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Editor’s Choice Articles

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

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39 pages, 4806 KiB  
Review
Designer Oncolytic Adenovirus: Coming of Age
by Alexander T. Baker, Carmen Aguirre-Hernández, Gunnel Halldén and Alan L. Parker
Cancers 2018, 10(6), 201; https://doi.org/10.3390/cancers10060201 - 14 Jun 2018
Cited by 65 | Viewed by 12874
Abstract
The licensing of talimogene laherparepvec (T-Vec) represented a landmark moment for oncolytic virotherapy, since it provided unequivocal evidence for the long-touted potential of genetically modified replicating viruses as anti-cancer agents. Whilst T-Vec is promising as a locally delivered virotherapy, especially in combination with [...] Read more.
The licensing of talimogene laherparepvec (T-Vec) represented a landmark moment for oncolytic virotherapy, since it provided unequivocal evidence for the long-touted potential of genetically modified replicating viruses as anti-cancer agents. Whilst T-Vec is promising as a locally delivered virotherapy, especially in combination with immune-checkpoint inhibitors, the quest continues for a virus capable of specific tumour cell killing via systemic administration. One candidate is oncolytic adenovirus (Ad); it’s double stranded DNA genome is easily manipulated and a wide range of strategies and technologies have been employed to empower the vector with improved pharmacokinetics and tumour targeting ability. As well characterised clinical and experimental agents, we have detailed knowledge of adenoviruses’ mechanisms of pathogenicity, supported by detailed virological studies and in vivo interactions. In this review we highlight the strides made in the engineering of bespoke adenoviral vectors to specifically infect, replicate within, and destroy tumour cells. We discuss how mutations in genes regulating adenoviral replication after cell entry can be used to restrict replication to the tumour, and summarise how detailed knowledge of viral capsid interactions enable rational modification to eliminate native tropisms, and simultaneously promote active uptake by cancerous tissues. We argue that these designer-viruses, exploiting the viruses natural mechanisms and regulated at every level of replication, represent the ideal platforms for local overexpression of therapeutic transgenes such as immunomodulatory agents. Where T-Vec has paved the way, Ad-based vectors now follow. The era of designer oncolytic virotherapies looks decidedly as though it will soon become a reality. Full article
(This article belongs to the Special Issue Oncolytic Virotherapy)
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21 pages, 950 KiB  
Review
TGF-β in T Cell Biology: Implications for Cancer Immunotherapy
by Amina Dahmani and Jean-Sébastien Delisle
Cancers 2018, 10(6), 194; https://doi.org/10.3390/cancers10060194 - 11 Jun 2018
Cited by 134 | Viewed by 13081
Abstract
Transforming Growth Factor beta (TGF-β) is a pleiotropic cytokine produced in large amounts within cancer microenvironments that will ultimately promote neoplastic progression, notably by suppressing the host’s T-cell immunosurveillance. This effect is mostly due to the well-known inhibitory effect of TGF-β on T [...] Read more.
Transforming Growth Factor beta (TGF-β) is a pleiotropic cytokine produced in large amounts within cancer microenvironments that will ultimately promote neoplastic progression, notably by suppressing the host’s T-cell immunosurveillance. This effect is mostly due to the well-known inhibitory effect of TGF-β on T cell proliferation, activation, and effector functions. Moreover, TGF-β subverts T cell immunity by favoring regulatory T-cell differentiation, further reinforcing immunosuppression within tumor microenvironments. These findings stimulated the development of many strategies to block TGF-β or its signaling pathways, either as monotherapy or in combination with other therapies, to restore anti-cancer immunity. Paradoxically, recent studies provided evidence that TGF-β can also promote differentiation of certain inflammatory populations of T cells, such as Th17, Th9, and resident-memory T cells (Trm), which have been associated with improved tumor control in several models. Here, we review current advances in our understanding of the many roles of TGF-β in T cell biology in the context of tumor immunity and discuss the possibility to manipulate TGF-β signaling to improve cancer immunotherapy. Full article
(This article belongs to the Special Issue TGF-Beta Signaling in Cancer)
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16 pages, 424 KiB  
Review
Gain-of-Function (GOF) Mutant p53 as Actionable Therapeutic Target
by Ramona Schulz-Heddergott and Ute M. Moll
Cancers 2018, 10(6), 188; https://doi.org/10.3390/cancers10060188 - 7 Jun 2018
Cited by 84 | Viewed by 8726
Abstract
p53 missense mutant alleles are present in nearly 40% of all human tumors. Such mutated alleles generate aberrant proteins that not only lose their tumor-suppressive functions but also frequently act as driver oncogenes, which promote malignant progression, invasion, metastasis, and chemoresistance, leading to [...] Read more.
