. This study demonstrated that CTC clusters contain EGFR amplified single CTCs within the cluster volume. This novel microfluidic chip demonstrates the efficient sorting and preservation of single CTCs, CTC clusters and CTMs. The authors intend to expand this study to a larger cohort to determine the clinical implication of the CTC subsets in HNC. Full article

(This article belongs to the Special Issue Liquid Biopsy for Cancer)

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19 pages, 2432 KiB

Open AccessEditor’s ChoiceArticle

Spectrum of Epithelial-Mesenchymal Transition Phenotypes in Circulating Tumour Cells from Early Breast Cancer Patients

by Aleksandra Markiewicz, Justyna Topa, Anna Nagel, Jaroslaw Skokowski, Barbara Seroczynska, Tomasz Stokowy, Marzena Welnicka-Jaskiewicz and Anna J. Zaczek

Cancers 2019, 11(1), 59; https://doi.org/10.3390/cancers11010059 - 9 Jan 2019

Cited by 44 | Viewed by 6212

Abstract

Circulating tumour cells (CTCs) can provide valuable prognostic information in a number of epithelial cancers. However, their detection is hampered due to their molecular heterogeneity, which can be induced by the epithelial-mesenchymal transition (EMT) process. Therefore, current knowledge about CTCs from clinical samples [...] Read more.

Circulating tumour cells (CTCs) can provide valuable prognostic information in a number of epithelial cancers. However, their detection is hampered due to their molecular heterogeneity, which can be induced by the epithelial-mesenchymal transition (EMT) process. Therefore, current knowledge about CTCs from clinical samples is often limited due to an inability to isolate wide spectrum of CTCs phenotypes. In the current work, we aimed at isolation and molecular characterization of CTCs with different EMT status in order to establish their clinical significance in early breast cancer patients. We have obtained CTCs-enriched blood fraction from 83 breast cancer patients in which we have tested the expression of epithelial, mesenchymal and general breast cancer CTCs markers (MGB1/HER2/CK19/CDH1/CDH2/VIM/PLS3), cancer stem cell markers (CD44, NANOG, ALDH1, OCT-4, CD133) and cluster formation gene (plakoglobin). We have shown that in the CTCs-positive patients, epithelial, epithelial-mesenchymal and mesenchymal CTCs markers were detected at a similar rate (in 28%, 24% and 24%, respectively). Mesenchymal CTCs were characterized by the most aggressive phenotype (significantly higher expression of CXCR4, uPAR, CD44, NANOG, p < 0.05 for all), presence of lymph node metastases (p = 0.043), larger tumour size (p = 0.023) and 7.33 higher risk of death in the multivariate analysis (95% CI 1.06–50.41, p = 0.04). Epithelial-mesenchymal subtype, believed to correspond to highly plastic and aggressive state, did not show significant impact on survival. Gene expression profile of samples with epithelial-mesenchymal CTCs group resembled pure epithelial or pure mesenchymal phenotypes, possibly underlining degree of EMT activation in particular patient’s sample. Molecular profiling of CTCs EMT phenotype provides more detailed and clinically informative results, proving the role of EMT in malignant cancer progression in early breast cancer. Full article

(This article belongs to the Special Issue Circulating Tumor Cells (CTCs))

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27 pages, 1397 KiB

Open AccessEditor’s ChoiceReview

Obesity, Leptin and Breast Cancer: Epidemiological Evidence and Proposed Mechanisms

by Sebastiano Andò, Luca Gelsomino, Salvatore Panza, Cinzia Giordano, Daniela Bonofiglio, Ines Barone and Stefania Catalano

Cancers 2019, 11(1), 62; https://doi.org/10.3390/cancers11010062 - 9 Jan 2019

Cited by 146 | Viewed by 13845

Abstract

The prevalence of obesity has been steadily increasing over the past few decades in several developed and developing countries, with resultant hazardous health implications. Substantial epidemiological evidence has shown that excessive adiposity strongly influences risk, prognosis, and progression of various malignancies, including breast [...] Read more.

The prevalence of obesity has been steadily increasing over the past few decades in several developed and developing countries, with resultant hazardous health implications. Substantial epidemiological evidence has shown that excessive adiposity strongly influences risk, prognosis, and progression of various malignancies, including breast cancer. Indeed, it is now well recognized that obesity is a complex physiologic state associated with multiple molecular changes capable of modulating the behavior of breast tumor cells as well of the surrounding microenvironment. Particularly, insulin resistance, hyperactivation of insulin-like growth factor pathways, and increased levels of estrogen due to aromatization by the adipose tissue, inflammatory cytokines, and adipokines contribute to breast cancerogenesis. Among adipokines, leptin, whose circulating levels increase proportionally to total adipose tissue mass, has been identified as a key member of the molecular network in obesity. This review summarizes the current knowledge on the epidemiological link existing between obesity and breast cancer and outlines the molecular mechanisms underlying this connection. The multifaceted role of the obesity adipokine leptin in this respect is also discussed. Full article

(This article belongs to the Special Issue Obesity as a Risk Factor for Cancer)

