Cancers

12 pages, 1183 KB

Open AccessEditor’s ChoiceArticle

A Phase II Study of Pelareorep (REOLYSIN^®) in Combination with Gemcitabine for Patients with Advanced Pancreatic Adenocarcinoma

by Devalingam Mahalingam, Sanjay Goel, Santiago Aparo, Sukeshi Patel Arora, Nicole Noronha, Hue Tran, Romit Chakrabarty, Giovanni Selvaggi, Andres Gutierrez, Matthew Coffey, Steffan T. Nawrocki, Gerard Nuovo and Monica M. Mita

Cancers 2018, 10(6), 160; https://doi.org/10.3390/cancers10060160 - 25 May 2018

Cited by 106 | Viewed by 9098

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with 1 and 5-year survival rates of ~18% and 7% respectively. FOLFIRINOX or gemcitabine in combination with nab-paclitaxel are standard treatment options for metastatic disease. However, both regimens are more toxic than gemcitabine alone. Pelareorep [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with 1 and 5-year survival rates of ~18% and 7% respectively. FOLFIRINOX or gemcitabine in combination with nab-paclitaxel are standard treatment options for metastatic disease. However, both regimens are more toxic than gemcitabine alone. Pelareorep (REOLYSIN^®), a proprietary isolate of reovirus Type 3 Dearing, has shown antitumor activity in clinical and preclinical models. In addition to direct cytotoxic effects, pelareorep can trigger antitumor immune responses. Due to the high frequency of RAS mutations in PDAC, we hypothesized that pelareorep would promote selective reovirus replication in pancreatic tumors and enhance the anticancer activity of gemcitabine. Chemotherapy-naïve patients with advanced PDAC were eligible for the study. The primary objective was Clinical Benefit Rate (complete response (CR) + partial response (PR) + stable disease (SD) ≥ 12 weeks) and secondary objectives include overall survival (OS), toxicity, and pharmacodynamics (PD) analysis. The study enrolled 34 patients; results included one partial response, 23 stable disease, and 5 progressive disease. The median OS was 10.2 months, with a 1- and 2-year survival rate of 45% and 24%, respectively. The treatment was well tolerated with manageable nonhematological toxicities. PD analysis revealed reovirus replication within pancreatic tumor and associated apoptosis. Upregulation of immune checkpoint marker PD-L1 suggests future consideration of combining oncolytic virus therapy with anti-PD-L1 inhibitors. We conclude that pelareorep complements single agent gemcitabine in PDAC. Full article

(This article belongs to the Special Issue Oncolytic Virotherapy)

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20 pages, 1661 KB

Open AccessEditor’s ChoiceReview

Targeted Tumor Therapy Remixed—An Update on the Use of Small-Molecule Drugs in Combination Therapies

by Martina V. Gatzka

Cancers 2018, 10(6), 155; https://doi.org/10.3390/cancers10060155 - 24 May 2018

Cited by 45 | Viewed by 11423

Abstract

Over the last decade, the treatment of tumor patients has been revolutionized by the highly successful introduction of novel targeted therapies, in particular small-molecule kinase inhibitors and monoclonal antibodies, as well as by immunotherapies. Depending on the mutational status, BRAF and MEK inhibitor [...] Read more.

Over the last decade, the treatment of tumor patients has been revolutionized by the highly successful introduction of novel targeted therapies, in particular small-molecule kinase inhibitors and monoclonal antibodies, as well as by immunotherapies. Depending on the mutational status, BRAF and MEK inhibitor combinations or immune checkpoint inhibitors are current first-line treatments for metastatic melanoma. However, despite great improvements of survival rates limitations due to tumor heterogeneity, primary and acquired therapy resistance, immune evasion, and economical considerations will need to be overcome. Accordingly, ongoing clinical trials explore the individualized use of small-molecule drugs in new targeted therapy combinations based on patient parameters and tumor biopsies. With focus on melanoma therapy this review aims at providing a comprehensive overview of such novel alternative and combinational therapy strategies currently emerging from basic research. The molecular principles and drug classes that may hold promise for improved tumor therapy combination regimens including kinase inhibition, induction of apoptosis, DNA-damage response inhibition, epigenetic reprogramming, telomerase inhibition, redox modulation, metabolic reprogramming, proteasome inhibition, cancer stem cell transdifferentiation, immune cell signaling modulation, and others, are explained in brief. In addition, relevant targeted therapy combinations in current clinical trials and individualized treatment strategies are highlighted. Full article

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19 pages, 305 KB

Open AccessEditor’s ChoiceReview

Reversal of Resistance in Targeted Therapy of Metastatic Melanoma: Lessons Learned from Vemurafenib (BRAF^V600E-Specific Inhibitor)

by Antoni Xavier Torres-Collado, Jeffrey Knott and Ali R. Jazirehi

Cancers 2018, 10(6), 157; https://doi.org/10.3390/cancers10060157 - 24 May 2018

Cited by 44 | Viewed by 6685

Abstract

Malignant melanoma is the most aggressive form of skin cancer and has a very low survival rate. Over 50% of melanomas harbor various BRAF mutations with the most common being the V600E. BRAF^V600E mutation that causes constitutive activation of the MAPK pathway [...] Read more.

Malignant melanoma is the most aggressive form of skin cancer and has a very low survival rate. Over 50% of melanomas harbor various BRAF mutations with the most common being the V600E. BRAF^V600E mutation that causes constitutive activation of the MAPK pathway leading to drug-, immune-resistance, apoptosis evasion, proliferation, survival, and metastasis of melanomas. The ATP competitive BRAF^V600E selective inhibitor, vemurafenib, has shown dramatic success in clinical trials; promoting tumor regression and an increase in overall survival of patients with metastatic melanoma. Regrettably, vemurafenib-resistance develops over an average of six months, which renders melanomas resistant to other therapeutic strategies. Elucidation of the underlying mechanism(s) of acquisition of vemurafenib-resistance and design of novel approaches to override resistance is the subject of intense clinical and basic research. In this review, we summarize recent developments in therapeutic approaches and clinical investigations on melanomas with BRAF^V600E mutation to establish a new platform for the treatment of melanoma. Full article

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

17 pages, 888 KB

Open AccessEditor’s ChoiceReview

40 Years of Research Put p53 in Translation

by Virginie Marcel, Flora Nguyen Van Long and Jean-Jacques Diaz

Cancers 2018, 10(5), 152; https://doi.org/10.3390/cancers10050152 - 21 May 2018

Cited by 43 | Viewed by 7516

Abstract

Since its discovery in 1979, p53 has shown multiple facets. Initially the tumor suppressor p53 protein was considered as a stress sensor able to maintain the genome integrity by regulating transcription of genes involved in cell cycle arrest, apoptosis and DNA repair. However, [...] Read more.

Since its discovery in 1979, p53 has shown multiple facets. Initially the tumor suppressor p53 protein was considered as a stress sensor able to maintain the genome integrity by regulating transcription of genes involved in cell cycle arrest, apoptosis and DNA repair. However, it rapidly came into light that p53 regulates gene expression to control a wider range of biological processes allowing rapid cell adaptation to environmental context. Among them, those related to cancer have been extensively documented. In addition to its role as transcription factor, scattered studies reported that p53 regulates miRNA processing, modulates protein activity by direct interaction or exhibits RNA-binding activity, thus suggesting a role of p53 in regulating several layers of gene expression not restricted to transcription. After 40 years of research, it appears more and more clearly that p53 is strongly implicated in translational regulation as well as in the control of the production and activity of the translational machinery. Translation control of specific mRNAs could provide yet unsuspected capabilities to this well-known guardian of the genome. Full article

(This article belongs to the Special Issue p53 Signaling in Cancers)

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10 pages, 4221 KB

Open AccessEditor’s ChoiceArticle

AZD1775 Increases Sensitivity to Olaparib and Gemcitabine in Cancer Cells with p53 Mutations

by Xiangbing Meng, Jianling Bi, Yujun Li, Shujie Yang, Yuping Zhang, Mary Li, Haitao Liu, Yiyang Li, Megan E. Mcdonald, Kristina W. Thiel, Kuo-Kuang Wen, Xinhao Wang, Meng Wu and Kimberly K. Leslie

Cancers 2018, 10(5), 149; https://doi.org/10.3390/cancers10050149 - 19 May 2018

Cited by 53 | Viewed by 7627

Abstract

Tumor suppressor p53 is responsible for enforcing cell cycle checkpoints at G1/S and G2/M in response to DNA damage, thereby allowing both normal and tumor cells to repair DNA before entering S and M. However, tumor cells with absent or mutated p53 are [...] Read more.

Tumor suppressor p53 is responsible for enforcing cell cycle checkpoints at G1/S and G2/M in response to DNA damage, thereby allowing both normal and tumor cells to repair DNA before entering S and M. However, tumor cells with absent or mutated p53 are able to activate alternative signaling pathways that maintain the G2/M checkpoint, which becomes uniquely critical for the survival of such tumor cells. We hypothesized that abrogation of the G2 checkpoint might preferentially sensitize p53-defective tumor cells to DNA-damaging agents and spare normal cells with intact p53 function. The tyrosine kinase WEE1 regulates cdc2 activity at the G2/M checkpoint and prevents entry into mitosis in response to DNA damage or stalled DNA replication. AZD1775 is a WEE1 inhibitor that overrides and opens the G2/M checkpoint by preventing WEE1-mediated phosphorylation of cdc2 at tyrosine 15. In this study, we assessed the effect of AZD1775 on endometrial and ovarian cancer cells in the presence of two DNA damaging agents, the PARP1 inhibitor, olaparib, and the chemotherapeutic agent, gemcitabine. We show that AZD1775 alone is effective as a therapeutic agent against some p53 mutated cell models. Moreover, the combination of AZD1775 with olaparib or gemcitabine is synergistic in cells with mutant p53 and constitutes a new approach that should be considered in the treatment of advanced and recurrent gynecologic cancer. Full article

(This article belongs to the Special Issue p53 Signaling in Cancers)

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15 pages, 703 KB

Open AccessEditor’s ChoiceReview

The Guardian of the Genome Revisited: p53 Downregulates Genes Required for Telomere Maintenance, DNA Repair, and Centromere Structure

by Eléonore Toufektchan and Franck Toledo

Cancers 2018, 10(5), 135; https://doi.org/10.3390/cancers10050135 - 6 May 2018

Cited by 103 | Viewed by 10587

Abstract

The p53 protein has been extensively studied for its capacity to prevent proliferation of cells with a damaged genome. Surprisingly, however, our recent analysis of mice expressing a hyperactive mutant p53 that lacks the C-terminal domain revealed that increased p53 activity may alter [...] Read more.

