Cancers

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Open AccessFeature PaperPerspective

Genomic Destabilization Triggered by Replication Stress during Senescence

by Yusuke Minakawa, Atsuhiro Shimizu, Yusuke Matsuno and Ken-ichi Yoshioka

Cancers 2017, 9(11), 159; https://doi.org/10.3390/cancers9110159 - 21 Nov 2017

Cited by 3 | Viewed by 4594

Most cancers develop after middle age, and are often associated with multiple mutations and genomic instability, implying that genomic destabilization is critical for age-related tumor development. In this manuscript, we review current knowledge regarding (1) the senescent cellular background, which is associated with [...] Read more.

Most cancers develop after middle age, and are often associated with multiple mutations and genomic instability, implying that genomic destabilization is critical for age-related tumor development. In this manuscript, we review current knowledge regarding (1) the senescent cellular background, which is associated with a higher risk of genomic destabilization; and (2) the contributions of genomic destabilization to cancer development. Full article

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

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Open AccessReview

Alcohol and Cancer Stem Cells

by Mei Xu and Jia Luo

Cancers 2017, 9(11), 158; https://doi.org/10.3390/cancers9110158 - 20 Nov 2017

Cited by 18 | Viewed by 7615

Abstract

Heavy alcohol consumption has been associated with increased risk of several cancers, including cancer of the colon, rectum, female breast, oral cavity, pharynx, larynx, liver, and esophagus. It appears that alcohol exposure not only promotes carcinogenesis but also enhances the progression and aggressiveness [...] Read more.

Heavy alcohol consumption has been associated with increased risk of several cancers, including cancer of the colon, rectum, female breast, oral cavity, pharynx, larynx, liver, and esophagus. It appears that alcohol exposure not only promotes carcinogenesis but also enhances the progression and aggressiveness of existing cancers. The molecular mechanisms underlying alcohol tumor promotion, however, remain unclear. Cancer stem cells (CSC), a subpopulation of cancer cells with self-renewal and differentiation capacity, play an important role in tumor initiation, progression, metastasis, recurrence, and therapy resistance. The recent research evidence suggests that alcohol increases the CSC population in cancers, which may underlie alcohol-induced tumor promotion. This review discusses the recent progress in the research of alcohol promotion of CSC and underlying cellular/molecular mechanisms. The review will further explore the therapeutic potential of CSC inhibition in treating alcohol-induced tumor promotion. Full article

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

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Open AccessReview

Pancreatic Cancer Chemoresistance to Gemcitabine

by Manoj Amrutkar and Ivar P. Gladhaug

Cancers 2017, 9(11), 157; https://doi.org/10.3390/cancers9110157 - 16 Nov 2017

Cited by 358 | Viewed by 22104

Abstract

Pancreatic ductal adenocarcinoma (PDAC), commonly referred to as pancreatic cancer, ranks among the leading causes of cancer-related deaths in the Western world due to disease presentation at an advanced stage, early metastasis and generally a very limited response to chemotherapy or radiotherapy. Gemcitabine [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC), commonly referred to as pancreatic cancer, ranks among the leading causes of cancer-related deaths in the Western world due to disease presentation at an advanced stage, early metastasis and generally a very limited response to chemotherapy or radiotherapy. Gemcitabine remains a cornerstone of PDAC treatment in all stages of the disease despite suboptimal clinical effects primarily caused by molecular mechanisms limiting its cellular uptake and activation and overall efficacy, as well as the development of chemoresistance within weeks of treatment initiation. To circumvent gemcitabine resistance in PDAC, several novel therapeutic approaches, including chemical modifications of the gemcitabine molecule generating numerous new prodrugs, as well as new entrapment designs of gemcitabine in colloidal systems such as nanoparticles and liposomes, are currently being investigated. Many of these approaches are reported to be more efficient than the parent gemcitabine molecule when tested in cellular systems and in vivo in murine tumor model systems; however, although promising, their translation to clinical use is still in a very early phase. This review discusses gemcitabine metabolism, activation and chemoresistance entities in the gemcitabine cytotoxicity pathway and provides an overview of approaches to override chemoresistance in pancreatic cancer. Full article