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21 pages, 1174 KiB

Open AccessEditor’s ChoiceReview

Targeting Proteotoxic Stress in Cancer: A Review of the Role that Protein Quality Control Pathways Play in Oncogenesis

by Matthew Ho Zhi Guang, Emma L. Kavanagh, Luke Paul Dunne, Paul Dowling, Li Zhang, Sinéad Lindsay, Despina Bazou, Chia Yin Goh, Cathal Hanley, Giada Bianchi, Kenneth C. Anderson, Peter O’Gorman and Amanda McCann

Cancers 2019, 11(1), 66; https://doi.org/10.3390/cancers11010066 - 9 Jan 2019

Cited by 71 | Viewed by 8518

Abstract

Despite significant advances in cancer diagnostics and therapeutics the majority of cancer unfortunately remains incurable, which has led to continued research to better understand its exceptionally diverse biology. As a result of genomic instability, cancer cells typically have elevated proteotoxic stress. Recent appreciation [...] Read more.

Despite significant advances in cancer diagnostics and therapeutics the majority of cancer unfortunately remains incurable, which has led to continued research to better understand its exceptionally diverse biology. As a result of genomic instability, cancer cells typically have elevated proteotoxic stress. Recent appreciation of this functional link between the two secondary hallmarks of cancer: aneuploidy (oxidative stress) and proteotoxic stress, has therefore led to the development of new anticancer therapies targeting this emerging “Achilles heel” of malignancy. This review highlights the importance of managing proteotoxic stress for cancer cell survival and provides an overview of the integral role proteostasis pathways play in the maintenance of protein homeostasis. We further review the efforts undertaken to exploit proteotoxic stress in multiple myeloma (as an example of a hematologic malignancy) and triple negative breast cancer (as an example of a solid tumor), and give examples of: (1) FDA-approved therapies in routine clinical use; and (2) promising therapies currently in clinical trials. Finally, we provide new insights gleaned from the use of emerging technologies to disrupt the protein secretory pathway and repurpose E3 ligases to achieve targeted protein degradation. Full article

(This article belongs to the Special Issue Cellular Stress in Cancer Progression, Drug Resistance and Treatment)

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21 pages, 6632 KiB

Open AccessEditor’s ChoiceArticle

Oxymatrine Attenuates Tumor Growth and Deactivates STAT5 Signaling in a Lung Cancer Xenograft Model

by Young Yun Jung, Muthu K. Shanmugam, Acharan S. Narula, Chulwon Kim, Jong Hyun Lee, Ojas A. Namjoshi, Bruce E. Blough, Gautam Sethi and Kwang Seok Ahn

Cancers 2019, 11(1), 49; https://doi.org/10.3390/cancers11010049 - 7 Jan 2019

Cited by 91 | Viewed by 5461

Abstract

Oxymatrine (OMT) is a major alkaloid found in radix Sophorae flavescentis extract and has been reported to exhibit various pharmacological activities. We elucidated the detailed molecular mechanism(s) underlying the therapeutic actions of OMT in non-small cell lung cancer (NSCLC) cells and a xenograft [...] Read more.

Oxymatrine (OMT) is a major alkaloid found in radix Sophorae flavescentis extract and has been reported to exhibit various pharmacological activities. We elucidated the detailed molecular mechanism(s) underlying the therapeutic actions of OMT in non-small cell lung cancer (NSCLC) cells and a xenograft mouse model. Because the STAT5 signaling cascade has a significant role in regulating cell proliferation and survival in tumor cells, we hypothesized that OMT may disrupt this signaling cascade to exert its anticancer effects. We found that OMT can inhibit the constitutive activation of STAT5 by suppressing the activation of JAK1/2 and c-Src, nuclear localization, as well as STAT5 binding to DNA in A549 cells and abrogated IL-6-induced STAT5 phosphorylation in H1299 cells. We also report that a sub-optimal concentration of OMT when used in combination with a low dose of paclitaxel produced significant anti-cancer effects by inhibiting cell proliferation and causing substantial apoptosis. In a preclinical lung cancer mouse model, OMT when used in combination with paclitaxel produced a significant reduction in tumor volume. These results suggest that OMT in combination with paclitaxel can cause an attenuation of lung cancer growth both in vitro and in vivo. Full article

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26 pages, 2915 KiB

Open AccessEditor’s ChoiceReview

Gut Microbiota and Cancer: From Pathogenesis to Therapy

by Silvia Vivarelli, Rossella Salemi, Saverio Candido, Luca Falzone, Maria Santagati, Stefania Stefani, Francesco Torino, Giuseppe Luigi Banna, Giuseppe Tonini and Massimo Libra

Cancers 2019, 11(1), 38; https://doi.org/10.3390/cancers11010038 - 3 Jan 2019

Cited by 362 | Viewed by 25687

Abstract

Cancer is a multifactorial pathology and it represents the second leading cause of death worldwide. In the recent years, numerous studies highlighted the dual role of the gut microbiota in preserving host’s health. Gut resident bacteria are able to produce a number of [...] Read more.

