Reactive oxygen species (ROS) in multistage carcinogenesis

Reactive oxygen species (ROS) in multistage carcinogenesis

Available online at www.sciencedirect.com Cancer Letters 266 (2008) 3–5 www.elsevier.com/locate/canlet Editorial Reactive oxygen species (ROS) in m...

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Available online at www.sciencedirect.com

Cancer Letters 266 (2008) 3–5 www.elsevier.com/locate/canlet

Editorial

Reactive oxygen species (ROS) in multistage carcinogenesis All cancers have their own unique characteristics reflecting their morphological features that in turn are based on the tissue from which they arise. Therefore, it is exactly this principle that we are utilizing for diagnosis and perhaps even prognosis of a malignant tissue versus a normal one. Cancer biology is a complex multistage process and should never just be seen as simply the inability of an otherwise normal cell to control its growth and proliferation. In fact, a number of cellular processes are altered during malignant transformation such as those of replication, metastasis, angiogenesis, apoptosis, etc. Although some of these processes have been investigated in great detail there is still a great deal of mystery involved as to how they are altered during carcinogenesis. For example, although defective apoptosis is a well established part of the carcinogenic process, there is a gap in our understanding as to how apoptotic genes are involved and how is their expression regulated. If we look up the term ‘‘free radical”, in any textbook, it refers to any molecular species characterized by the presence of one or more unpaired electrons. Their ‘‘unstable” chemical nature confers them with the property of being highly reactive. They ultimately react with major macromolecules like DNA, RNA, proteins, and lipids and thus lead to cellular toxicity. Free radicals include both reactive oxygen (ROS) and nitrogen (RNS) species. When ROS generation exceeds the cell’s ability to metabolize and detoxify them, a state of oxidative stress emerges. ROS production can be of endogenous (mitochondrial oxidative metabolism, P450 metabolism, and inflammatory cell activation) as well as exogenous (radiation, ozone, industrial chemicals, and xenobiotics) origin. In fact, many of the environmental, occupational and industrial chemicals are able to generate free radical species

(primarily through their metabolism) that contribute to the pathophysiology of many human diseases including cancer. In this regard, only the last 10– 15 years have ROS been established as important molecules involved in the multistage process of carcinogenesis. In this Special Issue, we have assemble a number of concise review articles, by experts in their fields that discuss the potential molecular mechanisms by which ROS are involved during transformation to malignancy. I and colleagues at the University of Nevada-Reno and the National Institute of Environmental & Health Sciences (NIEHS/NIH) in USA, respectively, review the role of ROS in influencing the DNA methylation pathway. Only recently, gene expression has been shown to be regulated by the epigenetic pathway, which involves reversible heritable changes in gene regulation occurring without a change in DNA sequence. Thus, it may be that specific epigenetic alterations are underlying the altered gene expression characteristic of many tumors. In particular, epigenetic alterations involving changes in DNA methylation patterns have been shown to underlie specific gene expression profiles in various cancers. It is therefore important to identify the molecular mechanisms of how ROS modulate DNA methylation patterns and ultimately gene expression during carcinogenesis. Dr. Sandaltzopoulo’s group at the Democritus University of Thrace in Greece reviews the role of ROS in HIF-1 (Hypoxia-Inducible Factor-1) signaling and its consequences to carcinogenesis. Given that tumors require a hypoxic micro-environment this transcription factor represents the key mediator in controlling many genes important for the wellbeing of a tumor. Such genes can be those of angiogenesis, cell cycle control and inhibition of apoptosis all of which require HIF-1s increased

0304-3835/$ - see front matter Ó 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.canlet.2008.02.027

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Editorial / Cancer Letters 266 (2008) 3–5