The p53 protein has been extensively studied for its capacity to prevent proliferation of cells with a damaged genome. Surprisingly, however, our recent analysis of mice expressing a hyperactive mutant p53 that lacks the C-terminal domain revealed that increased p53 activity may alter genome maintenance. We showed that p53 downregulates genes essential for telomere metabolism, DNA repair, and centromere structure and that a sustained p53 activity leads to phenotypic traits associated with dyskeratosis congenita and Fanconi anemia. This downregulation is largely conserved in human cells, which suggests that our findings could be relevant to better understand processes involved in bone marrow failure as well as aging and tumor suppression. Full article

(This article belongs to the Special Issue p53 Signaling in Cancers)

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29 pages, 2367 KB

Open AccessEditor’s ChoiceReview

YAP and TAZ in Lung Cancer: Oncogenic Role and Clinical Targeting

by Federica Lo Sardo, Sabrina Strano and Giovanni Blandino

Cancers 2018, 10(5), 137; https://doi.org/10.3390/cancers10050137 - 6 May 2018

Cited by 100 | Viewed by 12898

Abstract

Lung cancer is the leading cause of cancer death in the world and there is no current treatment able to efficiently treat the disease as the tumor is often diagnosed at an advanced stage. Moreover, cancer cells are often resistant or acquire resistance [...] Read more.

Lung cancer is the leading cause of cancer death in the world and there is no current treatment able to efficiently treat the disease as the tumor is often diagnosed at an advanced stage. Moreover, cancer cells are often resistant or acquire resistance to the treatment. Further knowledge of the mechanisms driving lung tumorigenesis, aggressiveness, metastasization, and resistance to treatments could provide new tools for detecting the disease at an earlier stage and for a better response to therapy. In this scenario, Yes Associated Protein (YAP) and Trascriptional Coactivator with PDZ-binding motif (TAZ), the final effectors of the Hippo signaling transduction pathway, are emerging as promising therapeutic targets. Here, we will discuss the most recent advances made in YAP and TAZ biology in lung cancer and, more importantly, on the newly discovered mechanisms of YAP and TAZ inhibition in lung cancer as well as their clinical implications. Full article

(This article belongs to the Special Issue Hippo Pathway in Cancer, towards Realization of the Hippo-Targeted Therapy)

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10 pages, 661 KB

Open AccessEditor’s ChoiceReview

Insights of Crosstalk between p53 Protein and the MKK3/MKK6/p38 MAPK Signaling Pathway in Cancer

by Lorenzo Stramucci, Angelina Pranteda and Gianluca Bossi

Cancers 2018, 10(5), 131; https://doi.org/10.3390/cancers10050131 - 3 May 2018

Cited by 92 | Viewed by 10392

Abstract

TP53 is universally recognized as a pivotal protein in cell-cycle fate and apoptotic induction and, unsurprisingly, it is one of the most commonly hijacked control mechanisms in cancer. Recently, the kinase MKK3 emerged as a potential therapeutic target in different types of solid [...] Read more.

TP53 is universally recognized as a pivotal protein in cell-cycle fate and apoptotic induction and, unsurprisingly, it is one of the most commonly hijacked control mechanisms in cancer. Recently, the kinase MKK3 emerged as a potential therapeutic target in different types of solid tumor being linked to mutant p53 gain-of-function. In this review, we summarize the delicate relationship among p53 mutational status, MKK3/MKK6 and the downstream activated master kinase p38MAPK, dissecting a finely-tuned crosstalk, in a potentially cell-context dependent scenario that urges towards a deeper characterization of the different molecular players involved in this signaling cascade and their interactions. Full article

(This article belongs to the Special Issue p53 Signaling in Cancers)

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15 pages, 3343 KB

Open AccessEditor’s ChoiceArticle

Hypoxia-Induced Cisplatin Resistance in Non-Small Cell Lung Cancer Cells Is Mediated by HIF-1α and Mutant p53 and Can Be Overcome by Induction of Oxidative Stress

by Christophe Deben, Vanessa Deschoolmeester, Jorrit De Waele, Julie Jacobs, Jolien Van den Bossche, An Wouters, Marc Peeters, Christian Rolfo, Evelien Smits, Filip Lardon and Patrick Pauwels

Cancers 2018, 10(4), 126; https://doi.org/10.3390/cancers10040126 - 21 Apr 2018

Cited by 52 | Viewed by 8331

Abstract

The compound APR-246 (PRIMA-1^MET) is a known reactivator of (mutant) p53 and inducer of oxidative stress which can sensitize cancer cells to platinum-based chemotherapeutics. However, the effect of a hypoxic tumor environment has been largely overlooked in this interaction. This study [...] Read more.

The compound APR-246 (PRIMA-1^MET) is a known reactivator of (mutant) p53 and inducer of oxidative stress which can sensitize cancer cells to platinum-based chemotherapeutics. However, the effect of a hypoxic tumor environment has been largely overlooked in this interaction. This study focusses on the role of hypoxia-inducible factor-1α (HIF-1α) and the p53 tumor suppressor protein in hypoxia-induced cisplatin resistance in non-small cell lung cancer (NSCLC) cells and the potential of APR-246 to overcome this resistance. We observed that hypoxia-induced cisplatin resistance only occurred in the p53 mutant NCI-H2228^Q331* cell line, and not in the wild type A549 and mutant NCI-H1975^R273H cell lines. Cisplatin reduced HIF-1α protein levels in NCI-H2228^Q331* cells, leading to a shift in expression from HIF-1α-dependent to p53-dependent transcription targets under hypoxia. APR-246 was able to overcome hypoxia-induced cisplatin resistance in NCI-H2228^Q331* cells in a synergistic manner without affecting mutant p53^Q331* transcriptional activity, but significantly depleting total glutathione levels more efficiently under hypoxic conditions. Synergism was dependent on the presence of mutant p53^Q331* and the induction of reactive oxygen species, with depletion of one or the other leading to loss of synergism. Our data further support the rationale of combining APR-246 with cisplatin in NSCLC, since their synergistic interaction is retained or enforced under hypoxic conditions in the presence of mutant p53. Full article

(This article belongs to the Special Issue p53 Signaling in Cancers)

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29 pages, 853 KB

Open AccessEditor’s ChoiceReview

Innovative Diagnostic Methods for Early Prostate Cancer Detection through Urine Analysis: A Review

by Carmen Bax, Gianluigi Taverna, Lidia Eusebio, Selena Sironi, Fabio Grizzi, Giorgio Guazzoni and Laura Capelli

Cancers 2018, 10(4), 123; https://doi.org/10.3390/cancers10040123 - 18 Apr 2018

Cited by 65 | Viewed by 9157

Abstract

Prostate cancer is the second most common cause of cancer death among men. It is an asymptomatic and slow growing tumour, which starts occurring in young men, but can be detected only around the age of 40–50. Although its long latency period and [...] Read more.

Prostate cancer is the second most common cause of cancer death among men. It is an asymptomatic and slow growing tumour, which starts occurring in young men, but can be detected only around the age of 40–50. Although its long latency period and potential curability make prostate cancer a perfect candidate for screening programs, the current procedure lacks in specificity. Researchers are rising to the challenge of developing innovative tools able of detecting the disease during its early stage that is the most curable. In recent years, the interest in characterisation of biological fluids aimed at the identification of tumour-specific compounds has increased significantly, since cell neoplastic transformation causes metabolic alterations leading to volatile organic compounds release. In the scientific literature, different approaches have been proposed. Many studies focus on the identification of a cancer-characteristic “odour fingerprint” emanated from biological samples through the application of sensorial or senso-instrumental analyses, others suggest a chemical characterisation of biological fluids with the aim of identifying prostate cancer (PCa)-specific biomarkers. This paper focuses on the review of literary studies in the field of prostate cancer diagnosis, in order to provide an overview of innovative methods based on the analysis of urine, thereby comparing them with the traditional diagnostic procedures. Full article

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11 pages, 20100 KB

Open AccessEditor’s ChoiceCommentary

Roles of Polyploid/Multinucleated Giant Cancer Cells in Metastasis and Disease Relapse Following Anticancer Treatment

by Razmik Mirzayans, Bonnie Andrais and David Murray

Cancers 2018, 10(4), 118; https://doi.org/10.3390/cancers10040118 - 15 Apr 2018

Cited by 152 | Viewed by 13598

Abstract

Tumors and tumor-derived cell lines contain polyploid giant cells with significantly elevated genomic content, often with multiple nuclei. The frequency of giant cells can increase markedly following anticancer treatment. Although giant cells enter a dormant phase and therefore do not form macroscopic colonies [...] Read more.

Tumors and tumor-derived cell lines contain polyploid giant cells with significantly elevated genomic content, often with multiple nuclei. The frequency of giant cells can increase markedly following anticancer treatment. Although giant cells enter a dormant phase and therefore do not form macroscopic colonies (aggregates of ≥50 cells) in the conventional in vitro colony formation assay, they remain viable and metabolically active. The purpose of this commentary is to underscore the potential importance of polyploid/multinucleated giant cells in metastasis and cancer recurrence following exposure to anticancer agents. We also discuss the possibility that most preclinical (cell-based and animal model) drug discovery approaches might not account for delayed responses that are associated with dormant giant cells. Full article

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16 pages, 3999 KB

Open AccessFeature PaperEditor’s ChoiceReview

ALK in Neuroblastoma: Biological and Therapeutic Implications

by Ricky M. Trigg and Suzanne D. Turner

Cancers 2018, 10(4), 113; https://doi.org/10.3390/cancers10040113 - 10 Apr 2018

Cited by 126 | Viewed by 12881

Abstract

Neuroblastoma (NB) is the most common and deadly solid tumour in children. Despite the development of new treatment options for high-risk NB, over half of patients relapse and five-year survival remains at 40–50%. Therefore, novel treatment strategies aimed at providing long-term disease remission [...] Read more.

Neuroblastoma (NB) is the most common and deadly solid tumour in children. Despite the development of new treatment options for high-risk NB, over half of patients relapse and five-year survival remains at 40–50%. Therefore, novel treatment strategies aimed at providing long-term disease remission are urgently sought. ALK, encoding the anaplastic lymphoma kinase receptor, is altered by gain-of-function point mutations in around 14% of high-risk NB and represents an ideal therapeutic target given its low or absent expression in healthy tissue postnatally. Small-molecule inhibitors of Anaplastic Lymphoma Kinase (ALK) approved in ALK fusion-positive lung cancer are currently undergoing clinical assessment in patients with ALK-mutant NB. Parallel pre-clinical studies are demonstrating the efficacy of ALK inhibitors against common ALK variants in NB; however, a complex picture of therapeutic resistance is emerging. It is anticipated that long-term use of these compounds will require combinatorial targeting of pathways downstream of ALK, functionally-related ‘bypass’ mechanisms and concomitant oncogenic pathways. Full article

(This article belongs to the Special Issue Advances in Our Understanding of ALK-Related Cancers: A Selection of Papers from the Joint Annual Meeting of the European Research Initiative for ALK-Related Malignancies (ERIA) and the European Union Marie Curie European Training Network ALKATRAS)

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37 pages, 28465 KB

Open AccessFeature PaperEditor’s ChoiceReview

YAP/TAZ Activation as a Target for Treating Metastatic Cancer

by Janine S. A. Warren, Yuxuan Xiao and John M. Lamar

Cancers 2018, 10(4), 115; https://doi.org/10.3390/cancers10040115 - 10 Apr 2018

Cited by 140 | Viewed by 15823

Abstract

Yes-Associated Protein (YAP) and Transcriptional Co-activator with PDZ-binding Motif (TAZ) have both emerged as important drivers of cancer progression and metastasis. YAP and TAZ are often upregulated or nuclear localized in aggressive human cancers. There is abundant experimental evidence demonstrating that YAP or [...] Read more.