Cancer is a multifactorial pathology and it represents the second leading cause of death worldwide. In the recent years, numerous studies highlighted the dual role of the gut microbiota in preserving host’s health. Gut resident bacteria are able to produce a number of metabolites and bioproducts necessary to protect host’s and gut’s homeostasis. Conversely, several microbiota subpopulations may expand during pathological dysbiosis and therefore produce high levels of toxins capable, in turn, to trigger both inflammation and tumorigenesis. Importantly, gut microbiota can interact with the host either modulating directly the gut epithelium or the immune system. Numerous gut populating bacteria, called probiotics, have been identified as protective against the genesis of tumors. Given their capability of preserving gut homeostasis, probiotics are currently tested to help to fight dysbiosis in cancer patients subjected to chemotherapy and radiotherapy. Most recently, three independent studies show that specific gut resident species may potentiate the positive outcome of anti-cancer immunotherapy. The highly significant studies, uncovering the tight association between gut microbiota and tumorigenesis, as well as gut microbiota and anti-cancer therapy, are here described. The role of the Lactobacillus rhamnosus GG (LGG), as the most studied probiotic model in cancer, is also reported. Overall, according to the findings here summarized, novel strategies integrating probiotics, such as LGG, with conventional anti-cancer therapies are strongly encouraged. Full article

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39 pages, 3238 KiB

Open AccessEditor’s ChoiceReview

Flavonoids in Cancer and Apoptosis

by Mariam Abotaleb, Samson Mathews Samuel, Elizabeth Varghese, Sharon Varghese, Peter Kubatka, Alena Liskova and Dietrich Büsselberg

Cancers 2019, 11(1), 28; https://doi.org/10.3390/cancers11010028 - 28 Dec 2018

Cited by 484 | Viewed by 25105

Abstract

Cancer is the second leading cause of death globally. Although, there are many different approaches to cancer treatment, they are often painful due to adverse side effects and are sometimes ineffective due to increasing resistance to classical anti-cancer drugs or radiation therapy. Targeting [...] Read more.

Cancer is the second leading cause of death globally. Although, there are many different approaches to cancer treatment, they are often painful due to adverse side effects and are sometimes ineffective due to increasing resistance to classical anti-cancer drugs or radiation therapy. Targeting delayed/inhibited apoptosis is a major approach in cancer treatment and a highly active area of research. Plant derived natural compounds are of major interest due to their high bioavailability, safety, minimal side effects and, most importantly, cost effectiveness. Flavonoids have gained importance as anti-cancer agents and have shown great potential as cytotoxic anti-cancer agents promoting apoptosis in cancer cells. In this review, a summary of flavonoids and their effectiveness in cancer treatment targeting apoptosis has been discussed. Full article

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22 pages, 655 KiB

Open AccessEditor’s ChoiceReview

NK Cell-Based Immunotherapy in Cancer Metastasis

by Seila Lorenzo-Herrero, Alejandro López-Soto, Christian Sordo-Bahamonde, Ana P Gonzalez-Rodriguez, Massimo Vitale and Segundo Gonzalez

Cancers 2019, 11(1), 29; https://doi.org/10.3390/cancers11010029 - 28 Dec 2018

Cited by 81 | Viewed by 11273

Abstract

Metastasis represents the leading cause of cancer-related death mainly owing to the limited efficacy of current anticancer therapies on advanced malignancies. Although immunotherapy is rendering promising results in the treatment of cancer, many adverse events and factors hampering therapeutic efficacy, especially in solid [...] Read more.

Metastasis represents the leading cause of cancer-related death mainly owing to the limited efficacy of current anticancer therapies on advanced malignancies. Although immunotherapy is rendering promising results in the treatment of cancer, many adverse events and factors hampering therapeutic efficacy, especially in solid tumors and metastases, still need to be solved. Moreover, immunotherapeutic strategies have mainly focused on modulating the activity of T cells, while Natural Killer (NK) cells have only recently been taken into consideration. NK cells represent an attractive target for cancer immunotherapy owing to their innate capacity to eliminate malignant tumors in a non-Major Histocompatibility Complex (MHC) and non-tumor antigen-restricted manner. In this review, we analyze the mechanisms and efficacy of NK cells in the control of metastasis and we detail the immunosubversive strategies developed by metastatic cells to evade NK cell-mediated immunosurveillance. We also share current and cutting-edge clinical approaches aimed at unleashing the full anti-metastatic potential of NK cells, including the adoptive transfer of NK cells, boosting of NK cell activity, redirecting NK cell activity against metastatic cells and the release of evasion mechanisms dampening NK cell immunosurveillance. Full article

(This article belongs to the Special Issue Natural Killer Cells and Cancer Therapy)

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21 pages, 1236 KiB

Open AccessEditor’s ChoiceReview

Obesity-Induced TNFα and IL-6 Signaling: The Missing Link between Obesity and Inflammation—Driven Liver and Colorectal Cancers

by Lara Kern, Melanie J. Mittenbühler, Anna Juliane Vesting, Anna Lena Ostermann, Claudia Maria Wunderlich and F. Thomas Wunderlich

Cancers 2019, 11(1), 24; https://doi.org/10.3390/cancers11010024 - 27 Dec 2018

Cited by 179 | Viewed by 13418

Abstract

Obesity promotes the development of numerous cancers, such as liver and colorectal cancers, which is at least partly due to obesity-induced, chronic, low-grade inflammation. In particular, the recruitment and activation of immune cell subsets in the white adipose tissue systemically increase proinflammatory cytokines, [...] Read more.

