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      Inflammatory Genetic Markers of Prostate Cancer Risk

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          Abstract

          Prostate cancer is the most common cancer in Western society males, with incidence rates predicted to rise with global aging. Etiology of prostate cancer is however poorly understood, while current diagnostic tools can be invasive (digital rectal exam or biopsy) and/or lack specificity for the disease (prostate-specific antigen (PSA) testing). Substantial histological, epidemiological and molecular genetic evidence indicates that inflammation is important in prostate cancer pathogenesis. In this review, we summarize the current status of inflammatory genetic markers influencing susceptibility to prostate cancer. The focus will be on inflammatory cytokines regulating T-helper cell and chemokine homeostasis, together with the Toll-like receptors as key players in the host innate immune system. Although association studies indicating a genetic basis for prostate cancer are presently limited mainly due to lack of replication, larger and more ethnically and clinically defined study populations may help elucidate the true contribution of inflammatory gene variants to prostate cancer risk.

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          Most cited references108

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          Inflammation in prostate carcinogenesis.

          About 20% of all human cancers are caused by chronic infection or chronic inflammatory states. Recently, a new hypothesis has been proposed for prostate carcinogenesis. It proposes that exposure to environmental factors such as infectious agents and dietary carcinogens, and hormonal imbalances lead to injury of the prostate and to the development of chronic inflammation and regenerative 'risk factor' lesions, referred to as proliferative inflammatory atrophy (PIA). By developing new experimental animal models coupled with classical epidemiological studies, genetic epidemiological studies and molecular pathological approaches, we should be able to determine whether prostate cancer is driven by inflammation, and if so, to develop new strategies to prevent the disease.
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            Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation.

            Tumor necrosis factor alpha (TNF alpha) is a potent immunomodulator and proinflammatory cytokine that has been implicated in the pathogenesis of autoimmune and infectious diseases. For example, plasma levels of TNF alpha are positively correlated with severity and mortality in malaria and leishmaniasis. We have previously described a polymorphism at -308 in the TNF alpha promoter and shown that the rare allele, TNF2, lies on the extended haplotype HLA-A1-B8-DR3-DQ2, which is associated with autoimmunity and high TNF alpha production. Homozygosity for TNF2 carries a sevenfold increased risk of death from cerebral malaria. Here we demonstrate, with reporter genes under the control of the two allelic TNF promoters, that TNF2 is a much stronger transcriptional activator than the common allele (TNF1) in a human B cell line. Footprint analysis using DNase I and B cell nuclear extract showed the generation of a hypersensitive site at -308 and an adjacent area of protection. There was no difference in affinity of the DNA-binding protein(s) between the two alleles. These results show that this polymorphism has direct effects on TNF alpha gene regulation and may be responsible for the association of TNF2 with high TNF alpha phenotype and more severe disease in infections such as malaria and leishmaniasis.
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              The role of CXC chemokines and their receptors in cancer.

              Chemokines, or chemotactic cytokines, and their receptors have been discovered as essential and selective mediators in leukocyte migration to inflammatory sites and to secondary lymphoid organs. Besides their functions in the immune system, they also play a critical role in tumor initiation, promotion and progression. There are four subgroups of chemokines: CXC, CC, CX(3)C, and C chemokine ligands. The CXC or alpha subgroup is further subdivided in the ELR(+) and ELR(-) chemokines. Members that contain the ELR motif bind to CXC chemokine receptor 2 (CXCR2) and are angiogenic. In contrast, most of the CXC chemokines without ELR motif bind to CXCR3 and are angiostatic. An exception is the angiogenic ELR(-)CXC chemokine stromal cell-derived factor-1 (CXCL12/SDF-1), which binds to CXCR4 and CXCR7 and is implicated in tumor metastasis. This review is focusing on the role of CXC chemokines and their receptors in tumorigenesis, including angiogenesis, attraction of leukocytes to tumor sites and induction of tumor cell migration and homing in metastatic sites. Finally, their therapeutic use in cancer treatment is discussed.
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                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                08 June 2010
                June 2010
                : 2
                : 2
                : 1198-1220
                Affiliations
                [1 ]Cancer Genetics Group, Children’s Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, University of New South Wales, PO Box 81, Randwick, NSW 2031, Australia; E-Mails: etindall@ 123456ccia.unsw.edu.au (E.A.T.); vhayes@ 123456ccia.unsw.edu.au (V.M.H.)
                [2 ]University of New South Wales, Kensington Campus, Sydney, NSW 2052, Australia
                Author notes
                [* ] Author to whom correspondence should be addressed; E-Mail: dpetersen@ 123456ccia.unsw.edu.au ; Tel.: +61-2-9385-1550; Fax: +61-2-9662-6583.
                Article
                cancers-02-01198
                10.3390/cancers2021198
                3835126
                61c35673-d980-4683-94be-ce9b2ee8e488
                © 2010 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                : 06 May 2010
                : 24 May 2010
                : 01 June 2010
                Categories
                Review

                prostate cancer,inflammation,toll like receptor (tlr),cytokine,chemokine,gene variant,inherited susceptibility

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