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Open AccessReview

Cell Line Secretome and Tumor Tissue Proteome Markers for Early Detection of Colorectal Cancer: A Systematic Review

by Megha Bhardwaj, Vanessa Erben, Petra Schrotz-King and Hermann Brenner

Cancers 2017, 9(11), 156; https://doi.org/10.3390/cancers9110156 - 16 Nov 2017

Cited by 14 | Viewed by 5716

Abstract

Objective: In order to find low abundant proteins secretome and tumor tissue proteome data have been explored in the last few years for the diagnosis of colorectal cancer (CRC). In this review we aim to summarize the results of studies evaluating markers derived [...] Read more.

Objective: In order to find low abundant proteins secretome and tumor tissue proteome data have been explored in the last few years for the diagnosis of colorectal cancer (CRC). In this review we aim to summarize the results of studies evaluating markers derived from the secretome and tumor proteome for blood based detection of colorectal cancer. Methods: Observing the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines PubMed and Web of Science databases were searched systematically for relevant studies published up to 18 July 2017. After screening for predefined eligibility criteria a total of 47 studies were identified. Information on diagnostic performance indicators, methodological procedures and validation was extracted. Functions of proteins were identified from the UniProt database and the the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool was used to assess study quality. Results: Forty seven studies meeting inclusion criteria were identified. Overall, 83 different proteins were identified, with carcinoembryonic Antigen (CEA) being by far the most commonly reported (reported in 24 studies). Evaluation of the markers or marker combinations in blood samples from CRC cases and controls yielded apparently very promising diagnostic performances, with area under the curve >0.9 in several cases, but lack of internal or external validation, overoptimism due to overfitting and spectrum bias due to evaluation in clinical setting rather than screening settings are major concerns. Conclusions: Secretome and tumor proteome-based biomarkers when validated in blood yield promising candidates. However, for discovered protein markers to be clinically applicable as screening tool they have to be specific for early stages and need to be validated externally in larger studies with participants recruited in true screening setting. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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Open AccessReview

Current and Prospective Protein Biomarkers of Lung Cancer

by Tatiana N. Zamay, Galina S. Zamay, Olga S. Kolovskaya, Ruslan A. Zukov, Marina M. Petrova, Ana Gargaun, Maxim V. Berezovski and Anna S. Kichkailo

Cancers 2017, 9(11), 155; https://doi.org/10.3390/cancers9110155 - 13 Nov 2017

Cited by 120 | Viewed by 16492

Abstract

Lung cancer is a malignant lung tumor with various histological variants that arise from different cell types, such as bronchial epithelium, bronchioles, alveoli, or bronchial mucous glands. The clinical course and treatment efficacy of lung cancer depends on the histological variant of the [...] Read more.

Lung cancer is a malignant lung tumor with various histological variants that arise from different cell types, such as bronchial epithelium, bronchioles, alveoli, or bronchial mucous glands. The clinical course and treatment efficacy of lung cancer depends on the histological variant of the tumor. Therefore, accurate identification of the histological type of cancer and respective protein biomarkers is crucial for adequate therapy. Due to the great diversity in the molecular-biological features of lung cancer histological types, detection is impossible without knowledge of the nature and origin of malignant cells, which release certain protein biomarkers into the bloodstream. To date, different panels of biomarkers are used for screening. Unfortunately, a uniform serum biomarker composition capable of distinguishing lung cancer types is yet to be discovered. As such, histological analyses of tumor biopsies and immunohistochemistry are the most frequently used methods for establishing correct diagnoses. Here, we discuss the recent advances in conventional and prospective aptamer based strategies for biomarker discovery. Aptamers like artificial antibodies can serve as molecular recognition elements for isolation detection and search of novel tumor-associated markers. Here we will describe how these small synthetic single stranded oligonucleotides can be used for lung cancer biomarker discovery and utilized for accurate diagnosis and targeted therapy. Furthermore, we describe the most frequently used in-clinic and novel lung cancer biomarkers, which suggest to have the ability of differentiating between histological types of lung cancer and defining metastasis rate. Full article

