Abstract 393: The chemokine receptor, CXCR2/IL8RB, contributes to the survival of pancreatic adenocarcinoma, and may play a role in stroma-tumor communication

Abstract

Abstract The failure of most chemotherapeutic agents to treat pancreatic cancer could be related to poor delivery of drug due to the physical barrier of dense fibrosis surrounding the tumor. Targeting and attenuating the fibrotic stroma may result in better access of drug to tumor. Our current studies show that CXCR2/IL8RB is over-expressed in the surrounding stroma of pancreatic ductal adenocarcinoma tumors. CXCR2/IL8RB and its ligands are well known to be involved in fibrosis, and recently published papers suggest a role for CXCR2 in tumor proliferation, as well. Therefore, CXCR2 is a good target for pancreatic cancer therapy, because it has the potential to target both the stroma surrounding the tumor, as well as the tumor itself. When comparing matched samples of patient tumor and adjacent normal tissue, the mean IHC score of stroma surrounding normal pancreatic ducts is 0.61 (95% CI 0.38-0.84), while the mean IHC score of stroma surrounding ductal adenocarcinoma is 1.6 (95% CI: 1.3-1.9; Mann-Whitney test p<.0001; n=31). We previously reported that a CXCR2 ligand, CXCL5, was highly expressed in patient tumor samples, but not in the stroma. Interestingly, our present data shows CXCR2 is also expressed in tumor cells, therefore, CXCR2 may be involved in both autocrine and paracrine signaling inducing tumor proliferation, as well as induction of fibrosis in the stroma. Supporting CXCR2's role in pancreatic tumor proliferation, specific knockdown of CXCR2 expression by siRNA reduces cell growth by approximately 50%. Additionally, drug dose response curve experiments show pancreatic cancer cell lines which express CXCR2 are more sensitive to the CXCR2 antagonist, SB225002, than cells which do not express CXCR2. For example, the CXCR2 expressing cell line PANC-1 is approximately 7 times more sensitive to SB225002 than the CXCR2 negative cell line BxPC-3 (0.12uM vs. 0.88uM in IC50). We are currently assessing the mechanism of death induced by CXCR2 inhibition in the cancer cells. CXCR2's role in tumor cell proliferation, as well as its over-expression in the stroma surrounding tumors, make it a good target for both weakening the protective stroma surrounding the tumor, and reducing tumor cell survival. This work was supported by NIH P01 Grant CA109552. 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 393. doi:10.1158/1538-7445.AM2011-393