Abstract 1094: Dynamics of Gemcitabine induced interleukin-8 (IL-8) expression in pancreatic tumor microenvironment

Abstract

Abstract Background: The clinical standard of care for patients with pancreatic ductal adenocarcinoma (PDAC) is treatment with Gemcitabine (Gem) despite Gem's limited benefits. To date, no surrogate marker has been identified to indicate whether Gem treatment directly affects PDAC tumor cells. In order to identify such a marker, we analyzed Gem treated cell lines and clinical samples. Methods: 12 PDAC cell lines were treated with 5μM Gem for three hours and then allowed to grow in the absence of Gem for 24hrs before mRNA expression analysis (Illumina Gene Expression Array). IHC and WB were used to quantify IL-8 expression. ShRNA mediated silencing was utilized to study the therapeutic value of IL-8. Results: mRNA expression and WB confirmed the induction of IL-8 after Gem treatment. Gem induced IL-8 expression was transcriptionally controlled by NFκB and C/EBP. PDAC cells (MPanc96 and BxPc-3-CXCR1), HPSC (Human Pancreatic Stellate Cells-CXCR1) and HUVEC (Human Umbilical Vein Endothelial cells-CXCR1 & 2) expressed the receptor of IL-8. Conditioned media from Gem treated cells and rIL-8 treated cells, stimulated cell growth (PDAC, HPSC and HUVEC), polygon formation in HUVEC and α-SMA expression in HPSC. Stable silencing of IL-8 in Capan2 cells, which develop an abundant stroma, led to a significant reduction in tumor volume. Histologically, IL-8 silenced tumors showed reduced micro-vessel density (CD37), as well as highly reduced desmoplasia (Trichrome stain & α-SMA) associated with necrosis. Further, IHC revealed strong IL-8 expression in neo-adjuvant Gem-treated human PDAC tissues (strong expression 42.1%, weak expression 57.9%, negative 0%) in comparison to tissue from patients that underwent surgery alone (strong expression 0%, weak expression 77.8%, negative 22.2%).Conclusion: Gem induced IL-8 functions as a growth factor for cancer cells and its microenvironment. Thus, IL-8 can serve as a surrogate marker to indicate Gem effects in PDAC. Citation Format: Sobeyda Gomez, Takahiko Fujii, Haojie Huang, Rosa Hwang, Viji Ramachandran, Craig Logsdon, Thiru Arumugam. Dynamics of Gemcitabine induced interleukin-8 (IL-8) expression in pancreatic tumor microenvironment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1094. doi:10.1158/1538-7445.AM2014-1094