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

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Graphical abstract

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Open AccessReview

Liquid Biopsy and Therapeutic Targets: Present and Future Issues in Thoracic Oncology

by Paul Hofman

Cancers 2017, 9(11), 154; https://doi.org/10.3390/cancers9110154 - 10 Nov 2017

Cited by 27 | Viewed by 4998

Abstract

The practice of liquid biopsy (LB) has revolutionized the care of patients with metastatic lung cancer. Many oncologists now use this approach in daily practice, applying precise procedures for the detection of activating or resistance mutations in EGFR. These tests are performed [...] Read more.

The practice of liquid biopsy (LB) has revolutionized the care of patients with metastatic lung cancer. Many oncologists now use this approach in daily practice, applying precise procedures for the detection of activating or resistance mutations in EGFR. These tests are performed with plasma DNA and have been approved as companion diagnostic test for patients treated with tyrosine kinase inhibitors. ALK is another important target in lung cancer since it leads to treatment of patients who are positive for a rearrangement in ALK identified with tumor tissue. By analogy with EGFR, LB for detection of genomic alterations in ALK (rearrangements or mutations) has been rapidly adopted in the clinic. However, this promising approach has some limitations and has not yet been disseminated as much as the blood test targeting EGFR. In addition to these two therapeutic targets LB can be used for evaluation of the genomic status of other genes of interest of patients with lung cancer (ROS1, RET, NTRK MET, BRAF, HER2, etc.). LB can be performed to evaluate a specific target or for a more or less complex panel of genes. Considering the number of potential targets for clinical trials, techniques of next-generation sequencing of circulating DNA are on the rise. This review will provide an update on the contribution of LB to care of patients with metastatic lung cancer, including the present limits of this approach, and will consider certain perspectives. Full article

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Open AccessFeature PaperReview

Role of LFA-1 and ICAM-1 in Cancer

by Manuel Reina and Enric Espel

Cancers 2017, 9(11), 153; https://doi.org/10.3390/cancers9110153 - 3 Nov 2017

Cited by 105 | Viewed by 9928

Abstract

The lymphocyte function-associated antigen-1 (LFA-1) (also known as CD11a/CD18 and α_Lβ₂), is just one of many integrins in the human body, but its significance is derived from its exclusive presence in leukocytes. In this review, we summarize the studies [...] Read more.

The lymphocyte function-associated antigen-1 (LFA-1) (also known as CD11a/CD18 and α_Lβ₂), is just one of many integrins in the human body, but its significance is derived from its exclusive presence in leukocytes. In this review, we summarize the studies relating LFA-1 and its major ligand ICAM-1 (or CD54) with cancer, through the function of lymphocytes and myeloid cells on tumor cells. We consider how LFA-1 mediates the interaction of leukocytes with tumors and the role of ICAM-1 in tumor dynamics, which can be independent of its interaction with LFA-1. We also offer a more detailed examination of the role of LFA-1 within B-cell chronic lymphocytic leukemia. Finally, we discuss the role that exosomes harboring LFA-1 play in tumor growth and metastasis. Full article

(This article belongs to the Special Issue Integrins in Cancer)

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Open AccessFeature PaperReview

Evolving Significance and Future Relevance of Anti-Angiogenic Activity of mTOR Inhibitors in Cancer Therapy

by Seraina Faes, Tania Santoro, Nicolas Demartines and Olivier Dormond

Cancers 2017, 9(11), 152; https://doi.org/10.3390/cancers9110152 - 1 Nov 2017

Cited by 37 | Viewed by 6050

Abstract

mTOR inhibitors have demonstrated remarkable anti-tumor activity in experimental models, mainly by reducing cancer cell growth and tumor angiogenesis. Their use in cancer patients as monotherapy has, however, generated only limited benefits, increasing median overall survival by only a few months. Likewise, in [...] Read more.

