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Cancers, Volume 9, Issue 9 (September 2017) – 18 articles

Cover Story (view full-size image): Adoptive T cell transfer (ACT) using chimeric antigen receptors (CARs) has shown impressive clinical outcomes in leukemias and is now being explored in solid tumors. One target is malignant pleural mesothelioma (MPM), a pleural cancer with poor prognosis for which no effective treatment exists. Clinical trials using CARs are underway to target the tumor surface protein, mesothelin, and the cancer fibroblast surface protein, fibroblast activation protein. Preclinical studies targeting other attractive protein targets, as well as strategies to augment the function of CAR T cells, are also under way. View the paper
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1151 KiB  
Review
Liver Cancer: Molecular Characterization, Clonal Evolution and Cancer Stem Cells
by Germana Castelli, Elvira Pelosi and Ugo Testa
Cancers 2017, 9(9), 127; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers9090127 - 20 Sep 2017
Cited by 114 | Viewed by 12016
Abstract
Liver cancer is the second most common cause of cancer-related death. The major forms of primary liver cancer are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Both these tumors develop against a background of cirrhotic liver, non-alcoholic fatty liver disease, chronic liver damage [...] Read more.
Liver cancer is the second most common cause of cancer-related death. The major forms of primary liver cancer are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Both these tumors develop against a background of cirrhotic liver, non-alcoholic fatty liver disease, chronic liver damage and fibrosis. HCC is a heterogeneous disease which usually develops within liver cirrhosis related to various etiologies: hepatitis B virus (HBV) infection (frequent in Asia and Africa), hepatitis C virus (HCV), chronic alcohol abuse, or metabolic syndrome (frequent in Western countries). In cirrhosis, hepatocarcinogenesis is a multi-step process where pre-cancerous dysplastic macronodules transform progressively into HCC. The patterns of genomic alterations observed in these tumors were recently identified and were instrumental for the identification of potential targeted therapies that could improve patient care. Liver cancer stem cells are a small subset of undifferentiated liver tumor cells, responsible for cancer initiation, metastasis, relapse and chemoresistance, enriched and isolated according to immunophenotypic and functional properties: cell surface proteins (CD133, CD90, CD44, EpCAM, OV-6, CD13, CD24, DLK1, α2δ1, ICAM-1 and CD47); the functional markers corresponding to side population, high aldehyde dehydrogenase (ALDH) activity and autofluorescence. The identification and definition of liver cancer stem cells requires both immunophenotypic and functional properties. Full article
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Editorial
The Impact of DNA Repair Pathways in Cancer Biology and Therapy
by Anatoly Nikolaev and Eddy S. Yang
Cancers 2017, 9(9), 126; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers9090126 - 19 Sep 2017
Cited by 14 | Viewed by 4144
Abstract
Genomic instability is one of the key hallmarks of cancer progression [1].[...] Full article
(This article belongs to the Special Issue DNA Repair Pathways in Cancer)
3688 KiB  
Article
Integrin Activation Contributes to Lower Cisplatin Sensitivity in MV3 Melanoma Cells by Inducing the Wnt Signalling Pathway
by Maria B. R. Piva, Bastian Jakubzig and Gerd Bendas
Cancers 2017, 9(9), 125; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers9090125 - 16 Sep 2017
Cited by 13 | Viewed by 6947
Abstract
Background: integrins have been associated with the development of chemotherapy resistant tumour cells, mostly those of hematopoietic origin, by mediating the binding to the extracellular matrix. The relevance for solid tumour cells and the underlying mechanisms remain elusive. Methods: using MTT assays, we [...] Read more.
