Abstract 5189: An IL-8 dependent autocrine circuit promotes colorectal cancer tumorigenicity
Authors: Robert C. Fisher, Elizabeth A. Butterworth, Myron Chang, Edward W. Scott, Emina H. Huang
Journal: Cancer Research (2011)

Abstract Introduction: It is well established that chronic inflammation of the colon increases the incidence of colorectal cancer. One plausible mechanism involves inflammation-associated signals targeting the cancer stem cell (CSC). The CSC hypothesis posits that solid tumors originate from a rare cell population with stem cell-like properties, including self-renewal, and the ability to initiate tumor growth. We have previously demonstrated that CSC-like cells can be enriched from sporadic colorectal tumors (CRC) based on high level aldehyde dehydrogenase (ALDH) enzyme activity and expression of the epithelial cell adhesion molecule (EpCAM). The ALDHhigh/EpCAM+ population was shown to initiate tumors in NOD-SCID mice, and termed the colon cancer initiating cell (CCIC). CRC-derived CCICs were able to be propagated in vitro under serum-free conditions as non-adherent spheres. IL-8, an inflammatory chemokine with known proliferative and angiogenic properties, is detected in the serum of patients with CRC. We have shown that antibodies targeting IL-8 inhibited the growth of CRC tumor xenografts. We hypothesize that an IL-8-dependent autocrine circuit promotes colorectal cancer tumorigenicity. Methods: Immunochemical analysis was used to detect expression of the IL8 receptors, CXCR1 and CXCR2, by CRC-derived spheres and tumor xenografts. IL-8 secretion by CRC-derived spheres was quantified by an IL-8 ELISA. To assess effects of IL-8 on tumor growth, continuous release pellets containing IL-8 (2 ng/ml) or a placebo were implanted into the flanks of NOD-SCID mice prior to injection of CRC-derived CCICs. Tumor volume was measured biweekly. Tumor vessel density was quantified by immunochemical detection of MECA-32+ blood vessels. To assess effects of IL-8 on CRC-derived CCIC sphere formation and growth, cells were plated in the presence or absence of exogenous IL-8 (0 to 20 ng/ml). Sphere number and size were enumerated on days 2 and 7. Results: Immunochemical analysis detected selective expression of the IL-8 receptor, CXCR1, by both CRC-derived spheres and xenografts. Significant amounts of IL-8 were secreted by CRC-derived spheres (3000 cells; 1513 pg/ml). The tumor growth rate of mice receiving an exogenous source of IL-8 was significantly higher than the placebo group (p=0.008). The resulting tumors exhibited an increased level of angiogenesis. The addition of increasing concentrations of exogenous IL-8 to CRC-derived CCIC cultures increased the sphere size at day 2 (10 and 20 ng/ml; p&amp;lt;0.05) and number of spheres at day 7 (20 ng/ml; p&amp;lt;0.005) Conclusion: Collectively, these data suggest that colorectal cancer tumor initiation and growth can be modulated by the inflammation-associated chemokine IL-8 via an autocrine circuit. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5189. doi:10.1158/1538-7445.AM2011-5189