Abstract LB-349: Tumor associated macrophages mediate gemcitabine resistance of pancreatic adenocarcinoma by upregulating cytidine deaminase.

Abstract

Abstract Resistance to pharmacologic agents used in chemotherapy is a common phenomenon in most human carcinomas. Pancreatic ductal adenocarcinoma (PDA) is such a tumor, which is resistant to almost all drugs, including gemcitabine, a new nucleoside analog used as first-line treatment. For this reason the poor survival of patients with PDA have not change much during the last 4 decades. Recent data indicated that tumor-associated macrophages (TAMs) which are abundant in the microenvironment of several tumors, including PDA, secrete pro-tumorigenic factors which contribute to cancer progression and dissemination. In this study, we show for the first time that TAMs can also induce chemoresistance of PDA by reducing gemcitabine-induced apoptosis. Macrophages co-cultures with cancer cells or TAMs conditioned medium significantly reduced the levels of cleaved caspase-3 and caspase-3 during gemcitabine treatment. An in vivo PDA model of CCR2-deficient mice, which have reduced macrophage recruitment and activation, demonstrated improved response to gemcitabine compared to wild-types. Similarly, inhibition of monocytes/macrophages trafficking by a CSF1-receptors antagonist augmented the effect of gemcitabine in a transgenic mouse model of PDA that was resistant to gemcitabine alone. Analysis of multiple proteins involved in gemcitabine delivery and metabolism revealed that TAMs induced upregulation of cytidine deaminase (CDA), the enzyme that metabolizes the active form of the drug. Decreasing of CDA expression by PDA cells blocked the protective effect of TAMs against gemcitabine. Taken together, our results identify a paracrine effect of TAMs on PDA cells, which mediates acquire resistance of cancer cells to chemotherapy. Modulation of macrophage trafficking or inhibition of CDA may offer a new strategy for augmenting the response of PDA to chemotherapy. Citation Format: Yoav Binenboum, Noam Weissman, Yakov Kerlin, Ayelet Shabtai, Moran Amit, Ziv Gil. Tumor associated macrophages mediate gemcitabine resistance of pancreatic adenocarcinoma by upregulating cytidine deaminase. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-349. doi:10.1158/1538-7445.AM2013-LB-349 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.