Background: integrins have been associated with the development of chemotherapy resistant tumour cells, mostly those of hematopoietic origin, by mediating the binding to the extracellular matrix. The relevance for solid tumour cells and the underlying mechanisms remain elusive. Methods: using MTT assays, we detected the loss in cisplatin sensitivity of human MV3 melanoma cells upon integrin activation. Underlying cellular pathways were evaluated by flow cytometry. A crosstalk between integrin activation and the canonical wnt signalling pathway was tested by measuring β-catenin activity. Results: MV3 cells display a higher resistance against cisplatin cytotoxicity when cellular integrins were activated by manganese or collagen. Proteome profiler array showed a deregulation of the integrin expression pattern by cisplatin. Integrin activation by manganese induces the phosphorylation of PI3K/AKT. The inhibition of PI3K using BEZ235 strongly increases cell sensitivity to cisplatin, blocking manganese and collagen effects. PI3K/AKT activates wnt signalling by blocking Gsk3-β, which was confirmed by β-catenin up-regulation and nuclear localization. Integrins did not affect E-cadherin expression levels, thus endothelial to mesenchymal transition (EMT) can be excluded. Conclusion: This is the first report on an integrin/wnt signalling activation axis addressing the consequences for chemotherapy sensitiveness of melanoma cells, which thus offers novel therapeutic targets for approaches to interfere with chemoresistance. Full article
(This article belongs to the Special Issue Integrins in Cancer)
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235 KiB  
Review
MicroRNAs as Biomarkers in Colorectal Cancer
by Takaaki Masuda, Naoki Hayashi, Yosuke Kuroda, Shuhei Ito, Hidetoshi Eguchi and Koshi Mimori
Cancers 2017, 9(9), 124; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers9090124 - 13 Sep 2017
Cited by 89 | Viewed by 6009
Abstract
MicroRNAs (miRs) are small RNAs that repress mRNA translation, resulting in the degradation of mRNAs and regulation of the expression levels of various genes. Recent studies have shown that aberrant miR expression has a functional role in the initiation and progression of various [...] Read more.
MicroRNAs (miRs) are small RNAs that repress mRNA translation, resulting in the degradation of mRNAs and regulation of the expression levels of various genes. Recent studies have shown that aberrant miR expression has a functional role in the initiation and progression of various malignancies, including colorectal cancer (CRC), which is one of the leading causes of cancer-related death worldwide. miRs have also been shown to have applications as diagnostic, prognostic, and predictive biomarkers because of their high tissue specificity, stability, and altered expression in tumor development. In this report, we examined the role of miRs as biomarkers in CRC through a review of meta-analyses and large-scale analyses having strong statistical confidence in the study outcomes. We also discuss current issues in the clinical application of these miRs. Full article
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Review
Anaplastic Lymphoma Kinase in Cutaneous Malignancies
by Severine Cao and Vinod E. Nambudiri
Cancers 2017, 9(9), 123; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers9090123 - 12 Sep 2017
Cited by 7 | Viewed by 4259
Abstract
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that has been implicated in the pathogenesis of a variety of neoplasms. As suggested by its name, ALK was first described as part of a translocation product in cases of anaplastic large-cell lymphoma, with [...] Read more.
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that has been implicated in the pathogenesis of a variety of neoplasms. As suggested by its name, ALK was first described as part of a translocation product in cases of anaplastic large-cell lymphoma, with other genetic and cytogenetic ALK mutations subsequently coming to attention in the development of many other hematologic and solid organ malignancies. ALK has now been shown to play a role in the pathogenesis of several cutaneous malignancies, including secondary cutaneous systemic anaplastic large-cell lymphoma (ALCL) and primary cutaneous ALCL, melanoma, spitzoid tumors, epithelioid fibrous histiocytoma, Merkel cell carcinoma, and basal cell carcinoma. The characterization of ALK-positivity in these cutaneous malignancies presents exciting opportunities for utilizing ALK-targeted inhibitors in the treatment of these diseases. Full article
(This article belongs to the Special Issue Targeting ALK in Cancer)
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Review
EMT and Treatment Resistance in Pancreatic Cancer
by Nicola Gaianigo, Davide Melisi and Carmine Carbone
Cancers 2017, 9(9), 122; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers9090122 - 12 Sep 2017
Cited by 111 | Viewed by 9634
Abstract
Pancreatic cancer (PC) is the third leading cause of adult cancer mortality in the United States. The poor prognosis for patients with PC is mainly due to its aggressive course, the limited efficacy of active systemic treatments, and a metastatic behavior, demonstrated throughout [...] Read more.