mTOR inhibitors have demonstrated remarkable anti-tumor activity in experimental models, mainly by reducing cancer cell growth and tumor angiogenesis. Their use in cancer patients as monotherapy has, however, generated only limited benefits, increasing median overall survival by only a few months. Likewise, in other targeted therapies, cancer cells develop resistance mechanisms to overcome mTOR inhibition. Hence, novel therapeutic strategies have to be designed to increase the efficacy of mTOR inhibitors in cancer. In this review, we discuss the present and future relevance of mTOR inhibitors in cancer therapy by focusing on their effects on tumor angiogenesis. Full article

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

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Open AccessReview

Evolving Therapeutic Strategies to Exploit Chromosome Instability in Cancer

by Laura L. Thompson, Lucile M-P. Jeusset, Chloe C. Lepage and Kirk J. McManus

Cancers 2017, 9(11), 151; https://doi.org/10.3390/cancers9110151 - 1 Nov 2017

Cited by 57 | Viewed by 8414

Abstract

Cancer is a devastating disease that claims over 8 million lives each year. Understanding the molecular etiology of the disease is critical to identify and develop new therapeutic strategies and targets. Chromosome instability (CIN) is an abnormal phenotype, characterized by progressive numerical and/or [...] Read more.

Cancer is a devastating disease that claims over 8 million lives each year. Understanding the molecular etiology of the disease is critical to identify and develop new therapeutic strategies and targets. Chromosome instability (CIN) is an abnormal phenotype, characterized by progressive numerical and/or structural chromosomal changes, which is observed in virtually all cancer types. CIN generates intratumoral heterogeneity, drives cancer development, and promotes metastatic progression, and thus, it is associated with highly aggressive, drug-resistant tumors and poor patient prognosis. As CIN is observed in both primary and metastatic lesions, innovative strategies that exploit CIN may offer therapeutic benefits and better outcomes for cancer patients. Unfortunately, exploiting CIN remains a significant challenge, as the aberrant mechanisms driving CIN and their causative roles in cancer have yet to be fully elucidated. The development and utilization of CIN-exploiting therapies is further complicated by the associated risks for off-target effects and secondary cancers. Accordingly, this review will assess the strengths and limitations of current CIN-exploiting therapies, and discuss emerging strategies designed to overcome these challenges to improve outcomes and survival for patients diagnosed with cancer. Full article

(This article belongs to the Special Issue Chromosomal Instability and Cancers)

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Open AccessEditorial

CAR-T Cell Therapy: From the Bench to the Bedside

by Vita Golubovskaya

Cancers 2017, 9(11), 150; https://doi.org/10.3390/cancers9110150 - 31 Oct 2017

Cited by 27 | Viewed by 6245

Abstract

CAR (Chimeric Antigen receptor)-T cell therapy is a novel type of therapy that uses engineered T cells with an antibody single-chain variable fragment (ScFv) extracellular domain that binds tumor-associated antigens[...] Full article

(This article belongs to the Special Issue CAR-T Cell Therapy against Different Types of Cancer)

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Open AccessFeature PaperArticle

Novel Mechanisms of ALK Activation Revealed by Analysis of the Y1278S Neuroblastoma Mutation

by Jikui Guan, Yasuo Yamazaki, Damini Chand, Jesper R. Van Dijk, Kristina Ruuth, Ruth H. Palmer and Bengt Hallberg

Cancers 2017, 9(11), 149; https://doi.org/10.3390/cancers9110149 - 30 Oct 2017

Cited by 15 | Viewed by 5773

Abstract

Numerous mutations have been observed in the Anaplastic Lymphoma Kinase (ALK) receptor tyrosine kinase (RTK) in both germline and sporadic neuroblastoma. Here, we have investigated the Y1278S mutation, observed in four patient cases, and its potential importance in the activation of the full [...] Read more.