Obesity promotes the development of numerous cancers, such as liver and colorectal cancers, which is at least partly due to obesity-induced, chronic, low-grade inflammation. In particular, the recruitment and activation of immune cell subsets in the white adipose tissue systemically increase proinflammatory cytokines, such as tumor necrosis factor α (TNFα) and interleukin-6 (IL-6). These proinflammatory cytokines not only impair insulin action in metabolic tissues, but also favor cancer development. Here, we review the current state of knowledge on how obesity affects inflammatory TNFα and IL-6 signaling in hepatocellular carcinoma and colorectal cancers. Full article

(This article belongs to the Special Issue Obesity as a Risk Factor for Cancer)

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22 pages, 7324 KiB

Open AccessEditor’s ChoiceArticle

Effects of SAHA and EGCG on Growth Potentiation of Triple-Negative Breast Cancer Cells

by Kayla A. Lewis, Harrison R. Jordan and Trygve O. Tollefsbol

Cancers 2019, 11(1), 23; https://doi.org/10.3390/cancers11010023 - 27 Dec 2018

Cited by 50 | Viewed by 6463

Abstract

Triple-negative breast cancer comprises approximately 15–20% of all breast cancers diagnosed and is nearly twice as common in black women than white women in the United States. We evaluated the effects of two epigenetic-modifying compounds on markers of growth potential in several triple-negative [...] Read more.

Triple-negative breast cancer comprises approximately 15–20% of all breast cancers diagnosed and is nearly twice as common in black women than white women in the United States. We evaluated the effects of two epigenetic-modifying compounds on markers of growth potential in several triple-negative breast cancer cell lines. Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor currently used in the treatment of cutaneous T cell lymphoma, was administered to triple-negative breast cancer cells alone or in combination with epigallocatechin-3-gallate (EGCG), a DNA methyltransferase (DNMT) inhibitor isolated from green tea. The compounds affected the expression of oncogenic miR-221/222 and tumor suppressors, p27 and PTEN, in addition to estrogen receptor alpha (ERα). E-cadherin expression was increased while N-cadherin was decreased, indicating a more epithelial phenotype. In addition, the activity of DNMTs was diminished with the treatments, and there was a significant enrichment of AcH3 within the promoter of p27 and PTEN, suggesting a role of epigenetic mechanisms for the aforementioned changes. These results translated to reduced migration of the triple-negative breast cancer cells with the treatments. Together, these findings support the role of SAHA and EGCG in limiting growth and proliferation of breast cancer cells. Full article

(This article belongs to the Special Issue Epigenetic Influence on Cancer Metastasis and/or Treatment Resistance)

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35 pages, 1360 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Non-Coding RNAs in Glioma

by Ryte Rynkeviciene, Julija Simiene, Egle Strainiene, Vaidotas Stankevicius, Jurgita Usinskiene, Edita Miseikyte Kaubriene, Ingrida Meskinyte, Jonas Cicenas and Kestutis Suziedelis

Cancers 2019, 11(1), 17; https://doi.org/10.3390/cancers11010017 - 22 Dec 2018

Cited by 100 | Viewed by 8907

Abstract

Glioma is the most aggressive brain tumor of the central nervous system. The ability of glioma cells to migrate, rapidly diffuse and invade normal adjacent tissue, their sustained proliferation, and heterogeneity contribute to an overall survival of approximately 15 months for most patients [...] Read more.

Glioma is the most aggressive brain tumor of the central nervous system. The ability of glioma cells to migrate, rapidly diffuse and invade normal adjacent tissue, their sustained proliferation, and heterogeneity contribute to an overall survival of approximately 15 months for most patients with high grade glioma. Numerous studies indicate that non-coding RNA species have critical functions across biological processes that regulate glioma initiation and progression. Recently, new data emerged, which shows that the cross-regulation between long non-coding RNAs and small non-coding RNAs contribute to phenotypic diversity of glioblastoma subclasses. In this paper, we review data of long non-coding RNA expression, which was evaluated in human glioma tissue samples during a five-year period. Thus, this review summarizes the following: (I) the role of non-coding RNAs in glioblastoma pathogenesis, (II) the potential application of non-coding RNA species in glioma-grading, (III) crosstalk between lncRNAs and miRNAs (IV) future perspectives of non-coding RNAs as biomarkers for glioma. Full article

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17 pages, 3426 KiB

Open AccessEditor’s ChoiceReview

Glioblastoma: Microenvironment and Niche Concept

by Davide Schiffer, Laura Annovazzi, Cristina Casalone, Cristiano Corona and Marta Mellai

Cancers 2019, 11(1), 5; https://doi.org/10.3390/cancers11010005 - 20 Dec 2018

Cited by 137 | Viewed by 8167

Abstract

The niche concept was originally developed to describe the location of normal neural stem cells (NSCs) in the subependymal layer of the sub-ventricular zone. In this paper, its significance has been extended to the location of tumor stem cells in glioblastoma (GB) to [...] Read more.