Pancreatic cancer (PC) is the third leading cause of adult cancer mortality in the United States. The poor prognosis for patients with PC is mainly due to its aggressive course, the limited efficacy of active systemic treatments, and a metastatic behavior, demonstrated throughout the evolution of the disease. On average, 80% of patients with PC are diagnosed with metastatic disease, and the half of those who undergo surgery and adjuvant therapy develop liver metastasis within two years. Metastatic dissemination is an early event in PC and is mainly attributed to an evolutionary biological process called epithelial-to-mesenchymal transition (EMT). This innate mechanism could have a dual role during embryonic growth and organ differentiation, and in cancer progression, cancer stem cell intravasation, and metastasis settlement. Many of the molecular pathways decisive in EMT progression have been already unraveled, but little is known about the causes behind the induction of this mechanism. EMT is one of the most distinctive and critical features of PC, occurring even in the very first stages of tumor development. This is known as pancreatic intraepithelial neoplasia (PanIN) and leads to early dissemination, drug resistance, and unfavorable prognosis and survival. The intention of this review is to shed new light on the critical role assumed by EMT during PC progression, with a particular focus on its role in PC resistance. Full article
(This article belongs to the Special Issue The Epithelial-to-Mesenchymal Transition (EMT) in Cancer)
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Article
The PI3Kδ Inhibitor Idelalisib Inhibits Homing in an in Vitro and in Vivo Model of B ALL
by Etai Adam, Hye Na Kim, Eun Ji Gang, Caitlin Schnair, Solomon Lee, Solah Lee, Sajad Khazal, Osanna Kosoyan, Marina Konopleva, Chintan Parekh, Deepa Bhojwani, Alan S. Wayne, Hisham Abdel-Azim, Nora Heisterkamp and Yong-Mi Kim
Cancers 2017, 9(9), 121; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers9090121 - 10 Sep 2017
Cited by 13 | Viewed by 5316
Abstract
The quest continues for targeted therapies to reduce the morbidity of chemotherapy and to improve the response of resistant leukemia. Adhesion of acute lymphoblastic leukemia (ALL) cells to bone marrow stromal cells triggers intracellular signals that promote cell-adhesion-mediated drug resistance (CAM-DR). Idelalisib, an [...] Read more.
The quest continues for targeted therapies to reduce the morbidity of chemotherapy and to improve the response of resistant leukemia. Adhesion of acute lymphoblastic leukemia (ALL) cells to bone marrow stromal cells triggers intracellular signals that promote cell-adhesion-mediated drug resistance (CAM-DR). Idelalisib, an U.S. Food and Drug Administration (FDA)-approved PI3Kδ-specific inhibitor has been shown to be effective in CLL in down-regulating p-Akt and prolonging survival in combination with Rituximab; herein we explore the possibility of its use in B ALL and probe the mechanism of action. Primary B ALL in contact with OP9 stromal cells showed increased p-Aktser473. Idelalisib decreased p-Akt in patient samples of ALL with diverse genetic lesions. Addition of idelalisib to vincristine inhibited proliferation when compared to vincristine monotherapy in a subset of samples tested. Idelalisib inhibited ALL migration to SDF-1α in vitro and blocked homing of ALL cells to the bone marrow in vivo. This report tests PI3Kδ inhibitors in a more diverse group of ALL than has been previously reported and is the first published report of idelalisib inhibiting homing of ALL cells to bone marrow. Our data support further pre-clinical evaluation of idelalisib for the therapy of B ALL. Full article
(This article belongs to the Special Issue Integrins in Cancer)
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762 KiB  
Review
Acute and Late Toxicities of Concurrent Chemoradiotherapy for Locally-Advanced Non-Small Cell Lung Cancer
by Vivek Verma, Charles B. Simone II and Maria Werner-Wasik
Cancers 2017, 9(9), 120; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers9090120 - 08 Sep 2017
Cited by 70 | Viewed by 6099
Abstract
For patients with unresectable locally-advanced non-small cell lung cancer (LA-NSCLC), concurrent chemoradiotherapy improves overall survival as compared to sequential chemotherapy and radiation therapy, but is associated with higher rates of toxicities. Acute, clinically significant esophagitis or pneumonitis can occur in one in five [...] Read more.