Yes-Associated Protein (YAP) and Transcriptional Co-activator with PDZ-binding Motif (TAZ) have both emerged as important drivers of cancer progression and metastasis. YAP and TAZ are often upregulated or nuclear localized in aggressive human cancers. There is abundant experimental evidence demonstrating that YAP or TAZ activation promotes cancer formation, tumor progression, and metastasis. In this review we summarize the evidence linking YAP/TAZ activation to metastasis, and discuss the roles of YAP and TAZ during each step of the metastatic cascade. Collectively, this evidence strongly suggests that inappropriate YAP or TAZ activity plays a causal role in cancer, and that targeting aberrant YAP/TAZ activation is a promising strategy for the treatment of metastatic disease. To this end, we also discuss several potential strategies for inhibiting YAP/TAZ activation in cancer and the challenges each strategy poses. Full article

(This article belongs to the Special Issue Hippo Pathway in Cancer, towards Realization of the Hippo-Targeted Therapy)

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23 pages, 44166 KB

Open AccessEditor’s ChoiceReview

Immunohistochemistry for Diagnosis of Metastatic Carcinomas of Unknown Primary Site

by Janick Selves, Elodie Long-Mira, Marie-Christine Mathieu, Philippe Rochaix and Marius Ilié

Cancers 2018, 10(4), 108; https://doi.org/10.3390/cancers10040108 - 5 Apr 2018

Cited by 151 | Viewed by 35795

Abstract

Immunohistochemistry has become an essential ancillary examination for the identification and classification of carcinomas of unknown primary site (CUPs). Over the last decade, the diagnostic accuracy of organ- or tumour-specific immunomarkers and the clinical validation of effective immunohistochemical panels has improved significantly. When [...] Read more.

Immunohistochemistry has become an essential ancillary examination for the identification and classification of carcinomas of unknown primary site (CUPs). Over the last decade, the diagnostic accuracy of organ- or tumour-specific immunomarkers and the clinical validation of effective immunohistochemical panels has improved significantly. When dealing with small sample sizes, diagnostic accuracy is crucial, particularly in the current era of targeted molecular and immune-based therapies. Effective systematic use of appropriate immunohistochemical panels enables accurate classification of most of the undifferentiated carcinomas as well as careful preservation of tissues for potential molecular or other ancillary tests. This review discusses the algorithmic approach to the diagnosis of CUPs using CK7 and CK20 staining patterns. It outlines the most frequently used tissue-specific antibodies, provides some pitfalls essential in avoiding potential diagnostic errors and discusses the complementary tools, such as molecular tumour profiling and mutation-specific antibodies, for the improvement of diagnosis and prediction of the treatment response. Full article

(This article belongs to the Special Issue Immunohistochemistry and Cancer Diagnosis)

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15 pages, 295 KB

Open AccessFeature PaperEditor’s ChoiceReview

Inhibiting TRK Proteins in Clinical Cancer Therapy

by Allison M. Lange and Hui-Wen Lo

Cancers 2018, 10(4), 105; https://doi.org/10.3390/cancers10040105 - 4 Apr 2018

Cited by 148 | Viewed by 11094

Abstract

Gene rearrangements resulting in the aberrant activity of tyrosine kinases have been identified as drivers of oncogenesis in a variety of cancers. The tropomyosin receptor kinase (TRK) family of tyrosine receptor kinases is emerging as an important target for cancer therapeutics. The TRK [...] Read more.

Gene rearrangements resulting in the aberrant activity of tyrosine kinases have been identified as drivers of oncogenesis in a variety of cancers. The tropomyosin receptor kinase (TRK) family of tyrosine receptor kinases is emerging as an important target for cancer therapeutics. The TRK family contains three members, TRKA, TRKB, and TRKC, and these proteins are encoded by the genes NTRK1, NTRK2, and NTRK3, respectively. To activate TRK receptors, neurotrophins bind to the extracellular region stimulating dimerization, phosphorylation, and activation of downstream signaling pathways. Major known downstream pathways include RAS/MAPK/ERK, PLCγ, and PI3K/Akt. While being rare in most cancers, TRK fusions with other proteins have been well-established as oncogenic events in specific malignancies, including glioblastoma, papillary thyroid carcinoma, and secretory breast carcinomas. TRK protein amplification as well as alternative splicing events have also been described as contributors to cancer pathogenesis. For patients harboring alterations in TRK expression or activity, TRK inhibition emerges as an important therapeutic target. To date, multiple trials testing TRK-inhibiting compounds in various cancers are underway. In this review, we will summarize the current therapeutic trials for neoplasms involving NTKR gene alterations, as well as the promises and setbacks that are associated with targeting gene fusions. Full article

22 pages, 88948 KB

Open AccessFeature PaperEditor’s ChoiceReview

The Pathological Spectrum of Systemic Anaplastic Large Cell Lymphoma (ALCL)

by Ivonne A. Montes-Mojarro, Julia Steinhilber, Irina Bonzheim, Leticia Quintanilla-Martinez and Falko Fend

Cancers 2018, 10(4), 107; https://doi.org/10.3390/cancers10040107 - 4 Apr 2018

Cited by 64 | Viewed by 14712

Abstract

Anaplastic large cell lymphoma (ALCL) represents a group of malignant T-cell lymphoproliferations that share morphological and immunophenotypical features, namely strong CD30 expression and variable loss of T-cell markers, but differ in clinical presentation and prognosis. The recognition of anaplastic lymphoma kinase (ALK) fusion [...] Read more.

Anaplastic large cell lymphoma (ALCL) represents a group of malignant T-cell lymphoproliferations that share morphological and immunophenotypical features, namely strong CD30 expression and variable loss of T-cell markers, but differ in clinical presentation and prognosis. The recognition of anaplastic lymphoma kinase (ALK) fusion proteins as a result of chromosomal translocations or inversions was the starting point for the distinction of different subgroups of ALCL. According to their distinct clinical settings and molecular findings, the 2016 revised World Health Organization (WHO) classification recognizes four different entities: systemic ALK-positive ALCL (ALK+ ALCL), systemic ALK-negative ALCL (ALK− ALCL), primary cutaneous ALCL (pC-ALCL), and breast implant-associated ALCL (BI-ALCL), the latter included as a provisional entity. ALK is rearranged in approximately 80% of systemic ALCL cases with one of its partner genes, most commonly NPM1, and is associated with favorable prognosis, whereas systemic ALK− ALCL shows heterogeneous clinical, phenotypical, and genetic features, underlining the different oncogenesis between these two entities. Recognition of the pathological spectrum of ALCL is crucial to understand its pathogenesis and its boundaries with other entities. In this review, we will focus on the morphological, immunophenotypical, and molecular features of systemic ALK+ and ALK− ALCL. In addition, BI-ALCL will be discussed. Full article

(This article belongs to the Special Issue Advances in Our Understanding of ALK-Related Cancers: A Selection of Papers from the Joint Annual Meeting of the European Research Initiative for ALK-Related Malignancies (ERIA) and the European Union Marie Curie European Training Network ALKATRAS)

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14 pages, 65406 KB

Open AccessEditor’s ChoiceReview

Bladder Cancer: New Insights into Its Molecular Pathology

by Kentaro Inamura

Cancers 2018, 10(4), 100; https://doi.org/10.3390/cancers10040100 - 1 Apr 2018

Cited by 88 | Viewed by 16482

Abstract

Bladder cancer is one of the most prevalent cancers worldwide. Unfortunately, there have been few advances in its clinical management due to a poor understanding of the correlations between its molecular and clinical features. Mounting evidence suggests that bladder cancer comprises a group [...] Read more.

Bladder cancer is one of the most prevalent cancers worldwide. Unfortunately, there have been few advances in its clinical management due to a poor understanding of the correlations between its molecular and clinical features. Mounting evidence suggests that bladder cancer comprises a group of molecularly heterogeneous diseases that undergo a variety of clinical courses and possess diverse therapeutic responses. Owing to the close association between its molecular subtypes and clinicopathological features, specific therapeutic strategies have recently been suggested. This review summarizes the current understanding of the molecular pathology of bladder cancer, including its molecular biomarkers/pathways and molecular subtypes that have been newly identified using high-throughput technologies. It also discusses advances in our understanding of personalized treatments for specific molecular subtypes. Full article

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21 pages, 3536 KB

Open AccessEditor’s ChoiceReview

Epigenetic Modifications as Biomarkers of Tumor Development, Therapy Response, and Recurrence across the Cancer Care Continuum

by Margaret L. Thomas and Paola Marcato

Cancers 2018, 10(4), 101; https://doi.org/10.3390/cancers10040101 - 1 Apr 2018

Cited by 347 | Viewed by 9809

Abstract

Aberrant epigenetic modifications are an early event in carcinogenesis, with the epigenetic landscape continuing to change during tumor progression and metastasis—these observations suggest that specific epigenetic modifications could be used as diagnostic and prognostic biomarkers for many cancer types. DNA methylation, post-translational histone [...] Read more.

Aberrant epigenetic modifications are an early event in carcinogenesis, with the epigenetic landscape continuing to change during tumor progression and metastasis—these observations suggest that specific epigenetic modifications could be used as diagnostic and prognostic biomarkers for many cancer types. DNA methylation, post-translational histone modifications, and non-coding RNAs are all dysregulated in cancer and are detectable to various degrees in liquid biopsies such as sputum, urine, stool, and blood. Here, we will focus on the application of liquid biopsies, as opposed to tissue biopsies, because of their potential as non-invasive diagnostic tools and possible use in monitoring therapy response and progression to metastatic disease. This includes a discussion of septin-9 (SEPT9) DNA hypermethylation for detecting colorectal cancer, which is by far the most developed epigenetic biomarker assay. Despite their potential as prognostic and diagnostic biomarkers, technical issues such as inconsistent methodology between studies, overall low yield of epigenetic material in samples, and the need for improved histone and non-coding RNA purification methods are limiting the use of epigenetic biomarkers. Once these technical limitations are overcome, epigenetic biomarkers could be used to monitor cancer development, disease progression, therapeutic response, and recurrence across the entire cancer care continuum. Full article

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

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22 pages, 5147 KB

Open AccessFeature PaperEditor’s ChoiceReview

The Role of Activator Protein-1 (AP-1) Family Members in CD30-Positive Lymphomas

by Ines Garces de los Fayos Alonso, Huan-Chang Liang, Suzanne D. Turner, Sabine Lagger, Olaf Merkel and Lukas Kenner

Cancers 2018, 10(4), 93; https://doi.org/10.3390/cancers10040093 - 28 Mar 2018

Cited by 119 | Viewed by 15089

Abstract

The Activator Protein-1 (AP-1) transcription factor (TF) family, composed of a variety of members including c-JUN, c-FOS and ATF, is involved in mediating many biological processes such as proliferation, differentiation and cell death. Since their discovery, the role of AP-1 TFs in cancer [...] Read more.

