TITLE : CXCL 5 is a Novel Mediator of Prostate Cancer Proliferation and Migration

CXCL5 is a proangiogenic CXC-type chemokine that is an inflammatory mediator and a powerful attractant for granulocytic immune cells. Unlike many other chemokines, CXCL5 is secreted by both immune (neutrophil, monocyte, and macrophage) and nonimmune (epithelial, endothelial, and fibroblastic) cell types. The current study was intended to determine which of these cell types express CXCL5 in normal and malignant human prostatic tissues, whether expression levels correlated with malignancy and whether CXCL5 stimulated biologic effects consistent with a benign or malignant prostate epithelial phenotype. The results of these studies show that CXCL5 protein expression levels are concordant with prostate tumor progression, are highly associated with inflammatory infiltrate, and are frequently detected in the lumens of both benign and malignant prostate glands. Exogenous administration of CXCL5 stimulates cellular proliferation and gene transcription in both nontransformed and transformed prostate epithelial cells and induces highly aggressive prostate cancer cells to invade through synthetic basement membrane in vitro. These findings suggest that the inflammatory mediator, CXCL5, may play multiple roles in the etiology of both benign and malignant proliferative diseases in the prostate. Neoplasia (2008) 10, 244–254 Address all correspondence to: Jill A. Macoska, PhD, Department of Urology, University of Michigan, 6217 CCGC, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0944. E-mail: [email protected] This work was supported by the National Institutes of Health awards from the George M. O’Brien Center for Urologic Research at the University of Michigan 1 P50 DK065313 (J.A.M.), the University of Michigan Comprehensive Cancer Center support grant 5 P30 CA46592 (J.A.M., A.M.C.), the University of Michigan Prostate Cancer Specialized Program of Research Excellence (SPORE) grant 5 P50 CA068568 (A.M.C.), W81XWH-07-1-0385 from the Department of Defense’s Congressionally Directed Medical Research Program (J.A.M.), and funds awarded by Domino’s Pizza, L.L.C. (J.A.M.) Received 16 November 2007; Revised 20 December 2007; Accepted 28 December 2007 Copyright © 2008 Neoplasia Press, Inc. All rights reserved 1522-8002/08/$25.00 DOI 10.1593/neo.07976 Introduction The American Cancer Society estimates that there will be nearly 219,000 newly diagnosed cases of prostate cancer in the United States in 2007 and that an estimated 27,000 patients, or more than 10% of those diagnosed with prostate cancer, will die of this disease. It is also estimated that prostate cancer alone will account for almost 30% of cancer incidents in American men and almost 10% of cancer deaths. Although deaths due to prostate cancer have declined over the past decades, it is still the most commonly diagnosed cancer and accounts for the second highest death rate from cancer among American men [1]. Clearly, a better understanding of the biology of prostate cancer initiation and progression that would facilitate the development of strategies for the successful prevention or therapeutic intervention of this common malignancy is needed. Although successful interventional therapeutic strategies for prostate cancer have hinged on hormonal ablation therapies, recent studies have shown that growth factors other than steroid hormones play key roles in the development and progression of prostate cancer. Among these molecules are a large class of immunomodulator proteins termed chemokines. Chemokines are soluble mediators involved in angiogenesis, cellular growth control, cellular motility, wound healing, and inflammatory responses [2]. Although extensively studied as part of the immune Neoplasia Vol. 10, No. 3, 2008 CXCL5 Promotes Prostate Cancer Progression Begley et al. 245 system, chemokines have recently been investigated as possible mediators of mammalian tumor development and progression. Our laboratory has shown that the CXC-type chemokine, CXCL12, is secreted at subnanomolar quantities by aging prostate stroma and stimulates both a proliferative and transcriptional response from both nontransformed and transformed prostate epithelial cells [3,4]. Several other laboratories have shown that stromally secreted CXCL12 stimulates prostate cancer cells to become motile and invade through both synthetic basement membrane and endothelial cell barriers in vitro, and promotes prostate tumor growth and metastasis in vivo [5–8]. More recently, another CXC-type chemokine, CXCL5, has been the focus of studies examining the role(s) of chemokines in tumorigenesis. Like other chemokines that recognize and bind the Gprotein–coupled receptor CXCR2, CXCL5 is proangiogenic and is a powerful attractant for granulocytic immune cells. Unlike many other chemokines, however, CXCL5 is secreted by several cell types, including epithelial cells, endothelial cells, fibroblasts, neutrophils, monocytes, and macrophages [2,9]. Studies examining the expression of CXCL5 in human tumors and tumor cells in vitro have reported that CXCL5 transcripts are significantly upregulated in sporadic endometrioid endometrial adenocarcinomas compared to normal endometrium [10]. CXCL5 transcript and secreted protein have also been observed as significantly upregulated in cells derived from metastatic compared to primary head and neck squamous cell carcinomas, and RNA interference of the CXCL5 transcript reduced the ability of head and neck squamous carcinoma cells to migrate and invade through the Matrigel in vitro [11,12]. Studies by Park et al. [13] have shown that CXCL5 protein overexpression was associated with latestage gastric cancer and high N stage, suggesting a role for CXCL5 in the progression of gastric cancer, specifically in lymph node metastasis. The current study was intended to investigate whether CXCL5 was expressed concordantly with prostate tumor progression, and whether CXCL5 could stimulate phenotypic responses in prostate epithelial cells consistent with malignant progression.