For patients with unresectable locally-advanced non-small cell lung cancer (LA-NSCLC), concurrent chemoradiotherapy improves overall survival as compared to sequential chemotherapy and radiation therapy, but is associated with higher rates of toxicities. Acute, clinically significant esophagitis or pneumonitis can occur in one in five patients. The risks of esophagitis and pneumonitis can impact the decision to deliver concurrent therapy and limit the total dose of radiation therapy that is delivered. Hematologic toxicities and emesis are common toxicities from systemic therapies for LA-NSCLC and can result in delaying chemotherapy dosing or chemotherapy dose reductions. Late treatment morbidities, including pulmonary fibrosis and cardiac toxicities, can also significantly impact quality of life and potentially even survival. Recent advances in radiation therapy treatment delivery, better knowledge of normal tissue radiotherapy tolerances and more widespread and improved uses of supportive care and medical management of systemic therapy toxicities have improved the therapeutic ratio and reduced the rates of chemoradiotherapy-induced toxicities. This review details the acute and late toxicities associated with definitive chemoradiotherapy for LA-NSCLC and discusses toxicity management and strategies to mitigate the risks of treatment-related toxicities. Full article
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Article
Predicting Organ-Specific Risk Interactions between Radiation and Chemotherapy in Secondary Cancer Survivors
by Venkata S.K. Manem, Clemens Grassberger and Harald Paganetti
Cancers 2017, 9(9), 119; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers9090119 - 06 Sep 2017
Cited by 5 | Viewed by 5233
Abstract
Several studies have shown that pediatric patients have an increased risk of developing a secondary malignancy several decades after treatment with radiotherapy and chemotherapy. In this work, we use a biologically motivated mathematical formalism to estimate the relative risks of breast, lung and [...] Read more.
Several studies have shown that pediatric patients have an increased risk of developing a secondary malignancy several decades after treatment with radiotherapy and chemotherapy. In this work, we use a biologically motivated mathematical formalism to estimate the relative risks of breast, lung and thyroid cancers in childhood cancer survivors due to concurrent therapy regimen. This model specifically includes possible organ-specific interaction between radiotherapy and chemotherapy. The model predicts relative risks for developing secondary cancers after chemotherapy in breast, lung and thyroid tissues, and compared with the epidemiological data. For a concurrent therapy protocol, our model predicted relative risks of 3.2, 9.3, 4.5 as compared to the clinical data, i.e., 1.4, 8.0, 2.3 for secondary breast, lung and thyroid cancer risks, respectively. The extracted chemotherapy mutation induction rates for breast, lung and thyroid are 10−9, 0.5 × 10−6, 0.9 × 10−7 respectively. We found that there exists no synergistic interaction between radiation and chemotherapy for neither mutation induction nor cell kill in lung tissue, but there is an interaction in cell kill for the breast and thyroid organs. These findings help understand the risks of current clinical protocols and might provide rational guidance to develop future multi-modality treatment protocols to minimize secondary cancer risks. Full article
(This article belongs to the Special Issue Radiation-Induced Carcinogenesis)
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358 KiB  
Review
EML4-ALK Variants: Biological and Molecular Properties, and the Implications for Patients
by Sarah R. Sabir, Sharon Yeoh, George Jackson and Richard Bayliss
Cancers 2017, 9(9), 118; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers9090118 - 05 Sep 2017
Cited by 144 | Viewed by 14747
Abstract
Since the discovery of the fusion between EML4 (echinoderm microtubule associated protein-like 4) and ALK (anaplastic lymphoma kinase), EML4-ALK, in lung adenocarcinomas in 2007, and the subsequent identification of at least 15 different variants in lung cancers, there has been a revolution in [...] Read more.
Since the discovery of the fusion between EML4 (echinoderm microtubule associated protein-like 4) and ALK (anaplastic lymphoma kinase), EML4-ALK, in lung adenocarcinomas in 2007, and the subsequent identification of at least 15 different variants in lung cancers, there has been a revolution in molecular-targeted therapy that has transformed the outlook for these patients. Our recent focus has been on understanding how and why the expression of particular variants can affect biological and molecular properties of cancer cells, as well as identifying the key signalling pathways triggered, as a result. In the clinical setting, this understanding led to the discovery that the type of variant influences the response of patients to ALK therapy. Here, we discuss what we know so far about the EML4-ALK variants in molecular signalling pathways and what questions remain to be answered. In the longer term, this analysis may uncover ways to specifically treat patients for a better outcome. Full article
(This article belongs to the Special Issue Targeting ALK in Cancer)
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1005 KiB  
Article
Reduced Cytokine Release in Ex Vivo Response to Cilengitide and Cetuximab Is a Marker for Improved Survival of Head and Neck Cancer Patients
by Susan Cedra, Susanne Wiegand, Marlen Kolb, Andreas Dietz and Gunnar Wichmann
Cancers 2017, 9(9), 117; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers9090117 - 05 Sep 2017
Cited by 6 | Viewed by 4277
Abstract
Targeting of αVβ3 and αVβ5 integrins by cilengitide may reduce growth of solid tumors including head and neck squamous cell carcinoma (HNSCC). Preclinical investigations suggest increased activity of cilengitide in combination with other treatment modalities. The only published trial [...] Read more.