The Activator Protein-1 (AP-1) transcription factor (TF) family, composed of a variety of members including c-JUN, c-FOS and ATF, is involved in mediating many biological processes such as proliferation, differentiation and cell death. Since their discovery, the role of AP-1 TFs in cancer development has been extensively analysed. Multiple in vitro and in vivo studies have highlighted the complexity of these TFs, mainly due to their cell-type specific homo- or hetero-dimerization resulting in diverse transcriptional response profiles. However, as a result of the increasing knowledge of the role of AP-1 TFs in disease, these TFs are being recognized as promising therapeutic targets for various malignancies. In this review, we focus on the impact of deregulated expression of AP-1 TFs in CD30-positive lymphomas including Classical Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma. Full article

(This article belongs to the Special Issue Advances in Our Understanding of ALK-Related Cancers: A Selection of Papers from the Joint Annual Meeting of the European Research Initiative for ALK-Related Malignancies (ERIA) and the European Union Marie Curie European Training Network ALKATRAS)

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20 pages, 13761 KB

Open AccessEditor’s ChoiceReview

The Hippo Pathway: Immunity and Cancer

by Zaid Taha, Helena J. Janse van Rensburg and Xiaolong Yang

Cancers 2018, 10(4), 94; https://doi.org/10.3390/cancers10040094 - 28 Mar 2018

Cited by 124 | Viewed by 18218

Abstract

Since its discovery, the Hippo pathway has emerged as a central signaling network in mammalian cells. Canonical signaling through the Hippo pathway core components (MST1/2, LATS1/2, YAP and TAZ) is important for development and tissue homeostasis while aberrant signaling through the Hippo pathway [...] Read more.

Since its discovery, the Hippo pathway has emerged as a central signaling network in mammalian cells. Canonical signaling through the Hippo pathway core components (MST1/2, LATS1/2, YAP and TAZ) is important for development and tissue homeostasis while aberrant signaling through the Hippo pathway has been implicated in multiple pathologies, including cancer. Recent studies have uncovered new roles for the Hippo pathway in immunology. In this review, we summarize the mechanisms by which Hippo signaling in pathogen-infected or neoplastic cells affects the activities of immune cells that respond to these threats. We further discuss how Hippo signaling functions as part of an immune response. Finally, we review how immune cell-intrinsic Hippo signaling modulates the development/function of leukocytes and propose directions for future work. Full article

(This article belongs to the Special Issue Hippo Pathway in Cancer, towards Realization of the Hippo-Targeted Therapy)

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15 pages, 2589 KB

Open AccessEditor’s ChoiceReview

Targeting the Hippo Pathway and Cancer through the TEAD Family of Transcription Factors

by Jeffrey K. Holden and Christian N. Cunningham

Cancers 2018, 10(3), 81; https://doi.org/10.3390/cancers10030081 - 20 Mar 2018

Cited by 141 | Viewed by 17236

Abstract

The Hippo pathway is a critical transcriptional signaling pathway that regulates cell growth, proliferation and organ development. The transcriptional enhanced associate domain (TEAD) protein family consists of four paralogous transcription factors that function to modulate gene expression in response to the Hippo signaling [...] Read more.

The Hippo pathway is a critical transcriptional signaling pathway that regulates cell growth, proliferation and organ development. The transcriptional enhanced associate domain (TEAD) protein family consists of four paralogous transcription factors that function to modulate gene expression in response to the Hippo signaling pathway. Transcriptional activation of these proteins occurs upon binding to the co-activator YAP/TAZ whose entry into the nucleus is regulated by Lats1/2 kinase. In recent years, it has become apparent that the dysregulation and/or overexpression of Hippo pathway effectors is implicated in a wide range of cancers, including prostate, gastric and liver cancer. A large body of work has been dedicated to understanding the therapeutic potential of modulating the phosphorylation and localization of YAP/TAZ. However, YAP/TAZ are considered to be natively unfolded and may be intractable as drug targets. Therefore, TEAD proteins present themselves as an excellent therapeutic target for intervention of the Hippo pathway. This review summarizes the functional role of TEAD proteins in cancer and assesses the therapeutic potential of antagonizing TEAD function in vivo. Full article

(This article belongs to the Special Issue Hippo Pathway in Cancer, towards Realization of the Hippo-Targeted Therapy)

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29 pages, 1260 KB

Open AccessEditor’s ChoiceReview

The Complex Interplay between Chronic Inflammation, the Microbiome, and Cancer: Understanding Disease Progression and What We Can Do to Prevent It

by Heather Armstrong, Michael Bording-Jorgensen, Stephanie Dijk and Eytan Wine

Cancers 2018, 10(3), 83; https://doi.org/10.3390/cancers10030083 - 20 Mar 2018

Cited by 89 | Viewed by 18503

Abstract

Cancer is a multifaceted condition, in which a senescent cell begins dividing in an irregular manner due to various factors such as DNA damage, growth factors and inflammation. Inflammation is not typically discussed as carcinogenic; however, a significant percentage of cancers arise from [...] Read more.

Cancer is a multifaceted condition, in which a senescent cell begins dividing in an irregular manner due to various factors such as DNA damage, growth factors and inflammation. Inflammation is not typically discussed as carcinogenic; however, a significant percentage of cancers arise from chronic microbial infections and damage brought on by chronic inflammation. A hallmark cancer-inducing microbe is Helicobacter pylori and its causation of peptic ulcers and potentially gastric cancer. This review discusses the recent developments in understanding microbes in health and disease and their potential role in the progression of cancer. To date, microbes can be linked to almost every cancer, including colon, pancreatic, gastric, and even prostate. We discuss the known mechanisms by which these microbes can induce cancer growth and development and how inflammatory cells may contribute to cancer progression. We also discuss new treatments that target the chronic inflammatory conditions and their associated cancers, and the impact microbes have on treatment success. Finally, we examine common dietary misconceptions in relation to microbes and cancer and how to avoid getting caught up in the misinterpretation and over inflation of the results. Full article

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

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22 pages, 919 KB

Open AccessFeature PaperEditor’s ChoiceReview

Aptamer Therapeutics in Cancer: Current and Future

by Yoshihiro Morita, Macall Leslie, Hiroyasu Kameyama, David E. Volk and Takemi Tanaka

Cancers 2018, 10(3), 80; https://doi.org/10.3390/cancers10030080 - 19 Mar 2018

Cited by 186 | Viewed by 13398

Abstract

Aptamer-related technologies represent a revolutionary advancement in the capacity to rapidly develop new classes of targeting ligands. Structurally distinct RNA and DNA oligonucleotides, aptamers mimic small, protein-binding molecules and exhibit high binding affinity and selectivity. Although their molecular weight is relatively small—approximately one-tenth [...] Read more.

Aptamer-related technologies represent a revolutionary advancement in the capacity to rapidly develop new classes of targeting ligands. Structurally distinct RNA and DNA oligonucleotides, aptamers mimic small, protein-binding molecules and exhibit high binding affinity and selectivity. Although their molecular weight is relatively small—approximately one-tenth that of monoclonal antibodies—their complex tertiary folded structures create sufficient recognition surface area for tight interaction with target molecules. Additionally, unlike antibodies, aptamers can be readily chemically synthesized and modified. In addition, aptamers’ long storage period and low immunogenicity are favorable properties for clinical utility. Due to their flexibility of chemical modification, aptamers are conjugated to other chemical entities including chemotherapeutic agents, siRNA, nanoparticles, and solid phase surfaces for therapeutic and diagnostic applications. However, as relatively small sized oligonucleotides, aptamers present several challenges for successful clinical translation. Their short plasma half-lives due to nuclease degradation and rapid renal excretion necessitate further structural modification of aptamers for clinical application. Since the US Food and Drug Administration (FDA) approval of the first aptamer drug, Macugen^® (pegaptanib), which treats wet-age-related macular degeneration, several aptamer therapeutics for oncology have followed and shown promise in pre-clinical models as well as clinical trials. This review discusses the advantages and challenges of aptamers and introduces therapeutic aptamers under investigation and in clinical trials for cancer treatments. Full article

(This article belongs to the Special Issue Aptamers: Promising Tools for Cancer Diagnosis and Therapy)

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33 pages, 1685 KB

Open AccessEditor’s ChoiceReview

New Insights into Protein Kinase B/Akt Signaling: Role of Localized Akt Activation and Compartment-Specific Target Proteins for the Cellular Radiation Response

by Klaudia Szymonowicz, Sebastian Oeck, Nathalie M. Malewicz and Verena Jendrossek

Cancers 2018, 10(3), 78; https://doi.org/10.3390/cancers10030078 - 18 Mar 2018

Cited by 99 | Viewed by 16037

Abstract

Genetic alterations driving aberrant activation of the survival kinase Protein Kinase B (Akt) are observed with high frequency during malignant transformation and cancer progression. Oncogenic gene mutations coding for the upstream regulators or Akt, e.g., growth factor receptors, RAS and phosphatidylinositol-3-kinase (PI3K), or [...] Read more.

