Abstract 1687: Carcinogen induced inflammation and pancreatic cancer

Abstract

Abstract National Toxicology Program (NTP) performs two-year cancer bioassays. We have analyzed the NTP rat data base and searched for gender differences in susceptibility to carcinogens. We identified 10 chemicals that induced exocrine pancreatic cancer in male rats only, but found no chemical that induced pancreatic cancer in female rats only. Furthermore, males were most affected by three chemicals that induced pancreatic cancer in both sexes. In an effort to understand this sex difference in susceptibility, we used a tool which builds on the technology published in BMC Bioinformatics 2009, 10, 303. This tool was built to assist cancer risk assessors in the analysis of literature data on modes of action (MOA). We used this tool in the analysis of 2041 PubMed abstracts on the 10 male-specific carcinogens. The tool automatically selected 634 abstracts as relevant for cancer and sorted them in taxonomies. The sorting suggested that induction of oxidative stress and inflammation was a common feature among the 10 carcinogens. As chronic pancreatitis is a risk factor for human exocrine pancreatic cancer, we investigated the effects of the 10 carcinogens on Ca2+ signaling and on inflammatory markers in pancreatic cancer cell line Panc-1. It was found that many the 10 male specific carcinogens rapidly increased intracellular [Ca2+] and interfered with extracellular ATP-induced Ca2+ release in Panc-1 cells. The effect on [Ca2+] was followed by activation of calcineurin and phosphorylation of Erk. Some of these effects were blocked by inhibitors of the purinergic P2X7 receptor, a receptor which may rapidly increase intracellular [Ca2+]. We further studied the induction of mRNA levels of inflammatory mediators, and found that IL8 was significantly up-regulated by most of the 10 chemicals. Our data suggest that inflammation is important for chemically induced exocrine pancreatic cancer in the rat and that male rats are more susceptible. Our data may have a bearing on human pancreatic cancer as men, and in particular young men, have a higher incidence of pancreatic cancer than women. Increased levels of the P2X7 receptor has also been detected in chronic pancreatitis in humans. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1687.