Special Issue "Oxidative Stress and Cancer"

Guest Editor
Prof. Dr. Alba Minelli
Cellular Biochemistry Unit, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06124, Perugia, Italy
E-Mail:
Interests: prostate cancer; oxidative stress; prostasomes; adenosine

Dear Colleagues,

Over 7,500 articles on oxidative stress related cancers are substantial evidence of the paramount importance of the control of cellular redox homeostasis which is challenged, throughout life, by sustained oxidative stress, chronic inflammation, and excessive antigen-loading. Oxidative stress-induced activation of NADPH oxidase and peroxisome proliferators-activated receptors, oxidants and inflammatory mediators, i.e. IL-6, IL-10, TNF-α, PGs, alterations of redox state of binding proteins, DNA mutations and induction of early response genes and hematopoietic activation seem to be common elements in the induction of hyperplasia, neoplasia, cancer metastasis, and angiogenesis. Therefore, potential health benefits of a number of antioxidants or anti-inflammatory agents, and maintenance of cellular oxido-redox status are crucial for optimal tissue function. This is a complicated topic which can be investigated from a number of perspectives. Our final goal is the compilation of a special issue providing an integrated understanding / identification of developmental phases of oxidative stress-induced cancers that will assist professionals towards effective progress on cancer war.

Thank you for your collaboration.

Prof. Dr. Alba Minelli
Guest Editor

Submission Information

All manuscripts should be submitted to cancers@mdpi.org with a copy to the Guest Editor. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed Open Access monthly journal published by MDPI.

For the first two issues, to be published in 2009 and 2010, the Article Processing Charges (APC) will be waived for well-prepared manuscripts. English correction and/or formatting fees of 250 CHF (Swiss Francs) will be charged in certain cases for those articles accepted for publication that require extensive additional formatting and/or English corrections.

Type of Paper: Article
Title: Nrf2 and Nf-kb and their concerted modulation in cancer pathogenesis and progression
Authors: Ilaria Bellezza and Alba Minelli
Affiliation: Dipartimento Medicina Sperimentale Scienze Biochimiche, Sezione Biochimica cellulare, Università di Perugia, Via del giochetto, 06124 Perugia, Italia; E-Mail: ilaria.bellezza@unipg.it
Abstract: The pathogenesis of cancer can be ascribed either to genetic mutation or to chemical insults caused by environmental toxicants and endogenous oxidants. Reactive oxygen species, produced by oxidative stress, implicated in the initiation, promotion, and malignant conversion of carcinogenesis are the major source of endogenous DNA damage in aerobic organisms. Many transcription factors are redox-sensitive and are activated in response to oxidative stress. NF-E2-related factor 2 (Nrf2), activated upon oxidative conditions, binds to the antioxidant response element (ARE) in the promoter regions of several genes encoding proteins for antioxidant and general cytoprotection. NF-κB, an inducible, pleiotropic transcription factor, regulates the expression of the target genes by binding to the κB responsive element in their promoter region. Beside the classical pathway, NF-kB activation is stimulated by oxidising conditions, therefore it can be considered a redox-sensitive transcription factor. A variety of anti-inflammatory or anti-carcinogenetic phytochemicals suppresses NF-κB signalling and activates Nrf2- ARE pathway, therefore in this review we consider the role of Nrf2 and NF-kb, as redox sensitive transcription factors, in cancer pathogenesis and progression focusing on their concerted modulation and potential cross-talk.

Type of Paper: Review
Title: Oxidative stress induced mechanisms in the progression of periodontal diseases and cancer: A common approach to redox homeostasis?
Author: Mena Soory
Affiliation: Periodontology, King’s College London Dental Institute, UK; E-Mail: mena.soory@kcl.ac.uk
Abstract: Severe forms of periodontal diseases impose a significant inflammatory loading which could impact on the progression of systemic conditions including carcinogenesis. Conversely malignant progression of tumours has been shown to be associated with the development of oxidative stress, which highlights the relevance of antioxidants in anti-cancer therapeutics, also relevant to the adjunctive management of periodontal diseases. There is documented evidence of significant associations between cancer of the lung, kidney, pancreas, haematological cancers and periodontal diseases. Enhanced lipid peroxidation, raised levels of TBARS and the oxidative stress marker malondealdehyde have been detected in breast cancer with reduced total antioxidant capacity, also characteristic of periodontal diseases. Antioxidants could overcome this deficit and attenuate disease progression. For example, dehydroascorbic acid reacts with homocysteine thiolactone in cancer cells leading to the formation of 3-mercaptopropionaldehyde, toxic to cancer cells. Other active agents reported in this context are green tea polyphenols, melatonin and vitamin D, relevant to periodontal disease outcome. Melatonin is also effective in promoting type 1 collagen and bone formation. Green tea polyphenols induce apoptosis in various tumour cell systems. This apoptotic mechanism targets mitochondria and is executed by caspase 3. Drug resistant cell populations can emerge in response to a milieu of oxidative stress. Nitric oxide mimetic agents restore their sensitivity to cytotoxic agents both in vivo and in vitro. Mechanisms involved include antioxidant effects, down regulation of the glutathione detoxification / redox buffering system and inhibition of key transcription factors. Periodontal disease is associated with a small but significant overall cancer risk which persists in non-smokers. It may be a useful marker of a susceptible immune system, or directly affect cancer risk as a result of a pro-oxidant inflammatory profile. There is a case for adjunctive antioxidant formulations which could minimize side effects of conventional therapeutics, of relevance to both periodontal disease and cancer progression.