Targeting of αVβ3 and αVβ5 integrins by cilengitide may reduce growth of solid tumors including head and neck squamous cell carcinoma (HNSCC). Preclinical investigations suggest increased activity of cilengitide in combination with other treatment modalities. The only published trial in HNSCC (ADVANTAGE) investigated cisplatin, 5-fluorouracil, and cetuximab (PFE) without or with once (PFE+CIL1W) or twice weekly cilengitide (PFE+CIL2W) in recurrent/metastatic HNSCC. ADVANTAGE showed good tolerability of the cilengitide arms and even lower adverse events (AEs) compared to PFE but not the benefit in overall survival expected based on preclinical data. As we found in the FLAVINO assay, a short-time ex vivo assay for prediction of chemosensitivity, only a subgroup of HNSCC had an increased suppressive effect of cilengitide containing combination therapies on colony formation of epithelial cells (CFec) and release of pro-angiogenetic and pro-inflammatory cytokines, whereas other HNSCC failed to respond. Response to αVβ3 and αVβ5 integrin targeting by cilengitide classifies HNSCC regarding outcome. We present FLAVINO data arguing for further development of cilengitide plus cetuximab in treatment of a subgroup of HNSCC potentially identified by the FLAVINO assay using a set of biomarkers for response evaluation. Full article
(This article belongs to the Special Issue Integrins in Cancer)
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2843 KiB  
Review
Exploring the Role of RGD-Recognizing Integrins in Cancer
by Markus Nieberler, Ute Reuning, Florian Reichart, Johannes Notni, Hans-Jürgen Wester, Markus Schwaiger, Michael Weinmüller, Andreas Räder, Katja Steiger and Horst Kessler
Cancers 2017, 9(9), 116; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers9090116 - 04 Sep 2017
Cited by 303 | Viewed by 22394
Abstract
Integrins are key regulators of communication between cells and with their microenvironment. Eight members of the integrin superfamily recognize the tripeptide motif Arg-Gly-Asp (RGD) within extracelluar matrix (ECM) proteins. These integrins constitute an important subfamily and play a major role in cancer progression [...] Read more.
Integrins are key regulators of communication between cells and with their microenvironment. Eight members of the integrin superfamily recognize the tripeptide motif Arg-Gly-Asp (RGD) within extracelluar matrix (ECM) proteins. These integrins constitute an important subfamily and play a major role in cancer progression and metastasis via their tumor biological functions. Such transmembrane adhesion and signaling receptors are thus recognized as promising and well accessible targets for novel diagnostic and therapeutic applications for directly attacking cancer cells and their fatal microenvironment. Recently, specific small peptidic and peptidomimetic ligands as well as antibodies binding to distinct integrin subtypes have been developed and synthesized as new drug candidates for cancer treatment. Understanding the distinct functions and interplay of integrin subtypes is a prerequisite for selective intervention in integrin-mediated diseases. Integrin subtype-specific ligands labelled with radioisotopes or fluorescent molecules allows the characterization of the integrin patterns in vivo and later the medical intervention via subtype specific drugs. The coating of nanoparticles, larger proteins, or encapsulating agents by integrin ligands are being explored to guide cytotoxic reagents directly to the cancer cell surface. These ligands are currently under investigation in clinical studies for their efficacy in interference with tumor cell adhesion, migration/invasion, proliferation, signaling, and survival, opening new treatment approaches in personalized medicine. Full article
(This article belongs to the Special Issue Integrins in Cancer)
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Review
Chimeric Antigen Receptor (CAR) T Cell Therapy for Malignant Pleural Mesothelioma (MPM)
by Astero Klampatsa, Andrew R. Haas, Edmund K. Moon and Steven M. Albelda
Cancers 2017, 9(9), 115; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers9090115 - 01 Sep 2017
Cited by 27 | Viewed by 17131
Abstract
Cancer immunotherapy has now become a recognized approach to treating cancers. In addition to checkpoint blockade, adoptive T cell transfer (ACT) using chimeric antigen receptors (CARs) has shown impressive clinical outcomes in leukemias and is now being explored in solid tumors. CARs are [...] Read more.