p53 missense mutant alleles are present in nearly 40% of all human tumors. Such mutated alleles generate aberrant proteins that not only lose their tumor-suppressive functions but also frequently act as driver oncogenes, which promote malignant progression, invasion, metastasis, and chemoresistance, leading to reduced survival in patients and mice. Notably, these oncogenic gain-of-function (GOF) missense mutant p53 proteins (mutp53) are constitutively and tumor-specific stabilised. This stabilisation is one key pre-requisite for their GOF and is largely due to mutp53 protection from the E3 ubiquitin ligases Mdm2 and CHIP by the HSP90/HDAC6 chaperone machinery. Recent mouse models provide convincing evidence that tumors with highly stabilized GOF mutp53 proteins depend on them for growth, maintenance, and metastasis, thus creating exploitable tumor-specific vulnerabilities that markedly increase lifespan if intercepted. This identifies mutp53 as a promising cancer-specific drug target. This review discusses direct mutp53 protein-targeting drug strategies that are currently being developed at various preclinical levels. Full article
(This article belongs to the Special Issue p53 Signaling in Cancers)
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17 pages, 1227 KiB  
Review
Clinico-Pathological Importance of TGF-β/Phospho-Smad Signaling during Human Hepatic Fibrocarcinogenesis
by Katsunori Yoshida, Koichi Matsuzaki, Miki Murata, Takashi Yamaguchi, Kanehiko Suwa and Kazuichi Okazaki
Cancers 2018, 10(6), 183; https://doi.org/10.3390/cancers10060183 - 5 Jun 2018
Cited by 63 | Viewed by 8260
Abstract
Chronic viral hepatitis is a global public health problem, with approximately 570 million persons chronically infected. Hepatitis B and C viruses increase the risk of morbidity and mortality from liver cirrhosis, hepatocellular carcinoma (HCC), and extrahepatic complications that develop. Hepatitis virus infection induces [...] Read more.
Chronic viral hepatitis is a global public health problem, with approximately 570 million persons chronically infected. Hepatitis B and C viruses increase the risk of morbidity and mortality from liver cirrhosis, hepatocellular carcinoma (HCC), and extrahepatic complications that develop. Hepatitis virus infection induces transforming growth factor (TGF)-β, which influences microenvironments within the infected liver. TGF-β promotes liver fibrosis by up-regulating extracellular matrix production by hepatic stellate cells. TGF-β is also up-regulated in patients with HCC, in whom it contributes importantly to bringing about a favorable microenvironment for tumor growth. Thus, TGF-β is thought to be a major factor regulating liver fibrosis and carcinogenesis. Since TGF-β carries out regulatory signaling by influencing the phosphorylation of Smads, we have generated several kinds of phospho-specific antibodies to Smad2/3. Using these, we have identified three types of phospohorylated forms: COOH-terminally phosphorylated Smad2/3 (pSmad2C and pSmad3C), linker phosphorylated Smad2/3 (pSmad2L and pSmad3L), and dually phosphorylated Smad3 (pSmad2L/C and pSmad3L/C). TGF-β-mediated pSmad2/3C signaling terminates cell proliferation; on the other hand, cytokine-induced pSmad3L signaling accelerates cell proliferation and promotes fibrogenesis. This review addresses TGF-β/Smad signal transduction in chronic liver injuries and carcinogenic processes. We also discuss the reversibility of Smad signaling after antiviral therapy. Full article
(This article belongs to the Special Issue TGF-Beta Signaling in Cancer)
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14 pages, 1308 KiB  
Review
Cutting to the Chase: How Matrix Metalloproteinase-2 Activity Controls Breast-Cancer-to-Bone Metastasis
by Marilena Tauro and Conor C. Lynch
Cancers 2018, 10(6), 185; https://doi.org/10.3390/cancers10060185 - 5 Jun 2018
Cited by 54 | Viewed by 7798
Abstract
Bone metastatic breast cancer is currently incurable and will be evident in more than 70% of patients that succumb to the disease. Understanding the factors that contribute to the progression and metastasis of breast cancer can reveal therapeutic opportunities. Matrix metalloproteinases (MMPs) are [...] Read more.