Genetic alterations driving aberrant activation of the survival kinase Protein Kinase B (Akt) are observed with high frequency during malignant transformation and cancer progression. Oncogenic gene mutations coding for the upstream regulators or Akt, e.g., growth factor receptors, RAS and phosphatidylinositol-3-kinase (PI3K), or for one of the three Akt isoforms as well as loss of the tumor suppressor Phosphatase and Tensin Homolog on Chromosome Ten (PTEN) lead to constitutive activation of Akt. By activating Akt, these genetic alterations not only promote growth, proliferation and malignant behavior of cancer cells by phosphorylation of various downstream signaling molecules and signaling nodes but can also contribute to chemo- and radioresistance in many types of tumors. Here we review current knowledge on the mechanisms dictating Akt’s activation and target selection including the involvement of miRNAs and with focus on compartmentalization of the signaling network. Moreover, we discuss recent advances in the cross-talk with DNA damage response highlighting nuclear Akt target proteins with potential involvement in the regulation of DNA double strand break repair. Full article

(This article belongs to the Special Issue Advances in the biological responses to radiation-induced DNA damage: A selection of papers from the Joint 43rd European Radiation Research Society (ERRS) and 20th German Society for Biological Radiation Research (GBS) Annual Meetings)

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25 pages, 834 KB

Open AccessFeature PaperEditor’s ChoiceReview

Coming of Age for Autotaxin and Lysophosphatidate Signaling: Clinical Applications for Preventing, Detecting and Targeting Tumor-Promoting Inflammation

by Matthew G.K. Benesch, Iain T.K. MacIntyre, Todd P.W. McMullen and David N. Brindley

Cancers 2018, 10(3), 73; https://doi.org/10.3390/cancers10030073 - 15 Mar 2018

Cited by 63 | Viewed by 7660

Abstract

A quarter-century after the discovery of autotaxin in cell culture, the autotaxin-lysophosphatidate (LPA)-lipid phosphate phosphatase axis is now a promising clinical target for treating chronic inflammatory conditions, mitigating fibrosis progression, and improving the efficacy of existing cancer chemotherapies and radiotherapy. Nearly half of [...] Read more.

A quarter-century after the discovery of autotaxin in cell culture, the autotaxin-lysophosphatidate (LPA)-lipid phosphate phosphatase axis is now a promising clinical target for treating chronic inflammatory conditions, mitigating fibrosis progression, and improving the efficacy of existing cancer chemotherapies and radiotherapy. Nearly half of the literature on this axis has been published during the last five years. In cancer biology, LPA signaling is increasingly being recognized as a central mediator of the progression of chronic inflammation in the establishment of a tumor microenvironment which promotes cancer growth, immune evasion, metastasis, and treatment resistance. In this review, we will summarize recent advances made in understanding LPA signaling with respect to chronic inflammation and cancer. We will also provide perspectives on the applications of inhibitors of LPA signaling in preventing cancer initiation, as adjuncts extending the efficacy of current cancer treatments by blocking inflammation caused by either the cancer or the cancer therapy itself, and by disruption of the tumor microenvironment. Overall, LPA, a simple molecule that mediates a plethora of biological effects, can be targeted at its levels of production by autotaxin, LPA receptors or through LPA degradation by lipid phosphate phosphatases. Drugs for these applications will soon be entering clinical practice. Full article

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

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15 pages, 8021 KB

Open AccessFeature PaperEditor’s ChoiceReview

Update on Immunohistochemistry for the Diagnosis of Lung Cancer

by Kentaro Inamura

Cancers 2018, 10(3), 72; https://doi.org/10.3390/cancers10030072 - 14 Mar 2018

Cited by 109 | Viewed by 19124

Abstract

Immunohistochemistry is a widely available technique that is less challenging and can provide clinically meaningful results quickly and cost-efficiently in comparison with other techniques. In addition, immunohistochemistry allows for the evaluation of cellular localization of proteins in the context of tumor structure. In [...] Read more.

Immunohistochemistry is a widely available technique that is less challenging and can provide clinically meaningful results quickly and cost-efficiently in comparison with other techniques. In addition, immunohistochemistry allows for the evaluation of cellular localization of proteins in the context of tumor structure. In an era of precision medicine, pathologists are required to classify lung cancer into specific subtypes and assess biomarkers relevant to molecular-targeted therapies. This review summarizes the hot topics of immunohistochemistry in lung cancer, including (i) adenocarcinoma vs squamous cell carcinoma; (ii) neuroendocrine markers; (iii) ALK, ROS1, and EGFR; (iv) PD-L1 (CD274); (v) lung carcinoma vs malignant mesothelioma; and (vi) NUT carcinoma. Major pitfalls in evaluating immunohistochemical results are also described. Full article

(This article belongs to the Special Issue Immunohistochemistry and Cancer Diagnosis)

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22 pages, 1615 KB

Open AccessFeature PaperEditor’s ChoiceReview

Evolution of Carbon Ion Radiotherapy at the National Institute of Radiological Sciences in Japan

by Osama Mohamad, Hirokazu Makishima and Tadashi Kamada

Cancers 2018, 10(3), 66; https://doi.org/10.3390/cancers10030066 - 6 Mar 2018

Cited by 71 | Viewed by 11250

Abstract

Charged particles can achieve better dose distribution and higher biological effectiveness compared to photon radiotherapy. Carbon ions are considered an optimal candidate for cancer treatment using particles. The National Institute of Radiological Sciences (NIRS) in Chiba, Japan was the first radiotherapy hospital dedicated [...] Read more.

Charged particles can achieve better dose distribution and higher biological effectiveness compared to photon radiotherapy. Carbon ions are considered an optimal candidate for cancer treatment using particles. The National Institute of Radiological Sciences (NIRS) in Chiba, Japan was the first radiotherapy hospital dedicated for carbon ion treatments in the world. Since its establishment in 1994, the NIRS has pioneered this therapy with more than 69 clinical trials so far, and hundreds of ancillary projects in physics and radiobiology. In this review, we will discuss the evolution of carbon ion radiotherapy at the NIRS and some of the current and future projects in the field. Full article

(This article belongs to the Special Issue Proton and Carbon Ion Therapy)

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30 pages, 1702 KB

Open AccessEditor’s ChoiceReview

Tumor Resistance against ALK Targeted Therapy-Where It Comes From and Where It Goes

by Geeta Geeta Sharma, Ines Mota, Luca Mologni, Enrico Patrucco, Carlo Gambacorti-Passerini and Roberto Chiarle

Cancers 2018, 10(3), 62; https://doi.org/10.3390/cancers10030062 - 28 Feb 2018

Cited by 87 | Viewed by 10828

Abstract

Anaplastic lymphoma kinase (ALK) is a validated molecular target in several ALK-rearranged malignancies, particularly in non-small-cell lung cancer (NSCLC), which has generated considerable interest and effort in developing ALK tyrosine kinase inhibitors (TKI). Crizotinib was the first ALK inhibitor to receive FDA approval [...] Read more.

Anaplastic lymphoma kinase (ALK) is a validated molecular target in several ALK-rearranged malignancies, particularly in non-small-cell lung cancer (NSCLC), which has generated considerable interest and effort in developing ALK tyrosine kinase inhibitors (TKI). Crizotinib was the first ALK inhibitor to receive FDA approval for ALK-positive NSCLC patients treatment. However, the clinical benefit observed in targeting ALK in NSCLC is almost universally limited by the emergence of drug resistance with a median of occurrence of approximately 10 months after the initiation of therapy. Thus, to overcome crizotinib resistance, second/third-generation ALK inhibitors have been developed and received, or are close to receiving, FDA approval. However, even when treated with these new inhibitors tumors became resistant, both in vitro and in clinical settings. The elucidation of the diverse mechanisms through which resistance to ALK TKI emerges, has informed the design of novel therapeutic strategies to improve patients disease outcome. This review summarizes the currently available knowledge regarding ALK physiologic function/structure and neoplastic transforming role, as well as an update on ALK inhibitors and resistance mechanisms along with possible therapeutic strategies that may overcome the development of resistance. Full article

(This article belongs to the Special Issue Advances in Our Understanding of ALK-Related Cancers: A Selection of Papers from the Joint Annual Meeting of the European Research Initiative for ALK-Related Malignancies (ERIA) and the European Union Marie Curie European Training Network ALKATRAS)

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25 pages, 1087 KB

Open AccessEditor’s ChoiceReview

Post-Translational Modifications of H2A Histone Variants and Their Role in Cancer

by David Corujo and Marcus Buschbeck

Cancers 2018, 10(3), 59; https://doi.org/10.3390/cancers10030059 - 27 Feb 2018

Cited by 74 | Viewed by 12185

Abstract

Histone variants are chromatin components that replace replication-coupled histones in a fraction of nucleosomes and confer particular characteristics to chromatin. H2A variants represent the most numerous and diverse group among histone protein families. In the nucleosomal structure, H2A-H2B dimers can be removed and [...] Read more.

Histone variants are chromatin components that replace replication-coupled histones in a fraction of nucleosomes and confer particular characteristics to chromatin. H2A variants represent the most numerous and diverse group among histone protein families. In the nucleosomal structure, H2A-H2B dimers can be removed and exchanged more easily than the stable H3-H4 core. The unstructured N-terminal histone tails of all histones, but also the C-terminal tails of H2A histones protrude out of the compact structure of the nucleosome core. These accessible tails are the preferential target sites for a large number of post-translational modifications (PTMs). While some PTMs are shared between replication-coupled H2A and H2A variants, many modifications are limited to a specific histone variant. The present review focuses on the H2A variants H2A.Z, H2A.X, and macroH2A, and summarizes their functions in chromatin and how these are linked to cancer development and progression. H2A.Z primarily acts as an oncogene and macroH2A and H2A.X as tumour suppressors. We further focus on the regulation by PTMs, which helps to understand a degree of context dependency. Full article

(This article belongs to the Collection Histone Modification in Cancer)

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9 pages, 226 KB

Open AccessEditor’s ChoiceReview

Early Diagnosis to Improve the Poor Prognosis of Pancreatic Cancer

by Masataka Kikuyama, Terumi Kamisawa, Sawako Kuruma, Kazuro Chiba, Shinya Kawaguchi, Shuzo Terada and Tatsunori Satoh

Cancers 2018, 10(2), 48; https://doi.org/10.3390/cancers10020048 - 11 Feb 2018

Cited by 59 | Viewed by 7929

Abstract

Pancreatic cancer (PC) has a poor prognosis due to delayed diagnosis. Early diagnosis is the most important factor for improving prognosis. For early diagnosis of PC, patients with clinical manifestations suggestive of PC and high risk for developing PC need to be selected [...] Read more.

Pancreatic cancer (PC) has a poor prognosis due to delayed diagnosis. Early diagnosis is the most important factor for improving prognosis. For early diagnosis of PC, patients with clinical manifestations suggestive of PC and high risk for developing PC need to be selected for examinations for PC. Signs suggestive of PC (e.g., symptoms, diabetes mellitus, acute pancreatitis, or abnormal results of blood examinations) should not be missed, and the details of risks for PC (e.g., familial history of PC, intraductal mucin producing neoplasm, chronic pancreatitis, hereditary pancreatitis, or life habit) should be understood. Multidetector computed tomography (MDCT) and magnetic resonance imaging (MRI) can be performed for diagnosing PC, but the diagnostic ability of these examinations for PC is limited. Endoscopic diagnostic procedures, such as endoscopic ultrasonography, including fine-needle aspiration, and endoscopic retrograde pancreatocholangiography, including Serial Pancreatic-juice Aspiration Cytologic Examination (SPACE), could be recommended for a detailed examination to diagnose pancreatic carcinoma earlier. Full article

(This article belongs to the Special Issue Latest Development in Pancreatic Cancer)

18 pages, 6315 KB

Open AccessFeature PaperEditor’s ChoiceReview

Bioapplications of Cell-SELEX-Generated Aptamers in Cancer Diagnostics, Therapeutics, Theranostics and Biomarker Discovery: A Comprehensive Review

by Xuehui Pang, Cheng Cui, Shuo Wan, Ying Jiang, Liangliang Zhang, Lian Xia, Long Li, Xiaowei Li and Weihong Tan

Cancers 2018, 10(2), 47; https://doi.org/10.3390/cancers10020047 - 9 Feb 2018

Cited by 95 | Viewed by 10830

Abstract

Currently, functional single-stranded oligonucleotide probes, termed aptamers, generated by an iterative technology, Systematic Evolution of Ligands by Exponential Enrichment (SELEX), are utilized to selectively target molecules or cells with high affinity. Aptamers hold considerable promise as multifunctional molecules or conjugates for challenging nanotechnologies [...] Read more.