Cancer immunotherapy has now become a recognized approach to treating cancers. In addition to checkpoint blockade, adoptive T cell transfer (ACT) using chimeric antigen receptors (CARs) has shown impressive clinical outcomes in leukemias and is now being explored in solid tumors. CARs are engineered receptors, stably or transiently transduced into T cells, that aim to enhance T cell effector function by recognizing and binding to a specific tumor-associated antigen. In this review, we provide a summary of CAR T cell preclinical studies and clinical trials for malignant pleural mesothelioma (MPM), a rare, locally invasive pleural cancer with poor prognosis. We list other attractive potential targets for CAR T cell therapy for MPM, and discuss augmentation strategies of CAR T cell therapy with other forms of immunotherapy in this disease. Full article
(This article belongs to the Special Issue CAR-T Cell Therapy against Different Types of Cancer)
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Article
Stem Cell-Like Properties of CK2β-down Regulated Mammary Cells
by Eve Duchemin-Pelletier, Megghane Baulard, Elodie Spreux, Magali Prioux, Mithila Burute, Baharia Mograbi, Laurent Guyon, Manuel Théry, Claude Cochet and Odile Filhol
Cancers 2017, 9(9), 114; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers9090114 - 31 Aug 2017
Cited by 5 | Viewed by 4237
Abstract
The ubiquitous protein kinase CK2 has been demonstrated to be overexpressed in a number of human tumours. This enzyme is composed of two catalytic α or α’ subunits and a dimer of β regulatory subunits whose expression levels are probably implicated in CK2 [...] Read more.
The ubiquitous protein kinase CK2 has been demonstrated to be overexpressed in a number of human tumours. This enzyme is composed of two catalytic α or α’ subunits and a dimer of β regulatory subunits whose expression levels are probably implicated in CK2 regulation. Several recent papers reported that unbalanced expression of CK2 subunits is sufficient to drive epithelial to mesenchymal transition, a process involved in cancer invasion and metastasis. Herein, through transcriptomic and miRNA analysis together with comparison of cellular properties between wild type and CK2β-knock-down MCF10A cells, we show that down-regulation of CK2β subunit in mammary epithelial cells induces the acquisition of stem cell-like properties associated with perturbed polarity, CD44high/CD24low antigenic phenotype and the ability to grow under anchorage-independent conditions. These data demonstrate that a CK2β level establishes a critical cell fate threshold in the control of epithelial cell plasticity. Thus, this regulatory subunit functions as a nodal protein to maintain an epithelial phenotype and its depletion drives breast cell stemness. Full article
(This article belongs to the Special Issue The Epithelial-to-Mesenchymal Transition (EMT) in Cancer)
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289 KiB  
Review
Novel Molecular Targets for Chemoprevention in Malignancies of the Head and Neck
by Aarti Bhatia and Barbara Burtness
Cancers 2017, 9(9), 113; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers9090113 - 31 Aug 2017
Cited by 20 | Viewed by 4592
Abstract
Cancers of the head and neck region are among the leading causes of cancer-related mortalities worldwide. Oral leukoplakia and erythroplakia are identified as precursor lesions to malignancy. Patients cured of an initial primary head and neck cancer are also susceptible to developing second [...] Read more.
Cancers of the head and neck region are among the leading causes of cancer-related mortalities worldwide. Oral leukoplakia and erythroplakia are identified as precursor lesions to malignancy. Patients cured of an initial primary head and neck cancer are also susceptible to developing second primary tumors due to cancerization of their mucosal field. Multi-step acquisition of genetic mutations leading to tumorigenesis and development of invasive cancer has been previously described. Recently, whole exome sequencing of tumor specimens has helped to identify driver mutations in this disease. For these reasons, chemoprevention or the use of systemic or biologic agents to prevent carcinogenesis is an attractive concept in head and neck cancers. Nonetheless, despite extensive clinical research in this field over the past couple decades, no standard of care option has emerged. This review article reports on targeted interventions that have been attempted in clinical trials to date, and focuses on novel molecular pathways and drugs in development that are worthy of being tested for this indication as part of future endeavors. Full article
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Article
Most Do, but Some Do Not: CD4+CD25 T Cells, but Not CD4+CD25+ Treg Cells, Are Cytolytic When Redirected by a Chimeric Antigen Receptor (CAR)
by Andreas A. Hombach and Hinrich Abken
Cancers 2017, 9(9), 112; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers9090112 - 29 Aug 2017
Cited by 10 | Viewed by 5486
Abstract
Evidences are accumulating that CD4+ T cells can physiologically mediate antigen specific target cell lysis. By circumventing major histocompatibility complex (MHC)-restrictions through an engineered chimeric antigen receptor (CAR), CD4+ T cells lyse defined target cells as efficiently as do CD8+ [...] Read more.
