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      The Roles of ROS in Cancer Heterogeneity and Therapy

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          Abstract

          Cancer comprises a group of heterogeneous diseases encompassing high rates of morbidity and mortality. Heterogeneity, which is a hallmark of cancer, is one of the main factors related to resistance to chemotherapeutic agents leading to poor prognosis. Heterogeneity is profoundly affected by increasing levels of ROS. Under low concentrations, ROS may function as signaling molecules favoring tumorigenesis and heterogeneity, while under high ROS concentrations, these species may work as cancer modulators due to their deleterious, genotoxic or even proapoptotic effect on cancer cells. This double-edged sword effect represented by ROS relies on their ability to cause genetic and epigenetic modifications in DNA structure. Antitumor therapeutic approaches may use molecules that prevent the ROS formation precluding carcinogenesis or use chemical agents that promote a sudden increase of ROS causing considerable oxidative stress inside tumor mass. Therefore, herein, we review what ROS are and how they are produced in normal and in cancer cells while providing an argumentative discussion about their role in cancer pathophysiology. We also describe the various sources of ROS in cancer and their role in tumor heterogeneity. Further, we also discuss some therapeutic strategies from the current landscape of cancer heterogeneity, ROS modulation, or ROS production.

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          Most cited references78

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          ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis.

          Reactive oxygen species (ROS) have been shown to be toxic but also function as signalling molecules. This biological paradox underlies mechanisms that are important for the integrity and fitness of living organisms and their ageing. The pathways that regulate ROS homeostasis are crucial for mitigating the toxicity of ROS and provide strong evidence about specificity in ROS signalling. By taking advantage of the chemistry of ROS, highly specific mechanisms have evolved that form the basis of oxidant scavenging and ROS signalling systems.
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            Epigenetics in cancer.

            Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Global changes in the epigenetic landscape are a hallmark of cancer. The initiation and progression of cancer, traditionally seen as a genetic disease, is now realized to involve epigenetic abnormalities along with genetic alterations. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer including DNA methylation, histone modifications, nucleosome positioning and non-coding RNAs, specifically microRNA expression. The reversible nature of epigenetic aberrations has led to the emergence of the promising field of epigenetic therapy, which is already making progress with the recent FDA approval of three epigenetic drugs for cancer treatment. In this review, we discuss the current understanding of alterations in the epigenetic landscape that occur in cancer compared with normal cells, the roles of these changes in cancer initiation and progression, including the cancer stem cell model, and the potential use of this knowledge in designing more effective treatment strategies.
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              Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression.

              Tumors are like new organs and are made of multiple cell types and components. The tumor competes with the normal microenvironment to overcome antitumorigenic pressures. Before that battle is won, the tumor may exist within the organ unnoticed by the host, referred to as 'occult cancer'. We review how normal tissue homeostasis and architecture inhibit progression of cancer and how changes in the microenvironment can shift the balance of these signals to the procancerous state. We also include a discussion of how this information is being tailored for clinical use.
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                Author and article information

                Contributors
                Journal
                Oxid Med Cell Longev
                Oxid Med Cell Longev
                OMCL
                Oxidative Medicine and Cellular Longevity
                Hindawi
                1942-0900
                1942-0994
                2017
                16 October 2017
                : 2017
                : 2467940
                Affiliations
                1Mogi das Cruzes University (UMC), Villa Lobos Campus, Sao Paulo, SP, Brazil
                2Laboratory of Genetics, Butantan Institute, Sao Paulo, SP, Brazil
                3Morphology and Genetic Department, University Federal of Sao Paulo, Sao Paulo, SP, Brazil
                4University of Sao Paulo, Sao Paulo, SP, Brazil
                5Department of Immunology, Laboratory of Tumor Immunology, Institute of Biomedical Science, University of Sao Paulo, Sao Paulo, SP, Brazil
                Author notes

                Academic Editor: Tullia Maraldi

                Author information
                http://orcid.org/0000-0002-7730-0859
                http://orcid.org/0000-0001-8288-2577
                http://orcid.org/0000-0002-2605-1899
                Article
                10.1155/2017/2467940
                5662836
                29123614
                6ccb71c4-5365-4f7e-80b5-ee495e077a74
                Copyright © 2017 Paulo Luiz de Sá Junior et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 5 May 2017
                : 3 August 2017
                : 27 August 2017
                Funding
                Funded by: Fundação de Amparo à Pesquisa do Estado de São Paulo
                Award ID: 2013/07273-2
                Award ID: 2015/18528-7
                Categories
                Review Article

                Molecular medicine
                Molecular medicine

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