The niche concept was originally developed to describe the location of normal neural stem cells (NSCs) in the subependymal layer of the sub-ventricular zone. In this paper, its significance has been extended to the location of tumor stem cells in glioblastoma (GB) to discuss the relationship between GB stem cells (GSCs) and endothelial cells (ECs). Their interaction is basically conceived as responsible for tumor growth, invasion and recurrence. Niches are described as the points of utmost expression of the tumor microenvironment (TME), therefore including everything in the tumor except for tumor cells: NSCs, reactive astrocytes, ECs, glioma-associated microglia/macrophages (GAMs), myeloid cells, pericytes, fibroblasts, etc. and all intrinsic and extrinsic signaling pathways. Perivascular (PVNs), perinecrotic (PNNs) and invasive niches were described from the pathological point of view, highlighting the basic significance of the EC/tumor stem cell couple. PNN development was reinterpreted based on the concept that hyperproliferative areas of GB are composed of GSCs/progenitors. TME was depicted in its function as the main regulator of everything that happens in the tumor. A particular emphasis was given to GAMs, pericytes and reactive astrocytes as important elements affecting proliferation, growth, invasion and resistance to therapies of tumor cells. Full article

(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)

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18 pages, 2415 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Immune Gene Signature Delineates a Subclass of Papillary Thyroid Cancer with Unfavorable Clinical Outcomes

by Kyuryung Kim, Sora Jeon, Tae-Min Kim and Chan Kwon Jung

Cancers 2018, 10(12), 494; https://doi.org/10.3390/cancers10120494 - 5 Dec 2018

Cited by 48 | Viewed by 6167

Abstract

Papillary thyroid carcinoma (PTC) represents a heterogeneous disease with diverse clinical outcomes highlighting a need to identify robust biomarkers with clinical relevance. We applied non-negative matrix factorization-based deconvolution to publicly available gene expression profiles of thyroid cancers in the Cancer Genome Atlas (TCGA) [...] Read more.

Papillary thyroid carcinoma (PTC) represents a heterogeneous disease with diverse clinical outcomes highlighting a need to identify robust biomarkers with clinical relevance. We applied non-negative matrix factorization-based deconvolution to publicly available gene expression profiles of thyroid cancers in the Cancer Genome Atlas (TCGA) consortium. Among three metagene signatures identified, two signatures were enriched in canonical BRAF-like and RAS-like thyroid cancers with up-regulation of genes involved in oxidative phosphorylation and cell adhesions, respectively. The third metagene signature representing up-regulation of immune-related genes further segregated BRAF-like and RAS-like PTCs into their respective subgroups of immunoreactive (IR) and immunodeficient (ID), respectively. BRAF-IR PTCs showed enrichment of tumor infiltrating immune cells, tall cell variant PTC, and shorter recurrence-free survival compared to BRAF-ID PTCs. RAS-IR and RAS-ID PTC subtypes included majority of normal thyroid tissues and follicular variant PTC, respectively. Immunopathological features of PTC subtypes such as immune cell fraction, repertoire of T cell receptors, cytolytic activity, and expression level of immune checkpoints such as and PD-L1 and CTLA-4 were consistently observed in two different cohorts. Taken together, an immune-related metagene signature can classify PTCs into four molecular subtypes, featuring the distinct histologic type, genetic and transcriptional alterations, and potential clinical significance. Full article

(This article belongs to the Special Issue Thyroid Cancer)

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24 pages, 1554 KiB

Open AccessEditor’s ChoiceReview

Recent Advances in Oncolytic Virotherapy and Immunotherapy for Glioblastoma: A Glimmer of Hope in the Search for an Effective Therapy?

by Aleksei A. Stepanenko and Vladimir P. Chekhonin

Cancers 2018, 10(12), 492; https://doi.org/10.3390/cancers10120492 - 5 Dec 2018

Cited by 47 | Viewed by 6310

Abstract

To date, no targeted drugs, antibodies or combinations of chemotherapeutics have been demonstrated to be more efficient than temozolomide, or to increase efficacy of standard therapy (surgery, radiotherapy, temozolomide, steroid dexamethasone). According to recent phase III trials, standard therapy may ensure a median [...] Read more.