Type of Paper: Review
Title: Oxidative Stress-induced Tumor Stemness Switch: A New Perspective on Tumor Progression and Metastasis
Author: Bikul Das
Affiliation: Medical Oncology, Stanford University Medical School, CA, USA; E-Mail: bikuldas@stanford.edu
Abstract: One of the hallmarks of tumor microenvironment is the prevailing stress of hypoxia and oxidative stress injury. This “injured microenvironment” may act as a niche for tumor stem cells (TSC), and activate key signaling pathways that switch the quiescent population of TSC to an active mode of self-renewal and expansion (stemness switch)”. The stemness switch may be an important early event of tumor progression and metastasis. Signaling pathways such as HIF/VEGF mediated upregulation of stemenss related transcription factors such as Oct4 may be invoved in the oxidative-stress induced tumor stemness switch. The review will discuss the idea and preliminary findings on tumor stemness switch model.

Type of Paper: Review
Title: Role of Oxidative Stresses in Stem, Cancer, and Cancer Stem Cells
Authors: Abdal Dayem, A. M. H., Jung-Hyun Kim, and Ssang-Goo Cho
Affiliation: Department of Animal Biotechnology (BK21), Bio/Molecular Informatics Center, and Animal Resources Research Center, Konkuk University, Seoul 143-701, Korea; E-Mail: ssangoo@konkuk.ac.kr
Abstract: The concept of cancer stem cells arose from observation of similarities between the self-renewal mechanism of stem cells and that of cancer stem cells, but compared to normal stem cells, the cancer stem cells are believed to have no control on the cell numbers. The term ‘‘oxidative stress”, referring to a cell’s state characterized by excessive production of reactive oxygen species (ROS) and oxidative stress, is one of the most important regulatory mechanisms for cancer cells and stem and cancer stem cells. ROS have been implicated in diverse processes in various cancers and generally the increase of ROS in cancer cells was known to play an important role in the initiation and progression of cancer. Additionally, ROS were considered as the most significant mutagens in stem cells, when elevated, blocking self-renewal and at the same time, serve as a signal stimulating stem cell differentiation. Several signaling pathways enhanced by oxidative stress were suggested to have important roles in tumorigenesis of cancer or cancer stem cells and self-renewal ability of stem or cancer stem cells. This review elucidates the effect and the mechanism of the oxidative stress on regulation of stem, cancer, and cancer stem cells and focuses on the cell signaling cascades stimulated by oxidative stress and their mechanism in cancer stem cell formation, as very little known about the redox status in cancer stem cells.

Type of Paper: Review
Title: Oxidative and Nitrosative Stress in the Metastatic Microenvironment
Authors: Angel Ortega ^1,2, Salvador Mena ² and José M. Estrela ^1,2
Affiliations: ¹ Department of Physiology, University of Valencia, 15 Av. B. Ibanez, 46010 Valencia, Spain
² Green Molecular S.L., Paterna, Spain; E-Mail: jose.m.estrela@uv.es
Abstract: Metastases that are resistant to conventional therapies are the main cause of most cancer-related deaths in humans. Tumor cell heterogeneity, which associates with genomic and phenotypic instability, represents a major problem for cancer therapy. Besides additional factors, such as e.g. the attack of immune cells or organ-specific microenvironments, also influence metastatic cell behavior and the response to therapy. Interaction of cancer and cells in capillary beds, involving mechanical contact and transient adhesion, is a critical step in the initiation of metastasis. This interaction initiates a cascade of activation pathways that involves cytokines, growth factors, bioactive lipids, reactive oxygen and nitrogen species (ROS and RNS) produced by either the cancer cell or the endothelium. Vascular endothelium-derived NO and H₂O₂ are cytotoxic for the cancer cells, but also help to identify some critical molecular targets that appear essential for survival of invasive metastatic cell subsets. Surviving cancer cells that extravasate and start colonization of an organ or tissue still can be attacked by macrophages and be influenced by specific intraorgan microenvironment conditions. At all steps, from the primary tumor until colonization of a distant organ, metastatic cells undergo a dynamic process of constant adaptations that may lead to the survival of highly resistant malignant cell subsets. In this sequence of molecular events both ROS and RNS play key roles.

