Abstract

Abstract The systemic treatment of pancreatic cancer (PC) is hindered by the rapid development of chemoresistance to current cytotoxic therapies. Mechanisms governing the development of chemoresistance remain poorly characterized, particularly with respect to contributions from the tumor microenvironment. Here, intratumoral soluble mediator concentrations from resected PC specimens (n=26) as well as supernatants from co-cultures of PC cell lines and primary tumor-associated pancreatic stellate cells (PSCs) (n=16) were evaluated using a panel of 43 growth factors, chemokines and cytokines. CXCL10 levels were significantly increased in PC specimens as well as upon co-culture of PC cells with tumor-associated PSCs. In addition, high intratumoral CXCL10 concentrations correlated with reduced overall survival (HR 6.9; P = .006). Thus, the effect of CXCL10 on viability, proliferation, and apoptosis of PC cell lines was evaluated with and without gemcitabine treatment. While CXCL10 treatment had a small effect on the viability of PC cell lines, it significantly increased viability of these cells in the presence of gemcitabine. In addition, gemcitabine treatment induced the expression of the CXCL10 receptor, CXCR3. Thus, paracrine CXCL10 signaling between stromal, PC and immune cells within the pancreatic cancer microenvironment the may be responsible for chemoresistance to gemcitabine.

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