Numerous mutations have been observed in the Anaplastic Lymphoma Kinase (ALK) receptor tyrosine kinase (RTK) in both germline and sporadic neuroblastoma. Here, we have investigated the Y1278S mutation, observed in four patient cases, and its potential importance in the activation of the full length ALK receptor. Y1278S is located in the 1278-YRASYY-1283 motif of the ALK activation loop, which has previously been reported to be important in the activation of the ALK kinase domain. In this study, we have characterized activation loop mutations within the context of the full length ALK employing cell culture and Drosophila melanogaster model systems. Our results show that the Y1278S mutant observed in patients with neuroblastoma harbors gain-of-function activity. Secondly, we show that the suggested interaction between Y1278 and other amino acids might be of less importance in the activation process of the ALK kinase than previously proposed. Thirdly, of the three individual tyrosines in the 1278-YRASYY-1283 activation loop, we find that Y1283 is the critical tyrosine in the activation process. Taken together, our observations employing different model systems reveal new mechanistic insights on how the full length ALK receptor is activated and highlight differences with earlier described activation mechanisms observed in the NPM-ALK fusion protein, supporting a mechanism of activation more in line with those observed for the Insulin Receptor (InR). Full article

(This article belongs to the Special Issue Targeting ALK in Cancer)

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Open AccessReview

Novel Molecular Challenges in Targeting Anaplastic Lymphoma Kinase in ALK-Expressing Human Cancers

by Abdulraheem Alshareef

Cancers 2017, 9(11), 148; https://doi.org/10.3390/cancers9110148 - 28 Oct 2017

Cited by 6 | Viewed by 5325

Abstract

Targeting anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase receptor initially identified as a potent oncogenic driver in anaplastic large-cell lymphoma (ALCL) in the form of nucleophosmin (NPM)-ALK fusion protein, using tyrosine kinase inhibitors has shown to be a promising therapeutic approach for [...] Read more.

Targeting anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase receptor initially identified as a potent oncogenic driver in anaplastic large-cell lymphoma (ALCL) in the form of nucleophosmin (NPM)-ALK fusion protein, using tyrosine kinase inhibitors has shown to be a promising therapeutic approach for ALK-expressing tumors. However, clinical resistance to ALK inhibitors invariably occurs, and the molecular mechanisms are incompletely understood. Recent studies have clearly shown that clinical resistance to ALK inhibitors is a multifactorial and complex mechanism. While few of the mechanisms of clinical resistance to ALK inhibitors such as gene mutation are well known, there are others that are not well covered. In this review, the molecular mechanisms of cancer stem cells in mediating resistance to ALK inhibitors as well as the current understanding of the molecular challenges in targeting ALK in ALK-expressing human cancers will be discussed. Full article

(This article belongs to the Special Issue Targeting ALK in Cancer)

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Open AccessReview

Clinical and Functional Assays of Radiosensitivity and Radiation-Induced Second Cancer

by Mohammad Habash, Luis C. Bohorquez, Elizabeth Kyriakou, Tomas Kron, Olga A. Martin and Benjamin J. Blyth

Cancers 2017, 9(11), 147; https://doi.org/10.3390/cancers9110147 - 27 Oct 2017

Cited by 37 | Viewed by 8840

Abstract

Whilst the near instantaneous physical interaction of radiation energy with living cells leaves little opportunity for inter-individual variation in the initial yield of DNA damage, all the downstream processes in how damage is recognized, repaired or resolved and therefore the ultimate fate of [...] Read more.

Whilst the near instantaneous physical interaction of radiation energy with living cells leaves little opportunity for inter-individual variation in the initial yield of DNA damage, all the downstream processes in how damage is recognized, repaired or resolved and therefore the ultimate fate of cells can vary across the population. In the clinic, this variability is observed most readily as rare extreme sensitivity to radiotherapy with acute and late tissue toxic reactions. Though some radiosensitivity can be anticipated in individuals with known genetic predispositions manifest through recognizable phenotypes and clinical presentations, others exhibit unexpected radiosensitivity which nevertheless has an underlying genetic cause. Currently, functional assays for cellular radiosensitivity represent a strategy to identify patients with potential radiosensitivity before radiotherapy begins, without needing to discover or evaluate the impact of the precise genetic determinants. Yet, some of the genes responsible for extreme radiosensitivity would also be expected to confer susceptibility to radiation-induced cancer, which can be considered another late adverse event associated with radiotherapy. Here, the utility of functional assays of radiosensitivity for identifying individuals susceptible to radiotherapy-induced second cancer is discussed, considering both the common mechanisms and important differences between stochastic radiation carcinogenesis and the range of deterministic acute and late toxic effects of radiotherapy. Full article