Type of Paper: Review
Title: Role of Uncoupling Proteins in Cancer
Authors: Adamo Valle, Jordi Oliver and Pilar Roca
Affiliation: Department de Biologia Fonamental i Ciències de la Salut, Ed. Guillem Colom, Universitat de les Illes Balears, Cra. Valldemossa km 7.5, Palma de Mallorca – 07122, Spain; E-Mail: dbsprs0@uib.es (P.R.)
Abstract: Uncoupling proteins (UCPs) are a family of the inner mitochondrial membrane proteins whose function is to allow the re-entry of protons to the mitochondrial matrix, dissipating the proton gradient and, subsequently, decreasing membrane potential and production of reactive oxygen species (ROS). Due to their pivotal role in the intersection between energy efficiency and oxidative stress, UCPs are being investigated for a potential role in cancer. In this review we compile the latest evidence showing a link between uncoupling and the carcinogenic process, paying special attention to their involvement in cancer initiation, progression and drug chemoresistance.

Type of Paper: Review
Title: The Role of Oxidative Stress in Carcinogenesis Induced by Metals and Xenobiotics
Authors: Frank Henkler, Joseph Brinkmann and Andreas Luch
Affiliation: German Federal Institute for Risk Assessment, Department of Product Safety, Berlin, Germany; E-Mail: Andreas.Luch@bfr.bund.de
Abstract: In addition to a range of organ-specific adverse effects induced in the human body, toxic metals, such as cadmium, arsenic and nickel can also promote carcinogenesis. Cellular toxicity of these metals is partly dependent upon generation of reactive oxygen species (ROS) that can induce DNA damage and trigger activity of redox-dependent transcription factors. The precise mechanisms that induce oxidative stress are not fully understood. Further, it is not yet known whether chronic exposures to low doses of arsenic, cadmium or other metals are sufficient to induce mutations in vivo, leading to DNA repair responses, unbalanced cell proliferation and eventually tumorigenesis. Oxidative stress can also be induced by environmental xenobiotics through, e.g., patterns of metabolites capable of fostering continuous release of superoxide. Due to concurrent formation of DNA adducts by mutagenic metabolites of parent compounds, however, the specific contribution and role of superoxide dependent pathways to carcinogenesis is rather difficult to address. We will review here both mechanisms and toxicological consequences of oxidative stress triggered by metals and dietary or environmental pollutants in general. Besides DNA damage, ROS may induce further multiple intracellular signalling pathways, notably NFκB, JNK/SAPK/p38, as wells as Erk/MAPK. These signaling routes can lead to transcriptional induction of target genes that likely trigger proliferation or confer apoptosis resistance to those cells exposed. The importance and significance of these additional tumor-promoting pathways depends on the cell type and tissue, and will be discussed for dermal and oral exposures.

Type of Paper: Article
Title: Proteomic Analysis of Human Cell Models of Arsenic Carcinogenesis
Author: Yue Ge
Affiliation: National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA; E-Mail: Ge.Yue@epamail.epa.gov
Abstract: A variety of cancers including lung and bladder cancers have been linked to arsenic exposure. In order to unravel of the toxic processes as well as to obtain insight into molecular basis and mode of action of arsenic-induced tumorigenesis, we have performed a comprehensive proteomic analysis of human bladder cell line, Urota cells and human primary cells, keratinocytes exposed with arsenic using an integrated redox proteomics approach. Some important genes and pathways involved in oxidative stress have been identified, suggesting the roles of oxidative stress in arsenic-induced carcinogenesis.

Title: Oxidative Stress in the Transition to Androgen Independence in Prostate Cancer
Authors: Laure Marignol ^1,2, Donal Hollywood ² and Mark Lawler ²
Affiliations: ¹Division of Radiation Therapy, Trinity College Dublin, Ireland
² Department of Haematology and Academic Unit of Clinical and Molecular Oncology, Institute of Molecular Medicine, St James’s Hospital and Trinity College Dublin, Ireland; E-Mail: mplawler@tcd.ie
Abstract: Growing evidence has linked prostate cancer carcinogenesis with early loss of cellular protection to oxidative damage, participating in increased DNA damage and genetic instability, leading to aggressive treatment resistant disease. In prostate cancer, the transition from androgen-dependence to androgen-independence is a key event. Oxidative stress and tumour hypoxia have largely been associated with disease progression and treatment failure, but to date the effect of oxidative stress on known mechanisms of androgen resistance and disease progression is poorly understood. This review thus proposes to examine the involvement of oxidative stress in the transition to androgen-independence in prostate tumours and to examine how tumour hypoxia may be harnessed for therapeutic benefit.