Bone metastatic breast cancer is currently incurable and will be evident in more than 70% of patients that succumb to the disease. Understanding the factors that contribute to the progression and metastasis of breast cancer can reveal therapeutic opportunities. Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes whose role in cancer has been widely documented. They are capable of contributing to every step of the metastatic cascade, but enthusiasm for the use of MMP inhibition as a therapeutic approach has been dampened by the disappointing results of clinical trials conducted more than 20 years ago. Since the trials, our knowledge of MMP biology has expanded greatly. Combined with advances in the selective targeting of individual MMPs and the specific delivery of therapeutics to the tumor microenvironment, we may be on the verge of finally realizing the promise of MMP inhibition as a treatment strategy. Here, as a case in point, we focus specifically on MMP-2 as an example to show how it can contribute to each stage of breast-cancer-to-bone metastasis and also discuss novel approaches for the selective targeting of MMP-2 in the setting of the bone-cancer microenvironment. Full article
(This article belongs to the Special Issue Targeting Bone Metastasis in Cancer)
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37 pages, 3829 KiB  
Review
Cancer Metastases to Bone: Concepts, Mechanisms, and Interactions with Bone Osteoblasts
by Alison B. Shupp, Alexus D. Kolb, Dimpi Mukhopadhyay and Karen M. Bussard
Cancers 2018, 10(6), 182; https://doi.org/10.3390/cancers10060182 - 4 Jun 2018
Cited by 95 | Viewed by 9811
Abstract
The skeleton is a unique structure capable of providing support for the body. Bone resorption and deposition are controlled in a tightly regulated balance between osteoblasts and osteoclasts with no net bone gain or loss. However, under conditions of disease, the balance between [...] Read more.
The skeleton is a unique structure capable of providing support for the body. Bone resorption and deposition are controlled in a tightly regulated balance between osteoblasts and osteoclasts with no net bone gain or loss. However, under conditions of disease, the balance between bone resorption and deposition is upset. Osteoblasts play an important role in bone homeostasis by depositing new bone osteoid into resorption pits. It is becoming increasingly evident that osteoblasts additionally play key roles in cancer cell dissemination to bone and subsequent metastasis. Our laboratory has evidence that when osteoblasts come into contact with disseminated breast cancer cells, the osteoblasts produce factors that initially reduce breast cancer cell proliferation, yet promote cancer cell survival in bone. Other laboratories have demonstrated that osteoblasts both directly and indirectly contribute to dormant cancer cell reactivation in bone. Moreover, we have demonstrated that osteoblasts undergo an inflammatory stress response in late stages of breast cancer, and produce inflammatory cytokines that are maintenance and survival factors for breast cancer cells and osteoclasts. Advances in understanding interactions between osteoblasts, osteoclasts, and bone metastatic cancer cells will aid in controlling and ultimately preventing cancer cell metastasis to bone. Full article
(This article belongs to the Special Issue Targeting Bone Metastasis in Cancer)
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14 pages, 493 KiB  
Article
Factors Influencing the Clinical Presentation of Breakthrough Pain in Cancer Patients
by Sebastiano Mercadante, Paolo Marchetti, Arturo Cuomo, Augusto Caraceni, Rocco Domenico Mediati, Renato Vellucci, Massimo Mammucari, Silvia Natoli, Marzia Lazzari, Mario Dauri, Claudio Adile, Mario Airoldi, Giuseppe Azzarello, Mauro Bandera, Livio Blasi, Giacomo Cartenì, Bruno Chiurazzi, Benedetta Veruska Pierpaola Costanzo, Daniela Degiovanni, Flavio Fusco, Vittorio Guardamagna, Vincenzo Iaffaioli, Simeone Liguori, Loredana Palermo, Sergio Mameli, Francesco Masedu, Rodolfo Mattioli, Teresita Mazzei, Rita Maria Melotti, Valentino Menardo, Danilo Miotti, Stefano Moroso, Gaetano Pascoletti, Stefano De Santis, Remo Orsetti, Alfonso Papa, Sergio Ricci, Elvira Scelzi, Michele Sofia, Giuseppe Tonini, Alessandro Valle, Federica Aielli and On behalf of the IOPS-MS Study Groupadd Show full author list remove Hide full author list
Cancers 2018, 10(6), 175; https://doi.org/10.3390/cancers10060175 - 1 Jun 2018
Cited by 52 | Viewed by 6650
Abstract
Background: The aim of this study was to identify potential variables influencing the clinical presentation of breakthrough cancer pain (BTP). Methods: Cancer patients with a diagnosis of BTP were enrolled. Demographic and clinical characteristics, as well as background pain and BTP characteristics were [...] Read more.