To date, no targeted drugs, antibodies or combinations of chemotherapeutics have been demonstrated to be more efficient than temozolomide, or to increase efficacy of standard therapy (surgery, radiotherapy, temozolomide, steroid dexamethasone). According to recent phase III trials, standard therapy may ensure a median overall survival of up to 18–20 months for adult patients with newly diagnosed glioblastoma. These data explain a failure of positive non-controlled phase II trials to predict positive phase III trials and should result in revision of the landmark Stupp trial as a historical control for median overall survival in non-controlled trials. A high rate of failures in clinical trials and a lack of effective chemotherapy on the horizon fostered the development of conceptually distinct therapeutic approaches: dendritic cell/peptide immunotherapy, chimeric antigen receptor (CAR) T-cell therapy and oncolytic virotherapy. Recent early phase trials with the recombinant adenovirus DNX-2401 (Ad5-delta24-RGD), polio-rhinovirus chimera (PVSRIPO), parvovirus H-1 (ParvOryx), Toca 511 retroviral vector with 5-fluorocytosine, heat shock protein-peptide complex-96 (HSPPC-96) and dendritic cell vaccines, including DCVax-L vaccine, demonstrated that subsets of patients with glioblastoma/glioma may benefit from oncolytic virotherapy/immunotherapy (>3 years of survival after treatment). However, large controlled trials are required to prove efficacy of next-generation immunotherapeutics and oncolytic vectors. Full article

(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)

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20 pages, 1291 KiB

Open AccessEditor’s ChoiceReview

Role of BRCA Mutations in Cancer Treatment with Poly(ADP-ribose) Polymerase (PARP) Inhibitors

by Isabella Faraoni and Grazia Graziani

Cancers 2018, 10(12), 487; https://doi.org/10.3390/cancers10120487 - 4 Dec 2018

Cited by 149 | Viewed by 11461

Abstract

Inhibition of poly(ADP-ribose) polymerase (PARP) activity induces synthetic lethality in mutated BRCA1/2 cancers by selectively targeting tumor cells that fail to repair DNA double strand breaks (DSBs). Clinical studies have confirmed the validity of the synthetic lethality approach and four different PARP inhibitors [...] Read more.

Inhibition of poly(ADP-ribose) polymerase (PARP) activity induces synthetic lethality in mutated BRCA1/2 cancers by selectively targeting tumor cells that fail to repair DNA double strand breaks (DSBs). Clinical studies have confirmed the validity of the synthetic lethality approach and four different PARP inhibitors (PARPi; olaparib, rucaparib, niraparib and talazoparib) have been approved as monotherapies for BRCA-mutated or platinum-sensitive recurrent ovarian cancer and/or for BRCA-mutated HER2-negative metastatic breast cancer. PARPi therapeutic efficacy is higher against tumors harboring deleterious germline or somatic BRCA mutations than in BRCA wild-type tumors. BRCA mutations or intrinsic tumor sensitivity to platinum compounds are both regarded as indicators of deficiency in DSB repair by homologous recombination as well as of favorable response to PARPi. However, not all BRCA-mutated or platinum-responsive patients obtain clinical benefit from these agents. Conversely, a certain percentage of patients with wild-type BRCA or platinum-resistant tumors can still get benefit from PARPi. Thus, additional reliable markers need to be validated in clinical trials to select patients potentially eligible for PARPi-based therapies, in the absence of deleterious BRCA mutations or platinum sensitivity. In this review, we summarize the mechanisms of action of PARPi and the clinical evidence supporting their use as anticancer drugs as well as the additional synthetic lethal partners that might confer sensitivity to PARPi in patients with wild-type BRCA tumors. Full article

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18 pages, 1809 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Sensitization of Drug Resistant Cancer Cells: A Matter of Combination Therapy

by Meghan Leary, Sarah Heerboth, Karolina Lapinska and Sibaji Sarkar

Cancers 2018, 10(12), 483; https://doi.org/10.3390/cancers10120483 - 4 Dec 2018

Cited by 127 | Viewed by 10476

Abstract

Cancer drug resistance is an enormous problem. It is responsible for most relapses in cancer patients following apparent remission after successful therapy. Understanding cancer relapse requires an understanding of the processes underlying cancer drug resistance. This article discusses the causes of cancer drug [...] Read more.

Cancer drug resistance is an enormous problem. It is responsible for most relapses in cancer patients following apparent remission after successful therapy. Understanding cancer relapse requires an understanding of the processes underlying cancer drug resistance. This article discusses the causes of cancer drug resistance, the current combination therapies, and the problems with the combination therapies. The rational design of combination therapy is warranted to improve the efficacy. These processes must be addressed by finding ways to sensitize the drug-resistant cancers cells to chemotherapy, and to prevent formation of drug resistant cancer cells. It is also necessary to prevent the formation of cancer progenitor cells by epigenetic mechanisms, as cancer progenitor cells are insensitive to standard therapies. In this article, we emphasize the role for the rational development of combination therapy, including epigenetic drugs, in achieving these goals. Full article

(This article belongs to the Special Issue Sensitization Strategies in Cancer Treatment)

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29 pages, 3856 KiB

Open AccessEditor’s ChoiceReview

Dysregulation of Nrf2 in Hepatocellular Carcinoma: Role in Cancer Progression and Chemoresistance

by Azhwar Raghunath, Kiruthika Sundarraj, Frank Arfuso, Gautam Sethi and Ekambaram Perumal

Cancers 2018, 10(12), 481; https://doi.org/10.3390/cancers10120481 - 3 Dec 2018

Cited by 138 | Viewed by 8548

Abstract

The liver executes versatile functions and is the chief organ for metabolism of toxicants/xenobiotics. Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the third foremost cause of cancer death worldwide. Oxidative stress is a key factor related with the development [...] Read more.