Currently, functional single-stranded oligonucleotide probes, termed aptamers, generated by an iterative technology, Systematic Evolution of Ligands by Exponential Enrichment (SELEX), are utilized to selectively target molecules or cells with high affinity. Aptamers hold considerable promise as multifunctional molecules or conjugates for challenging nanotechnologies or bioapplications now and in the future. In this review, we first describe recent endeavors to select aptamers towards live cancer cells via cell-SELEX. We then introduce several characteristic applications of selected aptamers, especially in imaging, drug delivery and therapy. In part, these advances have been made possible via synthesis of aptamer-based nanomaterials, which, by their sizes, shapes, and physicochemical properties, allow such aptamer-nanomaterial complexes to function as signal reporters or drug carriers. We also describe how these aptamer-based molecular tools contribute to cancer biomarker discovery through high-affinity recognition of membrane protein receptors. Full article

(This article belongs to the Special Issue Aptamers: Promising Tools for Cancer Diagnosis and Therapy)

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20 pages, 4161 KB

Open AccessEditor’s ChoiceReview

Linking Extracellular Matrix Agrin to the Hippo Pathway in Liver Cancer and Beyond

by Sayan Chakraborty and Wanjin Hong

Cancers 2018, 10(2), 45; https://doi.org/10.3390/cancers10020045 - 6 Feb 2018

Cited by 51 | Viewed by 10963

Abstract

In addition to the structural and scaffolding role, the extracellular matrix (ECM) is emerging as a hub for biomechanical signal transduction that is frequently relayed to intracellular sensors to regulate diverse cellular processes. At a macroscopic scale, matrix rigidity confers long-ranging effects contributing [...] Read more.

In addition to the structural and scaffolding role, the extracellular matrix (ECM) is emerging as a hub for biomechanical signal transduction that is frequently relayed to intracellular sensors to regulate diverse cellular processes. At a macroscopic scale, matrix rigidity confers long-ranging effects contributing towards tissue fibrosis and cancer. The transcriptional co-activators YAP/TAZ, better known as the converging effectors of the Hippo pathway, are widely recognized for their new role as nuclear mechanosensors during organ homeostasis and cancer. Still, how YAP/TAZ senses these “stiffness cues” from the ECM remains enigmatic. Here, we highlight the recent perspectives on the role of agrin in mechanosignaling from the ECM via antagonizing the Hippo pathway to activate YAP/TAZ in the contexts of cancer, neuromuscular junctions, and cardiac regeneration. Full article

(This article belongs to the Special Issue Hippo Pathway in Cancer, towards Realization of the Hippo-Targeted Therapy)

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11 pages, 1546 KB

Open AccessEditor’s ChoiceArticle

Elevated Polyamines in Saliva of Pancreatic Cancer

by Yasutsugu Asai, Takao Itoi, Masahiro Sugimoto, Atsushi Sofuni, Takayoshi Tsuchiya, Reina Tanaka, Ryosuke Tonozuka, Mitsuyoshi Honjo, Shuntaro Mukai, Mitsuru Fujita, Kenjiro Yamamoto, Yukitoshi Matsunami, Takashi Kurosawa, Yuichi Nagakawa, Miku Kaneko, Sana Ota, Shigeyuki Kawachi, Motohide Shimazu, Tomoyoshi Soga, Masaru Tomita and Makoto Sunamura Show full author list Hide full author list

Cancers 2018, 10(2), 43; https://doi.org/10.3390/cancers10020043 - 5 Feb 2018

Cited by 78 | Viewed by 8618

Abstract

Detection of pancreatic cancer (PC) at a resectable stage is still difficult because of the lack of accurate detection tests. The development of accurate biomarkers in low or non-invasive biofluids is essential to enable frequent tests, which would help increase the opportunity of [...] Read more.

Detection of pancreatic cancer (PC) at a resectable stage is still difficult because of the lack of accurate detection tests. The development of accurate biomarkers in low or non-invasive biofluids is essential to enable frequent tests, which would help increase the opportunity of PC detection in early stages. Polyamines have been reported as possible biomarkers in urine and saliva samples in various cancers. Here, we analyzed salivary metabolites, including polyamines, using capillary electrophoresis-mass spectrometry. Salivary samples were collected from patients with PC (n = 39), those with chronic pancreatitis (CP, n = 14), and controls (C, n = 26). Polyamines, such as spermine, N₁-acetylspermidine, and N₁-acetylspermine, showed a significant difference between patients with PC and those with C, and the combination of four metabolites including N₁-acetylspermidine showed high accuracy in discriminating PC from the other two groups. These data show the potential of saliva as a source for tests screening for PC. Full article

(This article belongs to the Special Issue Latest Development in Pancreatic Cancer)

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0 pages, 1556 KB

Open AccessFeature PaperEditor’s ChoiceReview

Colorectal Cancer and Alcohol Consumption—Populations to Molecules

by Marco Rossi, Muhammad Jahanzaib Anwar, Ahmad Usman, Ali Keshavarzian and Faraz Bishehsari

Cancers 2018, 10(2), 38; https://doi.org/10.3390/cancers10020038 - 30 Jan 2018

Cited by 143 | Viewed by 19507

Abstract

Colorectal cancer (CRC) is a major cause of morbidity and mortality, being the third most common cancer diagnosed in both men and women in the world. Several environmental and habitual factors have been associated with the CRC risk. Alcohol intake, a common and [...] Read more.

Colorectal cancer (CRC) is a major cause of morbidity and mortality, being the third most common cancer diagnosed in both men and women in the world. Several environmental and habitual factors have been associated with the CRC risk. Alcohol intake, a common and rising habit of modern society, is one of the major risk factors for development of CRC. Here, we will summarize the evidence linking alcohol with colon carcinogenesis and possible underlying mechanisms. Some epidemiologic studies suggest that even moderate drinking increases the CRC risk. Metabolism of alcohol involves ethanol conversion to its metabolites that could exert carcinogenic effects in the colon. Production of ethanol metabolites can be affected by the colon microbiota, another recently recognized mediating factor to colon carcinogenesis. The generation of acetaldehyde and alcohol’s other metabolites leads to activation of cancer promoting cascades, such as DNA-adduct formation, oxidative stress and lipid peroxidation, epigenetic alterations, epithelial barrier dysfunction, and immune modulatory effects. Not only does alcohol induce its toxic effect through carcinogenic metabolites, but alcoholics themselves are predisposed to a poor diet, low in folate and fiber, and circadian disruption, which could further augment alcohol-induced colon carcinogenesis. Full article

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

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15 pages, 1244 KB

Open AccessEditor’s ChoiceReview

Precision Immuno-Oncology: Prospects of Individualized Immunotherapy for Pancreatic Cancer

by Jiajia Zhang, Christopher L. Wolfgang and Lei Zheng

Cancers 2018, 10(2), 39; https://doi.org/10.3390/cancers10020039 - 30 Jan 2018

Cited by 47 | Viewed by 10371

Abstract

Pancreatic cancer, most commonly referring to pancreatic ductal adenocarcinoma (PDAC), remains one of the most deadly diseases, with very few effective therapies available. Emerging as a new modality of modern cancer treatments, immunotherapy has shown promises for various cancer types. Over the past [...] Read more.

Pancreatic cancer, most commonly referring to pancreatic ductal adenocarcinoma (PDAC), remains one of the most deadly diseases, with very few effective therapies available. Emerging as a new modality of modern cancer treatments, immunotherapy has shown promises for various cancer types. Over the past decades, the potential of immunotherapy in eliciting clinical benefits in pancreatic cancer have also been extensively explored. It has been demonstrated in preclinical studies and early phase clinical trials that cancer vaccines were effective in eliciting anti-tumor immune response, but few have led to a significant improvement in survival. Despite the fact that immunotherapy with checkpoint blockade (e.g., anti-cytotoxic T-lymphocyte antigen 4 [CTLA-4] and anti-programmed cell death 1 [PD-1]/PD-L1 antibodies) has shown remarkable and durable responses in various cancer types, the application of checkpoint inhibitors in pancreatic cancer has been disappointing so far. It may, in part, due to the unique tumor microenvironment (TME) of pancreatic cancer, such as existence of excessive stromal matrix and hypovascularity, creating a TME of strong inhibitory signaling circuits and tremendous physical barriers for immune agent infiltration. This informs on the need for combination therapy approaches to engender a potent immune response that can translate to clinical benefits. On the other hand, lack of effective and validated biomarkers to stratify subgroup of patients who can benefit from immunotherapy poses further challenges for the realization of precision immune-oncology. Future studies addressing issues such as TME modulation, biomarker identification and therapeutic combination are warranted. In this review, advances in immunotherapy for pancreatic cancer were discussed and opportunities as well as challenges for personalized immune-oncology were addressed. Full article

(This article belongs to the Special Issue Latest Development in Pancreatic Cancer)

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14 pages, 678 KB

Open AccessFeature PaperEditor’s ChoiceReview

Targeted Therapies for Pancreatic Cancer

by Idoroenyi Amanam and Vincent Chung

Cancers 2018, 10(2), 36; https://doi.org/10.3390/cancers10020036 - 29 Jan 2018

Cited by 64 | Viewed by 9159

Abstract

Pancreatic cancer is the third leading cause of cancer related death and by 2030, it will be second only to lung cancer. We have seen tremendous advances in therapies for lung cancer as well as other solid tumors using a molecular targeted approach [...] Read more.

Pancreatic cancer is the third leading cause of cancer related death and by 2030, it will be second only to lung cancer. We have seen tremendous advances in therapies for lung cancer as well as other solid tumors using a molecular targeted approach but our progress in treating pancreatic cancer has been incremental with median overall survival remaining less than one year. There is an urgent need for improved therapies with better efficacy and less toxicity. Small molecule inhibitors, monoclonal antibodies and immune modulatory therapies have been used. Here we review the progress that we have made with these targeted therapies. Full article

(This article belongs to the Special Issue Latest Development in Pancreatic Cancer)

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26 pages, 5196 KB

Open AccessEditor’s ChoiceReview

The Ever-Evolving Concept of the Cancer Stem Cell in Pancreatic Cancer

by Sandra Valle, Laura Martin-Hijano, Sonia Alcalá, Marta Alonso-Nocelo and Bruno Sainz Jr.