transcriptional levels. Increased ROS generation has been linked with malfunction of the HIF-1 signaling pathway in various cancers including, but not restricted, to those of breast, ovarian and prostate origin. Dr. Galari’s group at the University of Ioannina Medical School in Greece reviews the role of ‘‘labile” iron in redox signaling during carcinogenesis. The so-called ‘‘labile” iron represents the redox-active form of iron that participates in the biochemistry of ROS-mediated cell signaling. In doing so, ‘‘labile” iron is actually involved in the signaling pathways crucial for cancer development by leading to altered expression of genes involved in cell proliferation and apoptosis. Dr. Cotter’s group at the University CollegeCork in Ireland, reviews the mechanisms by which ROS modulate cell survival during carcinogenesis. More specifically, this group focuses on the effect of ROS on the PI3-kinase/Akt signaling pathway. This is a cellular signaling pathway that is known to be redox regulated and as such influences cellular sensitivity to death-inducing signals. It can do so by directly influencing major apoptotic proteins (caspase-9 and BAD) and/or phosphatases (PP2A and PP1a), thus altering their dephosphorylation activity and ultimately providing tumors with a survival advantage. Dr. Ushio-Fukai’s group at the University of Illinois-Chicago in USA reviews the role of ROS in angiogenesis and particularly NADPH oxidase-induced ROS formation. Angiogenesis is essential for tumor development by providing cell growth and during metastasis. The underlying process requires endothelial cell proliferation and migration both of which are stimulated by vascular endothelial growth factor (VEGF) and specifically through VEGF receptor type-2 (VEGFR2). VEGF-induced activation of NADPH oxidase causes increased ROS generation that, in turn, is involved in VEGFR2 autophosphorylation leading to activation of genes critical in the angiogenic process. Dr. Nishikawa at the Kyoto University in Japan, reviews the role of ROS in tumor metastasis. His review emphasizes on the importance of the amount of ROS production in a way that while lethal concentrations are cytotoxic (and thus kill cancer cells) sub-lethal concentrations can act as second messengers and thus control transcription of adhesion molecules, growth and angiogenic factors all of which are implicated during metastasis.

Dr Livneh’s group at the Weizmann Institute of Science in Israel, reviews the DNA repair mechanisms involved in ROS-induced DNA damage during human carcinogenesis. In contrast to hereditary cancers where germ-line mutations ‘‘exist” in DNA repair genes, sporadic cancers have no germ-line mutations. This observation ‘‘translates” in that sporadic cancers have milder DNA repair deficiencies than hereditary ones making the assessment of the role of DNA repair in these cancers more difficult. For many years, 8-oxoguanine has been used as the most reliable marker of ROS-induced oxidative DNA damage. This finding together with recently developed approaches based on the functional analysis of DNA repair enzymatic activity, have provided us with the ability to identify DNA glycosylases (OGG: specific for repairing 8-oxoguanine lesions) with reduced activity, in various sporadic cancers (lung), that perhaps could be used as a risk factor for implementing better strategies regarding risk assessment. Dr. Luch’s group at the Federal Institute for Risk Assessment in Germany and at the Massachusetts Institute of Technology in USA, reviews the role of ROS in chemical carcinogenesis. It is apparent that many chemicals including xenobiotic compounds can induce ROS generation that could directly induce oxidative DNA damage and thus contribute to cell transformation and cancer initiation. In addition, both quinones and lipid peroxidation byproducts like malondialdehyde (MDA), 4hydroxynonenal (4-HNE) and alkenals can also damage DNA directly contributing to the carcinogenic process. Furthermore, a chemical’s susceptibility to chemical carcinogenesis depends not only on its metabolic profile but also on existing tissueand species-specific differences. Finally, Drs. Møller’s and Loft’s group at the University of Copenhagen in Denmark, reviews the impact of exposure to air pollution in ROS-induced oxidative DNA damage and its significance in human carcinogenesis. It is known that humans exposed to traffic-related air pollution particles like vehicle emissions show higher levels of oxidative DNA damage. In particular, the fraction of air pollution that pertains to particulate matter has shown to induce ROS generation through various reactions including transition metal catalyses, metabolism, redox-cycling of quinones, etc. Numerous studies have shown that air pollutioninduced generation of ROS leads to elevated levels of guanine oxidation in DNA that can be highly

Editorial / Cancer Letters 266 (2008) 3–5

mutagenic and thus contribute to lung cancer etiology. My goal as a guest editor of this special issue is to assist in enhancing our current understanding of the cellular and molecular mechanisms underlying ROS involvement in human carcinogenesis. For this reason, I would like to express my gratitude to all authors for contributing their expertise in this special issue of Cancer Letters in ‘‘Oxidative Stress and Carcinogenesis”.

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Last, but certainly not least, I would like to thank Dr. Manfred Schwab (Editor-in-Chief of Cancer Letters) for the opportunity he has given me as well as for his patience and support with putting this special issue together. Mihalis Panayiotidis* University of Nevada-Reno, School of Public Health, MS-274, Reno, NV 89557, USA E-mail address: [email protected]

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Tel.: +1 775 682 7082; fax: +1 775 784 1340.