The liver executes versatile functions and is the chief organ for metabolism of toxicants/xenobiotics. Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the third foremost cause of cancer death worldwide. Oxidative stress is a key factor related with the development and progression of HCC. Nuclear factor erythroid 2 [NF-E2]-related factor 2 (Nrf2) is a cytosolic transcription factor, which regulates redox homeostasis by activating the expression of an array of antioxidant response element-dependent genes. Nrf2 displays conflicting roles in normal, healthy liver and HCC; in the former, Nrf2 offers beneficial effects, whereas in the latter it causes detrimental effects favouring the proliferation and survival of HCC. Sustained Nrf2 activation has been observed in HCC and facilitates its progression and aggressiveness. This review summarizes the role and mechanism(s) of action of Nrf2 dysregulation in HCC and therapeutic options that can be employed to modulate this transcription factor. Full article

(This article belongs to the Special Issue Molecular Stress Response Dysregulation in Cancer: Therapeutic Targets and Opportunities)

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33 pages, 2953 KiB

Open AccessEditor’s ChoiceReview

Chemoresistance and the Self-Maintaining Tumor Microenvironment

by Gulcen Yeldag, Alistair Rice and Armando Del Río Hernández

Cancers 2018, 10(12), 471; https://doi.org/10.3390/cancers10120471 - 28 Nov 2018

Cited by 137 | Viewed by 8954

Abstract

The progression of cancer is associated with alterations in the tumor microenvironment, including changes in extracellular matrix (ECM) composition, matrix rigidity, hypervascularization, hypoxia, and paracrine factors. One key malignant phenotype of cancer cells is their ability to resist chemotherapeutics, and elements of the [...] Read more.

The progression of cancer is associated with alterations in the tumor microenvironment, including changes in extracellular matrix (ECM) composition, matrix rigidity, hypervascularization, hypoxia, and paracrine factors. One key malignant phenotype of cancer cells is their ability to resist chemotherapeutics, and elements of the ECM can promote chemoresistance in cancer cells through a variety of signaling pathways, inducing changes in gene expression and protein activity that allow resistance. Furthermore, the ECM is maintained as an environment that facilitates chemoresistance, since its constitution modulates the phenotype of cancer-associated cells, which themselves affect the microenvironment. In this review, we discuss how the properties of the tumor microenvironment promote chemoresistance in cancer cells, and the interplay between these external stimuli. We focus on both the response of cancer cells to the external environment, as well as the maintenance of the external environment, and how a chemoresistant phenotype emerges from the complex signaling network present. Full article

(This article belongs to the Special Issue Cancer Chemoresistance)

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23 pages, 26745 KiB

Open AccessEditor’s ChoiceArticle

Network Pharmacology to Unveil the Biological Basis of Health-Strengthening Herbal Medicine in Cancer Treatment

by Jiahui Zheng, Min Wu, Haiyan Wang, Shasha Li, Xin Wang, Yan Li, Dong Wang and Shao Li

Cancers 2018, 10(11), 461; https://doi.org/10.3390/cancers10110461 - 21 Nov 2018

Cited by 88 | Viewed by 8157

Abstract

Health-strengthening (Fu-Zheng) herbs is a representative type of traditional Chinese medicine (TCM) widely used for cancer treatment in China, which is in contrast to pathogen eliminating (Qu-Xie) herbs. However, the commonness in the biological basis of health-strengthening herbs remains [...] Read more.

Health-strengthening (Fu-Zheng) herbs is a representative type of traditional Chinese medicine (TCM) widely used for cancer treatment in China, which is in contrast to pathogen eliminating (Qu-Xie) herbs. However, the commonness in the biological basis of health-strengthening herbs remains to be holistically elucidated. In this study, an innovative high-throughput research strategy integrating computational and experimental methods of network pharmacology was proposed, and 22 health-strengthening herbs were selected for the investigation. Additionally, 25 pathogen-eliminating herbs were included for comparison. First, based on network-based, large-scale target prediction, we analyzed the target profiles of 1446 TCM compounds. Next, the actions of 166 compounds on 420 antitumor or immune-related genes were measured using a unique high-throughput screening strategy by high-throughput sequencing, referred to as HTS². Furthermore, the structural information and the antitumor activity of the compounds in health-strengthening and pathogen-eliminating herbs were compared. Using network pharmacology analysis, we discovered that: (1) Functionally, the predicted targets of compounds from health strengthening herbs were enriched in both immune-related and antitumor pathways, similar to those of pathogen eliminating herbs. As a case study, galloylpaeoniflorin, a compound in a health strengthening herb Radix Paeoniae Alba (Bai Shao), was found to exert antitumor effects both in vivo and in vitro. Yet the inhibitory effects of the compounds from pathogen eliminating herbs on tumor cells proliferation as a whole were significantly stronger than those in health-strengthening herbs (p < 0.001). Moreover, the percentage of assay compounds in health-strengthening herbs with the predicted targets enriched in the immune-related pathways (e.g., natural killer cell mediated cytotoxicity and antigen processing and presentation) were significantly higher than that in pathogen-eliminating herbs (p < 0.05). This finding was supported by the immune-enhancing effects of a group of compounds from health-strengthening herbs indicated by differentially expressed genes in the HTS² results. (2) Compounds in the same herb may exhibit the same or distinguished mechanisms in cancer treatment, which was demonstrated as the compounds influence pathway gene expressions in the same or opposite directions. For example, acetyl ursolic acid and specnuezhenide in a health-strengthening herb Fructus Ligustri lucidi (Nv Zhen Zi) both upregulated gene expressions in T cell receptor signaling pathway. Together, this study suggested greater potentials in tumor immune microenvironment regulation and tumor prevention than in direct killing tumor cells of health-strengthening herbs generally, and provided a systematic strategy for unveiling the commonness in the biological basis of health-strengthening herbs in cancer treatment. Full article

