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      The Chemokine CXCL8 in Carcinogenesis and Drug Response

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          Abstract

          Although the functions of chemokines in the regulation of immune processes have been studied in some detail, the role of these biomolecules in cancer is not fully understood. Chemokines mediate migration of immune cells and other functions related to immunity. They are also involved in oncogenesis and in tumor progression, invasion, and metastasis through mechanisms similar to their roles in immune functions. Various chemokines also promote cell proliferation and resistance to apoptosis of stressed cells. Consequently, chemokines and their receptors present potential therapeutic targets for anticancer drugs. The chemokine CXCL8, also known as interleukin-8 (IL8), is a proinflammatory molecule that has functions within the tumor microenvironment. Due to its potent angiogenic effects and the activity of the chemokine and its receptors in the promotion of invasion and metastasis, CXCL8 and its receptors are now considered as attractive targets for cancer therapy. This review relates the current understanding of the regulation, signaling, and functions of CXCL8 that contribute to tumor growth and metastasis, and of its role in drug response.

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          Most cited references93

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          Chemokine signaling via the CXCR2 receptor reinforces senescence.

          Cells enter senescence, a state of stable proliferative arrest, in response to a variety of cellular stresses, including telomere erosion, DNA damage, and oncogenic signaling, which acts as a barrier against malignant transformation in vivo. To identify genes controlling senescence, we conducted an unbiased screen for small hairpin RNAs that extend the life span of primary human fibroblasts. Here, we report that knocking down the chemokine receptor CXCR2 (IL8RB) alleviates both replicative and oncogene-induced senescence (OIS) and diminishes the DNA-damage response. Conversely, ectopic expression of CXCR2 results in premature senescence via a p53-dependent mechanism. Cells undergoing OIS secrete multiple CXCR2-binding chemokines in a program that is regulated by the NF-kappaB and C/EBPbeta transcription factors and coordinately induce CXCR2 expression. CXCR2 upregulation is also observed in preneoplastic lesions in vivo. These results suggest that senescent cells activate a self-amplifying secretory network in which CXCR2-binding chemokines reinforce growth arrest.
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            Chemokines: a new classification system and their role in immunity.

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              Anti-inflammatory therapy in chronic disease: challenges and opportunities.

              A number of widespread and devastating chronic diseases, including atherosclerosis, type 2 diabetes, and Alzheimer's disease, have a pathophysiologically important inflammatory component. In these diseases, the precise identity of the inflammatory stimulus is often unknown and, if known, is difficult to remove. Thus, there is interest in therapeutically targeting the inflammatory response. Although there has been success with anti-inflammatory therapy in chronic diseases triggered by primary inflammation dysregulation or autoimmunity, there are considerable limitations. In particular, the inflammatory response is critical for survival. As a result, redundancy, compensatory pathways, and necessity narrow the risk:benefit ratio of anti-inflammatory drugs. However, new advances in understanding inflammatory signaling and its links to resolution pathways, together with new drug development, offer promise in this area of translational biomedical research.
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                Author and article information

                Journal
                ISRN Oncol
                ISRN Oncol
                ISRN.ONCOLOGY
                ISRN Oncology
                Hindawi Publishing Corporation
                2090-5661
                2090-567X
                2013
                9 October 2013
                : 2013
                : 859154
                Affiliations
                1Center for Cancer Research and Department of Pathobiology, Tuskegee University, 1200 Old Montgomery Road, School of Veterinary Medicine, Tuskegee, AL 36830, USA
                2Morehouse School of Medicine, 720 Westview Drive, S.W., Atlanta, GA 30310, USA
                3Department of Pathology, and Comprehensive Cancer Center, University of Alabama, Birmingham, 1720 Second Avenue South, AL 35294, USA
                Author notes

                Academic Editors: P. Balaram, G. E. Lind, and K. van Golen

                Author information
                http://orcid.org/0000-0003-4335-2519
                http://orcid.org/0000-0001-9722-5318
                Article
                10.1155/2013/859154
                3810054
                24224100
                2390cc00-ba79-47d7-a463-14ca575b043c
                Copyright © 2013 Dominique Gales 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
                : 17 June 2013
                : 8 September 2013
                Funding
                Funded by: http://dx.doi.org/10.13039/100000002 National Institutes of Health
                Award ID: U54CA118623
                Categories
                Review Article

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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