Cancers 2018, 10(2), 33; https://doi.org/10.3390/cancers10020033 - 26 Jan 2018

Cited by 89 | Viewed by 13400

Abstract

Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is the 4th most frequent cause of cancer-related death worldwide, primarily due to the inherent chemoresistant nature and metastatic capacity of this tumor. The latter is believed to be mainly due to [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is the 4th most frequent cause of cancer-related death worldwide, primarily due to the inherent chemoresistant nature and metastatic capacity of this tumor. The latter is believed to be mainly due to the existence of a subpopulation of highly plastic “stem”-like cells within the tumor, known as cancer stem cells (CSCs), which have been shown to have unique metabolic, autophagic, invasive, and chemoresistance properties that allow them to continuously self-renew and escape chemo-therapeutic elimination. As such, current treatments for the majority of PDAC patients are not effective and do not significantly impact overall patient survival (<7 months) as they do not affect the pancreatic CSC (PaCSC) population. In this context, it is important to highlight the need to better understand the characteristics of the PaCSC population in order to develop new therapies to target these cells. In this review, we will provide the latest updates and knowledge on the inherent characteristics of PaCSCs, particularly their unique biological properties including chemoresistance, epithelial to mesenchymal transition, plasticity, metabolism and autophagy. Full article

(This article belongs to the Special Issue Latest Development in Pancreatic Cancer)

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17 pages, 505 KB

Open AccessEditor’s ChoiceReview

Tackling Cancer Resistance by Immunotherapy: Updated Clinical Impact and Safety of PD-1/PD-L1 Inhibitors

by Shifaa M. Abdin, Dana M. Zaher, El-Shaimaa A. Arafa and Hany A. Omar

Cancers 2018, 10(2), 32; https://doi.org/10.3390/cancers10020032 - 25 Jan 2018

Cited by 57 | Viewed by 15712

Abstract

Cancer therapy has been constantly evolving with the hope of finding the most effective agents with the least toxic effects to eradicate tumors. Cancer immunotherapy is currently among the most promising options, fulfilling this hope in a wide range of tumors. Immunotherapy aims [...] Read more.

Cancer therapy has been constantly evolving with the hope of finding the most effective agents with the least toxic effects to eradicate tumors. Cancer immunotherapy is currently among the most promising options, fulfilling this hope in a wide range of tumors. Immunotherapy aims to activate immunity to fight cancer in a very specific and targeted manner; however, some abnormal immune reactions known as immune-related adverse events (IRAEs) might occur. Therefore, many researchers are aiming to define the most proper protocols for managing these complications without interfering with the anticancer effect. One of these targeted approaches is the inhibition of the interaction between the checkpoint protein, programmed death-receptor 1 (PD-1), and its ligand, programmed death-ligand 1 (PD-L1), via a class of antibodies known as PD-1/PD-L1 inhibitors. These antibodies achieved prodigious success in a wide range of malignancies, including those where optimal treatment is not yet fully identified. In this review, we have critically explored and discussed the outcome of the latest PD-1 and PD-L1 inhibitor studies in different malignancies compared to standard chemotherapeutic alternatives with a special focus on the clinical efficacy and safety. The approval of the clinical applications of nivolumab, pembrolizumab, atezolizumab, avelumab, and durvalumab in the last few years clearly highlights the hopeful future of PD-1/PD-L1 inhibitors for cancer patients. These promising results of PD-1/PD-L1 inhibitors have encouraged many ongoing preclinical and clinical trials to explore the extent of antitumor activity, clinical efficacy and safety as well as to extend their applications. Full article

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15 pages, 2685 KB

Open AccessEditor’s ChoiceReview

Estrogen and Androgen Blockade for Advanced Prostate Cancer in the Era of Precision Medicine

by Tetsuya Fujimura, Kenichi Takayama, Satoru Takahashi and Satoshi Inoue

Cancers 2018, 10(2), 29; https://doi.org/10.3390/cancers10020029 - 23 Jan 2018

Cited by 26 | Viewed by 10897

Abstract

Androgen deprivation therapy (ADT) has been widely prescribed for patients with advanced prostate cancer (PC) to control key signaling pathways via androgen receptor (AR) and AR-collaborative transcriptional factors; however, PC gradually acquires a lethal phenotype and results in castration-resistant PC (CRPC) during ADT. [...] Read more.

Androgen deprivation therapy (ADT) has been widely prescribed for patients with advanced prostate cancer (PC) to control key signaling pathways via androgen receptor (AR) and AR-collaborative transcriptional factors; however, PC gradually acquires a lethal phenotype and results in castration-resistant PC (CRPC) during ADT. Therefore, new therapeutic strategies are required in clinical practice. In addition, ARs; estrogen receptors (ERs; ERα and ERβ); and estrogen-related receptors (ERRs; ERRα, ERRβ, and ERRγ) have been reported to be involved in the development or regulation of PC. Recent investigations have revealed the role of associated molecules, such as KLF5, FOXO1, PDGFA, VEGF-A, WNT5A, TGFβ1, and micro-RNA 135a of PC, via ERs and ERRs. Selective ER modulators (SERMs) have been developed. Recently, estrogen and androgen blockade (EAB) using a combination of toremifene and ADT has been demonstrated to improve biochemical recurrence rate in treatment-naïve bone metastatic PC. In the future, the suitability of ADT alone or EAB for individuals may be evaluated by making clinical decisions on the basis of information obtained from RT-PCR, gene-panel, or liquid biopsy to create a “personalized medicine” or “precision medicine”. In this review, we summarize ER and ERR signaling pathways, molecular diagnosis, and SERMs as candidates for advanced PC treatment. Full article

(This article belongs to the Special Issue Hormone Receptors in Genitourinary Tumors)

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18 pages, 3035 KB

Open AccessEditor’s ChoiceReview

Colorectal Cancers: An Update on Their Molecular Pathology

by Kentaro Inamura

Cancers 2018, 10(1), 26; https://doi.org/10.3390/cancers10010026 - 20 Jan 2018

Cited by 142 | Viewed by 24696

Abstract

Colorectal cancers (CRCs) are the third leading cause of cancer-related mortality worldwide. Rather than being a single, uniform disease type, accumulating evidence suggests that CRCs comprise a group of molecularly heterogeneous diseases that are characterized by a range of genomic and epigenomic alterations. [...] Read more.

Colorectal cancers (CRCs) are the third leading cause of cancer-related mortality worldwide. Rather than being a single, uniform disease type, accumulating evidence suggests that CRCs comprise a group of molecularly heterogeneous diseases that are characterized by a range of genomic and epigenomic alterations. This heterogeneity slows the development of molecular-targeted therapy as a form of precision medicine. Recent data regarding comprehensive molecular characterizations and molecular pathological examinations of CRCs have increased our understanding of the genomic and epigenomic landscapes of CRCs, which has enabled CRCs to be reclassified into biologically and clinically meaningful subtypes. The increased knowledge of the molecular pathological epidemiology of CRCs has permitted their evolution from a vaguely understood, heterogeneous group of diseases with variable clinical courses to characteristic molecular subtypes, a development that will allow the implementation of personalized therapies and better management of patients with CRC. This review provides a perspective regarding recent developments in our knowledge of the molecular and epidemiological landscapes of CRCs, including results of comprehensive molecular characterizations obtained from high-throughput analyses and the latest developments regarding their molecular pathologies, immunological biomarkers, and associated gut microbiome. Advances in our understanding of potential personalized therapies for molecularly specific subtypes are also reviewed. Full article

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15 pages, 254 KB

Open AccessEditor’s ChoiceReview

Contemporary Management of Localized Resectable Pancreatic Cancer

by Anuhya Kommalapati, Sri Harsha Tella, Gaurav Goyal, Wen Wee Ma and Amit Mahipal

Cancers 2018, 10(1), 24; https://doi.org/10.3390/cancers10010024 - 20 Jan 2018

Cited by 75 | Viewed by 6151

Abstract

Pancreatic cancer is the third most common cause of cancer deaths in the United States. Surgical resection with negative margins still constitutes the cornerstone of potentially curative therapy, but is possible only in 15–20% of patients at the time of initial diagnosis. Accumulating [...] Read more.

Pancreatic cancer is the third most common cause of cancer deaths in the United States. Surgical resection with negative margins still constitutes the cornerstone of potentially curative therapy, but is possible only in 15–20% of patients at the time of initial diagnosis. Accumulating evidence suggests that the neoadjuvant approach may improve R0 resection rate in localized resectable and borderline resectable diseases, and potentially downstage locally advanced disease to achieve surgical resection, though the impact on survival is to be determined. Despite advancements in the last decade in developing effective combinational chemo-radio therapeutic options, preoperative treatment strategies, and better peri-operative care, pancreatic cancer continues to carry a dismal prognosis in the majority. Prodigious efforts are currently being made in optimizing the neoadjuvant therapy with a better toxicity profile, developing novel agents, imaging techniques, and identification of biomarkers for the disease. Advancement in our understanding of the tumor microenvironment and molecular pathology is urgently needed to facilitate the development of novel targeted and immunotherapies for this setting. In this review, we detail the current literature on contemporary management of resectable, borderline resectable and locally advanced pancreatic cancer with a focus on future directions in the field. Full article

(This article belongs to the Special Issue Latest Development in Pancreatic Cancer)

30 pages, 3712 KB

Open AccessEditor’s ChoiceReview

mTOR Cross-Talk in Cancer and Potential for Combination Therapy

by Fabiana Conciatori, Ludovica Ciuffreda, Chiara Bazzichetto, Italia Falcone, Sara Pilotto, Emilio Bria, Francesco Cognetti and Michele Milella

Cancers 2018, 10(1), 23; https://doi.org/10.3390/cancers10010023 - 19 Jan 2018

Cited by 120 | Viewed by 13618

Abstract

The mammalian Target of Rapamycin (mTOR) pathway plays an essential role in sensing and integrating a variety of exogenous cues to regulate cellular growth and metabolism, in both physiological and pathological conditions. mTOR functions through two functionally and structurally distinct multi-component complexes, mTORC1 [...] Read more.