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

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24 pages, 1786 KiB

Open AccessEditor’s ChoiceReview

Aberrant RNA Splicing in Cancer and Drug Resistance

by Bi-Dar Wang and Norman H. Lee

Cancers 2018, 10(11), 458; https://doi.org/10.3390/cancers10110458 - 20 Nov 2018

Cited by 117 | Viewed by 10625

Abstract

More than 95% of the 20,000 to 25,000 transcribed human genes undergo alternative RNA splicing, which increases the diversity of the proteome. Isoforms derived from the same gene can have distinct and, in some cases, opposing functions. Accumulating evidence suggests that aberrant RNA [...] Read more.

More than 95% of the 20,000 to 25,000 transcribed human genes undergo alternative RNA splicing, which increases the diversity of the proteome. Isoforms derived from the same gene can have distinct and, in some cases, opposing functions. Accumulating evidence suggests that aberrant RNA splicing is a common and driving event in cancer development and progression. Moreover, aberrant splicing events conferring drug/therapy resistance in cancer is far more common than previously envisioned. In this review, aberrant splicing events in cancer-associated genes, namely BCL2L1, FAS, HRAS, CD44, Cyclin D1, CASP2, TMPRSS2-ERG, FGFR2, VEGF, AR and KLF6, will be discussed. Also highlighted are the functional consequences of aberrant splice variants (BCR-Abl35INS, BIM-γ, IK6, p61 BRAF V600E, CD19-∆2, AR-V7 and PIK3CD-S) in promoting resistance to cancer targeted therapy or immunotherapy. To overcome drug resistance, we discuss opportunities for developing novel strategies to specifically target the aberrant splice variants or splicing machinery that generates the splice variants. Therapeutic approaches include the development of splice variant-specific siRNAs, splice switching antisense oligonucleotides, and small molecule inhibitors targeting splicing factors, splicing factor kinases or the aberrant oncogenic protein isoforms. Full article

(This article belongs to the Special Issue Drug Resistance in Cancers)

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14 pages, 1781 KiB

Open AccessEditor’s ChoiceReview

Lipid Metabolic Reprogramming in Hepatocellular Carcinoma

by Hayato Nakagawa, Yuki Hayata, Satoshi Kawamura, Tomoharu Yamada, Naoto Fujiwara and Kazuhiko Koike

Cancers 2018, 10(11), 447; https://doi.org/10.3390/cancers10110447 - 15 Nov 2018

Cited by 106 | Viewed by 9753

Abstract

Metabolic reprogramming for adaptation to the local environment has been recognized as a hallmark of cancer. Although alterations in fatty acid (FA) metabolism in cancer cells have received less attention compared to other metabolic alterations such as glucose or glutamine metabolism, recent studies [...] Read more.

Metabolic reprogramming for adaptation to the local environment has been recognized as a hallmark of cancer. Although alterations in fatty acid (FA) metabolism in cancer cells have received less attention compared to other metabolic alterations such as glucose or glutamine metabolism, recent studies have uncovered the importance of lipid metabolic reprogramming in carcinogenesis. Obesity and nonalcoholic steatohepatitis (NASH) are well-known risk factors of hepatocellular carcinoma (HCC), and individuals with these conditions exhibit an increased intake of dietary FAs accompanied by enhanced lipolysis of visceral adipose tissue due to insulin resistance, resulting in enormous exogenous FA supplies to hepatocytes via the portal vein and lymph vessels. This “lipid-rich condition” is highly characteristic of obesity- and NASH-driven HCC. Although the way in which HCC cells adapt to such a condition and exploit it to aid their progression is not understood, we recently obtained new insights into this mechanism through lipid metabolic reprogramming. In addition, accumulating evidence supports the importance of lipid metabolic reprogramming in various situations of hepatocarcinogenesis. Thus, in this review, we discuss the latest findings regarding the role of FA metabolism pathways in hepatocarcinogenesis, focusing on obesity- and NASH-driven lipid metabolic reprogramming. Full article

(This article belongs to the Special Issue Obesity as a Risk Factor for Cancer)

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