Evidences are accumulating that CD4+ T cells can physiologically mediate antigen specific target cell lysis. By circumventing major histocompatibility complex (MHC)-restrictions through an engineered chimeric antigen receptor (CAR), CD4+ T cells lyse defined target cells as efficiently as do CD8+ T cells. However, the cytolytic capacity of redirected CD4+CD25 T cells, in comparison with CD4+CD25+ regulatory T (Treg) cells was so far not thoroughly defined. Treg cells require a strong CD28 signal together with CD3ζ for activation. We consequently used a CAR with combined CD28­CD3ζ signalling for redirecting CD4+CD25 T cells and CD4+CD25+ Treg cells from the same donor. CAR redirected activation of these T cell subsets and induced a distinct cytokine pattern with high IL-10 and a lack of IL-2 release by Treg cells. Despite strong antigen-specific activation, CAR Treg cells produced only weak target cell lysis, whereas CD4+CD25 CAR T cells were potent killers. Cytolysis did not correlate with the target cell sensitivity to Fas/FasL mediated killing; CD4+CD25 T cells upregulated perforin and granzyme B upon CAR activation, whereas Treg cells did less. The different cytolytic capacities of CAR redirected conventional CD4+ cells and Treg cells imply their use for different purposes in cell therapy. Full article
(This article belongs to the Special Issue CAR-T Cell Therapy against Different Types of Cancer)
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Review
Translocation Renal Cell Carcinoma: An Update on Clinicopathological and Molecular Features
by Kentaro Inamura
Cancers 2017, 9(9), 111; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers9090111 - 29 Aug 2017
Cited by 44 | Viewed by 6799
Abstract
Microphthalmia-associated transcription (MiT) family translocation renal cell carcinoma (tRCC) comprises Xp11 tRCC and t(6;11) RCC. Due to the presence of fusion genes, Xp11 tRCC and t(6;11) RCC are also known as TFE3- and TFEB-rearranged RCC, respectively. TFE3 and TFEB belong to [...] Read more.
Microphthalmia-associated transcription (MiT) family translocation renal cell carcinoma (tRCC) comprises Xp11 tRCC and t(6;11) RCC. Due to the presence of fusion genes, Xp11 tRCC and t(6;11) RCC are also known as TFE3- and TFEB-rearranged RCC, respectively. TFE3 and TFEB belong to the MiT family, which regulates melanocyte and osteoclast differentiation, and TFE3- and TFEB-rearranged RCC show characteristic clinicopathological and immunohistochemical features. Recent studies identified the fusion partner-dependent clinicopathological and immunohistochemical features in TFE3-rearranged RCC. Furthermore, RCC with chromosome 6p amplification, including TFEB, was identified as a unique subtype of RCC, along with ALK-rearranged RCC. This review summarizes these recent advancements in our tRCC-related knowledge. Full article
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Review
Integrins as Therapeutic Targets: Successes and Cancers
by Sabine Raab-Westphal, John F. Marshall and Simon L. Goodman
Cancers 2017, 9(9), 110; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers9090110 - 23 Aug 2017
Cited by 162 | Viewed by 15097
Abstract
Integrins are transmembrane receptors that are central to the biology of many human pathologies. Classically mediating cell-extracellular matrix and cell-cell interaction, and with an emerging role as local activators of TGFβ, they influence cancer, fibrosis, thrombosis and inflammation. Their ligand binding and some [...] Read more.
Integrins are transmembrane receptors that are central to the biology of many human pathologies. Classically mediating cell-extracellular matrix and cell-cell interaction, and with an emerging role as local activators of TGFβ, they influence cancer, fibrosis, thrombosis and inflammation. Their ligand binding and some regulatory sites are extracellular and sensitive to pharmacological intervention, as proven by the clinical success of seven drugs targeting them. The six drugs on the market in 2016 generated revenues of some US$3.5 billion, mainly from inhibitors of α4-series integrins. In this review we examine the current developments in integrin therapeutics, especially in cancer, and comment on the health economic implications of these developments. Full article
(This article belongs to the Special Issue Integrins in Cancer)
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