(This article belongs to the Special Issue Radiation-Induced Carcinogenesis)

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Open AccessConference Report

Advances in Precision Medicine: Tailoring Individualized Therapies

by Kyle B. Matchett, Niamh Lynam-Lennon, R. William Watson and James A. L. Brown

Cancers 2017, 9(11), 146; https://doi.org/10.3390/cancers9110146 - 25 Oct 2017

Cited by 21 | Viewed by 6046

Abstract

The traditional bench-to-bedside pipeline involves using model systems and patient samples to provide insights into pathways deregulated in cancer. This discovery reveals new biomarkers and therapeutic targets, ultimately stratifying patients and informing cohort-based treatment options. Precision medicine (molecular profiling of individual tumors combined [...] Read more.

The traditional bench-to-bedside pipeline involves using model systems and patient samples to provide insights into pathways deregulated in cancer. This discovery reveals new biomarkers and therapeutic targets, ultimately stratifying patients and informing cohort-based treatment options. Precision medicine (molecular profiling of individual tumors combined with established clinical-pathological parameters) reveals, in real-time, individual patient’s diagnostic and prognostic risk profile, informing tailored and tumor-specific treatment plans. Here we discuss advances in precision medicine presented at the Irish Association for Cancer Research Annual Meeting, highlighting examples where personalized medicine approaches have led to precision discovery in individual tumors, informing customized treatment programs. Full article

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

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Open AccessReview

Does Hypoxia Cause Carcinogenic Iron Accumulation in Alcoholic Liver Disease (ALD)?

by Inês Silva, Vanessa Rausch, Helmut-Karl Seitz and Sebastian Mueller

Cancers 2017, 9(11), 145; https://doi.org/10.3390/cancers9110145 - 25 Oct 2017

Cited by 22 | Viewed by 7852

Abstract

Alcoholic liver disease (ALD) is a leading health risk worldwide. Hepatic iron overload is frequently observed in ALD patients and it is an important and independent factor for disease progression, survival, and the development of primary liver cancer (HCC). At a systemic level, [...] Read more.

Alcoholic liver disease (ALD) is a leading health risk worldwide. Hepatic iron overload is frequently observed in ALD patients and it is an important and independent factor for disease progression, survival, and the development of primary liver cancer (HCC). At a systemic level, iron homeostasis is controlled by the liver-secreted hormone hepcidin. Hepcidin regulation is complex and still not completely understood. It is modulated by many pathophysiological conditions associated with ALD, such as inflammation, anemia, oxidative stress/H₂O_2, or hypoxia. Namely, the data on hypoxia-signaling of hepcidin are conflicting, which seems to be mainly due to interpretational limitations of in vivo data and methodological challenges. Hence, it is often overlooked that hepcidin-secreting hepatocytes are physiologically exposed to 2–7% oxygen, and that key oxygen species such as H₂O₂ act as signaling messengers in such a hypoxic environment. Indeed, with the recently introduced glucose oxidase/catalase (GOX/CAT) system it has been possible to independently study hypoxia and H₂O₂ signaling. First preliminary data indicate that hypoxia enhances H₂O₂-mediated induction of hepcidin, pointing towards oxidases such as NADPH oxidase 4 (NOX4). We here review and discuss novel concepts of hypoxia signaling that could help to better understand hepcidin-associated iron overload in ALD. Full article

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

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Cancers, Volume 9, Issue 11 (November 2017) – 15 articles

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