The mammalian Target of Rapamycin (mTOR) pathway plays an essential role in sensing and integrating a variety of exogenous cues to regulate cellular growth and metabolism, in both physiological and pathological conditions. mTOR functions through two functionally and structurally distinct multi-component complexes, mTORC1 and mTORC2, which interact with each other and with several elements of other signaling pathways. In the past few years, many new insights into mTOR function and regulation have been gained and extensive genetic and pharmacological studies in mice have enhanced our understanding of how mTOR dysfunction contributes to several diseases, including cancer. Single-agent mTOR targeting, mostly using rapalogs, has so far met limited clinical success; however, due to the extensive cross-talk between mTOR and other pathways, combined approaches are the most promising avenues to improve clinical efficacy of available therapeutics and overcome drug resistance. This review provides a brief and up-to-date narrative on the regulation of mTOR function, the relative contributions of mTORC1 and mTORC2 complexes to cancer development and progression, and prospects for mTOR inhibition as a therapeutic strategy. Full article

(This article belongs to the Special Issue mTOR Pathway in Cancer)

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27 pages, 959 KB

Open AccessEditor’s ChoiceReview

Alcohol-Derived Acetaldehyde Exposure in the Oral Cavity

by Alessia Stornetta, Valeria Guidolin and Silvia Balbo

Cancers 2018, 10(1), 20; https://doi.org/10.3390/cancers10010020 - 14 Jan 2018

Cited by 79 | Viewed by 16499

Abstract

Alcohol is classified by the International Agency for Research on Cancer (IARC) as a human carcinogen and its consumption has been associated to an increased risk of liver, breast, colorectum, and upper aerodigestive tract (UADT) cancers. Its mechanisms of carcinogenicity remain unclear and [...] Read more.

Alcohol is classified by the International Agency for Research on Cancer (IARC) as a human carcinogen and its consumption has been associated to an increased risk of liver, breast, colorectum, and upper aerodigestive tract (UADT) cancers. Its mechanisms of carcinogenicity remain unclear and various hypotheses have been formulated depending on the target organ considered. In the case of UADT cancers, alcohol’s major metabolite acetaldehyde seems to play a crucial role. Acetaldehyde reacts with DNA inducing modifications, which, if not repaired, can result in mutations and lead to cancer development. Despite alcohol being mainly metabolized in the liver, several studies performed in humans found higher levels of acetaldehyde in saliva compared to those found in blood immediately after alcohol consumption. These results suggest that alcohol-derived acetaldehyde exposure may occur in the oral cavity independently from liver metabolism. This hypothesis is supported by our recent results showing the presence of acetaldehyde-related DNA modifications in oral cells of monkeys and humans exposed to alcohol, overall suggesting that the alcohol metabolism in the oral cavity is an independent cancer risk factor. This review article will focus on illustrating the factors modulating alcohol-derived acetaldehyde exposure and effects in the oral cavity. Full article

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

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15 pages, 645 KB

Open AccessEditor’s ChoiceReview

mTOR Pathways in Cancer and Autophagy

by Mathieu Paquette, Leeanna El-Houjeiri and Arnim Pause

Cancers 2018, 10(1), 18; https://doi.org/10.3390/cancers10010018 - 12 Jan 2018

Cited by 257 | Viewed by 26497

Abstract

TOR (target of rapamycin), an evolutionarily-conserved serine/threonine kinase, acts as a central regulator of cell growth, proliferation and survival in response to nutritional status, growth factor, and stress signals. It plays a crucial role in coordinating the balance between cell growth and cell [...] Read more.

TOR (target of rapamycin), an evolutionarily-conserved serine/threonine kinase, acts as a central regulator of cell growth, proliferation and survival in response to nutritional status, growth factor, and stress signals. It plays a crucial role in coordinating the balance between cell growth and cell death, depending on cellular conditions and needs. As such, TOR has been identified as a key modulator of autophagy for more than a decade, and several deregulations of this pathway have been implicated in a variety of pathological disorders, including cancer. At the molecular level, autophagy regulates several survival or death signaling pathways that may decide the fate of cancer cells; however, the relationship between autophagy pathways and cancer are still nascent. In this review, we discuss the recent cellular signaling pathways regulated by TOR, their interconnections to autophagy, and the clinical implications of TOR inhibitors in cancer. Full article

(This article belongs to the Special Issue mTOR Pathway in Cancer)

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17 pages, 1624 KB

Open AccessEditor’s ChoiceReview

Oncogenic Signalling through Mechanistic Target of Rapamycin (mTOR): A Driver of Metabolic Transformation and Cancer Progression

by Ellie Rad, James T. Murray and Andrew R. Tee

Cancers 2018, 10(1), 5; https://doi.org/10.3390/cancers10010005 - 3 Jan 2018

Cited by 53 | Viewed by 10641

Abstract

Throughout the years, research into signalling pathways involved in cancer progression has led to many discoveries of which mechanistic target of rapamycin (mTOR) is a key player. mTOR is a master regulator of cell growth control. mTOR is historically known to promote cell [...] Read more.

Throughout the years, research into signalling pathways involved in cancer progression has led to many discoveries of which mechanistic target of rapamycin (mTOR) is a key player. mTOR is a master regulator of cell growth control. mTOR is historically known to promote cell growth by enhancing the efficiency of protein translation. Research in the last decade has revealed that mTOR’s role in promoting cell growth is much more multifaceted. While mTOR is necessary for normal human physiology, cancer cells take advantage of mTOR signalling to drive their neoplastic growth and progression. Oncogenic signal transduction through mTOR is a common occurrence in cancer, leading to metabolic transformation, enhanced proliferative drive and increased metastatic potential through neovascularisation. This review focuses on the downstream mTOR-regulated processes that are implicated in the “hallmarks” of cancer with focus on mTOR’s involvement in proliferative signalling, metabolic reprogramming, angiogenesis and metastasis. Full article

(This article belongs to the Special Issue mTOR Pathway in Cancer)

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13 pages, 432 KB

Open AccessEditor’s ChoiceReview

Modification of Epigenetic Histone Acetylation in Hepatocellular Carcinoma

by Kwei-Yan Liu, Li-Ting Wang and Shih-Hsien Hsu

Cancers 2018, 10(1), 8; https://doi.org/10.3390/cancers10010008 - 3 Jan 2018

Cited by 40 | Viewed by 7429

Abstract

Cells respond to various environmental factors such as nutrients, food intake, and drugs or toxins by undergoing dynamic epigenetic changes. An imbalance in dynamic epigenetic changes is one of the major causes of disease, oncogenic activities, and immunosuppressive effects. The aryl hydrocarbon receptor [...] Read more.

Cells respond to various environmental factors such as nutrients, food intake, and drugs or toxins by undergoing dynamic epigenetic changes. An imbalance in dynamic epigenetic changes is one of the major causes of disease, oncogenic activities, and immunosuppressive effects. The aryl hydrocarbon receptor (AHR) is a unique cellular chemical sensor present in most organs, and its dysregulation has been demonstrated in multiple stages of tumor progression in humans and experimental models; however, the effects of the pathogenic mechanisms of AHR on epigenetic regulation remain unclear. Apart from proto-oncogene activation, epigenetic repressions of tumor suppressor genes are involved in tumor initiation, procession, and metastasis. Reverse epigenetic repression of the tumor suppressor genes by epigenetic enzyme activity inhibition and epigenetic enzyme level manipulation is a potential path for tumor therapy. Current evidence and our recent work on deacetylation of histones on tumor-suppressive genes suggest that histone deacetylase (HDAC) is involved in tumor formation and progression, and treating hepatocellular carcinoma with HDAC inhibitors can, at least partially, repress tumor proliferation and transformation by recusing the expression of tumor-suppressive genes such as TP53 and RB1. Full article

(This article belongs to the Collection Histone Modification in Cancer)

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33 pages, 4543 KB

Open AccessFeature PaperEditor’s ChoiceReview

Current Advances in Aptamers for Cancer Diagnosis and Therapy

by Shin-ichiro Hori, Alberto Herrera, John J. Rossi and Jiehua Zhou

Cancers 2018, 10(1), 9; https://doi.org/10.3390/cancers10010009 - 3 Jan 2018

Cited by 150 | Viewed by 14778

Abstract

Nucleic acid aptamers are single-stranded oligonucleotides that interact with target molecules with high affinity and specificity in unique three-dimensional structures. Aptamers are generally isolated by a simple selection process called systematic evolution of ligands by exponential enrichment (SELEX) and then can be chemically [...] Read more.

Nucleic acid aptamers are single-stranded oligonucleotides that interact with target molecules with high affinity and specificity in unique three-dimensional structures. Aptamers are generally isolated by a simple selection process called systematic evolution of ligands by exponential enrichment (SELEX) and then can be chemically synthesized and modified. Because of their high affinity and specificity, aptamers are promising agents for biomarker discovery, as well as cancer diagnosis and therapy. In this review, we present recent progress and challenges in aptamer and SELEX technology and highlight some representative applications of aptamers in cancer therapy. Full article

(This article belongs to the Special Issue Aptamers: Promising Tools for Cancer Diagnosis and Therapy)

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16 pages, 585 KB

Open AccessEditor’s ChoiceReview

Immune Evasion in Pancreatic Cancer: From Mechanisms to Therapy

by Neus Martinez-Bosch, Judith Vinaixa and Pilar Navarro

Cancers 2018, 10(1), 6; https://doi.org/10.3390/cancers10010006 - 3 Jan 2018

Cited by 168 | Viewed by 13680

Abstract

Pancreatic ductal adenocarcinoma (PDA), the most frequent type of pancreatic cancer, remains one of the most challenging problems for the biomedical and clinical fields, with abysmal survival rates and poor therapy efficiency. Desmoplasia, which is abundant in PDA, can be blamed for much [...] Read more.

Pancreatic ductal adenocarcinoma (PDA), the most frequent type of pancreatic cancer, remains one of the most challenging problems for the biomedical and clinical fields, with abysmal survival rates and poor therapy efficiency. Desmoplasia, which is abundant in PDA, can be blamed for much of the mechanisms behind poor drug performance, as it is the main source of the cytokines and chemokines that orchestrate rapid and silent tumor progression to allow tumor cells to be isolated into an extensive fibrotic reaction, which results in inefficient drug delivery. However, since immunotherapy was proclaimed as the breakthrough of the year in 2013, the focus on the stroma of pancreatic cancer has interestingly moved from activated fibroblasts to the immune compartment, trying to understand the immunosuppressive factors that play a part in the strong immune evasion that characterizes PDA. The PDA microenvironment is highly immunosuppressive and is basically composed of T regulatory cells (Tregs), tumor-associated macrophages (TAMs), and myeloid-derived suppressive cells (MDSCs), which block CD8⁺ T-cell duties in tumor recognition and clearance. Interestingly, preclinical data have highlighted the importance of this immune evasion as the source of resistance to single checkpoint immunotherapies and cancer vaccines and point at pathways that inhibit the immune attack as a key to solve the therapy puzzle. Here, we will discuss the molecular mechanisms involved in PDA immune escape as well as the state of the art of the PDA immunotherapy. Full article

(This article belongs to the Special Issue Latest Development in Pancreatic Cancer)

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