Background: The aim of this study was to identify potential variables influencing the clinical presentation of breakthrough cancer pain (BTP). Methods: Cancer patients with a diagnosis of BTP were enrolled. Demographic and clinical characteristics, as well as background pain and BTP characteristics were collected. Multivariate analyses were conducted to assess the correlation between BTP characteristics and the variables examined. Results: Data of 4016 patients were analysed. Average daily number of BTP episodes was 2.4, mean intensity was 7.5, and a mean duration was 43.3 min. A short onset BTP was observed in 68.9% of patients. In 30.5% of patients BTP was predictable. There were 86.0% of participants who reported a marked interference of BTP with their daily activities. Furthermore, 86.8% of patients were receiving opioids for the management of BTP. The average time to meaningful pain relief was 16.5 min and 70.9% of patients were satisfied with their BTP medications. Age, head and neck cancer, Karnofsky, background pain intensity, predictable and fast onset BTP were independently associated with the number of BTP episodes. BTP pain intensity was independently associated with background pain intensity, fast onset BTP, and Karnofsky. Neuropathic pain mechanism was independently associated with unpredictable BTP. Variables independently associated with a longer duration of BTP were age, place of visit, cancer diagnosis, disease-oriented therapy, background pain intensity and mechanism, and unpredictable BTP. Age, Karnofsky, background pain intensity, fast onset, and long duration of BTP were independently associated with interference with daily activity. Conclusions: BTP has a variable presentation depending on interdependent relationships among its different characteristics. Full article
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13 pages, 1680 KiB  
Review
Clinical Importance of Epstein–Barr Virus-Associated Gastric Cancer
by Jun Nishikawa, Hisashi Iizasa, Hironori Yoshiyama, Kanami Shimokuri, Yuki Kobayashi, Sho Sasaki, Munetaka Nakamura, Hideo Yanai, Kohei Sakai, Yutaka Suehiro, Takahiro Yamasaki and Isao Sakaida
Cancers 2018, 10(6), 167; https://doi.org/10.3390/cancers10060167 - 29 May 2018
Cited by 68 | Viewed by 8120
Abstract
Epstein–Barr virus-associated gastric carcinoma (EBVaGC) is the most common malignancy caused by EBV infection. EBVaGC has definite histological characteristics similar to gastric carcinoma with lymphoid stroma. Clinically, EBVaGC has a significantly low frequency of lymph node metastasis compared with EBV-negative gastric cancer, resulting [...] Read more.
Epstein–Barr virus-associated gastric carcinoma (EBVaGC) is the most common malignancy caused by EBV infection. EBVaGC has definite histological characteristics similar to gastric carcinoma with lymphoid stroma. Clinically, EBVaGC has a significantly low frequency of lymph node metastasis compared with EBV-negative gastric cancer, resulting in a better prognosis. The Cancer Genome Atlas of gastric adenocarcinomas proposed a molecular classification divided into four molecular subtypes: (1) EBVaGC; (2) microsatellite instability; (3) chromosomal instability; and (4) genomically stable tumors. EBVaGC harbors a DNA methylation phenotype, PD-L1 and PD-L2 overexpression, and frequent alterations in the PIK3CA gene. We review clinical importance of EBVaGC and discuss novel therapeutic applications for EBVaGC. Full article
(This article belongs to the Special Issue Epstein–Barr Virus Associated Cancers)
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19 pages, 979 KiB  
Review
Deregulation of Negative Controls on TGF-β1 Signaling in Tumor Progression
by Jiaqi Tang, Cody C. Gifford, Rohan Samarakoon and Paul J. Higgins
Cancers 2018, 10(6), 159; https://doi.org/10.3390/cancers10060159 - 25 May 2018
Cited by 58 | Viewed by 6329
Abstract
The multi-functional cytokine transforming growth factor-β1 (TGF-β1) has growth inhibitory and anti-inflammatory roles during homeostasis and the early stages of cancer. Aberrant TGF-β activation in the late-stages of tumorigenesis, however, promotes development of aggressive growth characteristics and metastatic spread. Given the critical importance [...] Read more.
The multi-functional cytokine transforming growth factor-β1 (TGF-β1) has growth inhibitory and anti-inflammatory roles during homeostasis and the early stages of cancer. Aberrant TGF-β activation in the late-stages of tumorigenesis, however, promotes development of aggressive growth characteristics and metastatic spread. Given the critical importance of this growth factor in fibrotic and neoplastic disorders, the TGF-β1 network is subject to extensive, multi-level negative controls that impact receptor function, mothers against decapentaplegic homolog 2/3 (SMAD2/3) activation, intracellular signal bifurcation into canonical and non-canonical pathways and target gene promotor engagement. Such negative regulators include phosphatase and tensin homologue (PTEN), protein phosphatase magnesium 1A (PPM1A), Klotho, bone morphogenic protein 7 (BMP7), SMAD7, Sloan-Kettering Institute proto-oncogene/ Ski related novel gene (Ski/SnoN), and bone morphogenetic protein and activin membrane-bound Inhibitor (BAMBI). The progression of certain cancers is accompanied by loss of expression, overexpression, mislocalization, mutation or deletion of several endogenous repressors of the TGF-β1 cascade, further modulating signal duration/intensity and phenotypic reprogramming. This review addresses how their aberrant regulation contributes to cellular plasticity, tumor progression/metastasis and reversal of cell cycle arrest and discusses the unexplored therapeutic value of restoring the expression and/or function of these factors as a novel approach to cancer treatment. Full article
(This article belongs to the Special Issue TGF-Beta Signaling in Cancer)
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12 pages, 1183 KiB  
Article
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 92 | Viewed by 7928
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 KiB  
Review
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 41 | Viewed by 10082
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 KiB  
Review
Reversal of Resistance in Targeted Therapy of Metastatic Melanoma: Lessons Learned from Vemurafenib (BRAFV600E-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 39 | Viewed by 5981
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. BRAFV600E 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. BRAFV600E 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 BRAFV600E 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 BRAFV600E 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 KiB  
Review
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 41 | Viewed by 6677
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 KiB  
Article
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 50 | Viewed by 6760
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 KiB  
Review
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 92 | Viewed by 8931
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 KiB  
Review
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 84 | Viewed by 11553
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 KiB  
Review
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 85 | Viewed by 8927
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 KiB  
Article
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 46 | Viewed by 7551
Abstract
The compound APR-246 (PRIMA-1MET) 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-1MET) 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-H2228Q331* cell line, and not in the wild type A549 and mutant NCI-H1975R273H cell lines. Cisplatin reduced HIF-1α protein levels in NCI-H2228Q331* 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-H2228Q331* cells in a synergistic manner without affecting mutant p53Q331* transcriptional activity, but significantly depleting total glutathione levels more efficiently under hypoxic conditions. Synergism was dependent on the presence of mutant p53Q331* 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 KiB  
Review
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 56 | Viewed by 8017
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 KiB  
Commentary
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 141 | Viewed by 11811
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 KiB  
Review
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 111 | Viewed by 10272
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 KiB  
Review
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 125 | Viewed by 13901
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 KiB  
Review
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 123 | Viewed by 29677
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 KiB  
Review
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 135 | Viewed by 9834
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 KiB  
Review
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 54 | Viewed by 12785
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 KiB  
Review
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 78 | Viewed by 14681
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 KiB  
Review
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 312 | Viewed by 8609
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 KiB  
Review
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 100 | Viewed by 13328
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 KiB  
Review
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 120 | Viewed by 16153
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 KiB  
Review
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 129 | Viewed by 15362
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 KiB  
Review
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 80 | Viewed by 16417
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 KiB  
Review
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 162 | Viewed by 11165
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 KiB  
Review
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 84 | Viewed by 13004
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 KiB  
Review
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 57 | Viewed by 6808
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 KiB  
Review
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 94 | Viewed by 15923
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 KiB  
Review
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 66 | Viewed by 8696
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 KiB  
Review
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 79 | Viewed by 9408
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 KiB  
Review
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 64 | Viewed by 10632
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 Special Issue Histone Modification in Cancer)
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9 pages, 226 KiB  
Review
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 53 | Viewed by 7114
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 KiB  
Review
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 90 | Viewed by 9677
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 KiB  
Review
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 42 | Viewed by 9879
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 KiB  
Article
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 Sunamuraadd Show full author list remove Hide full author list
Cancers 2018, 10(2), 43; https://doi.org/10.3390/cancers10020043 - 5 Feb 2018
Cited by 63 | Viewed by 7381
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 KiB  
Review
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 113 | Viewed by 16695
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 KiB  
Review
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 45 | Viewed by 9644
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 KiB  
Review
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 61 | Viewed by 8222
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 KiB  
Review
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 86 | Viewed by 12012
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 KiB  
Review
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 54 | Viewed by 14376
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 KiB  
Review
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 24 | Viewed by 10104
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 KiB  
Review
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 128 | Viewed by 21492
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 KiB  
Review
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 57 | Viewed by 5381
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)
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