Auto-induction and growth stimulatory effect of betacellulin in human pancreatic cancer cells

Betacellulin (BTC) was identified in mouse pancreatic beta cell tumors as a member of the epidermal growth factor (EGF) family, and was found to bind and activate the EGF receptor. ETC is also expressed in some human malignan cies and may have an important role in tumor growth progression. We examine d whether ETC and EGF have a growth stimulatory effect on human pancreatic cancer cell lines both in vitro and in vivo. We also investigated the ETC e xpression and autonomous induction of ETC in pancreatic cancer cells, In vi tro, both ETC and EGF had almost the same proliferative effect on Panc-1, M IA PaCa-2 and AsPC-1. In vivo, in a Panc-1 inoculated athymic mice model, B TC-treated tumors grew approximately five times larger than in control. Imm unocytochemistry showed that ETC expression occurred in three pancreatic ca ncer cell lines, with MIA PaCa-2 showing the strongest intensity. Semi-quan titative RT-PCR of MIA Paca-2 showed that mRNA levels of ETC gradually incr eased after treatment with 1 nM ETC. Immunocytochemistry also demonstrated that the intensity of BTC-like immunoreactivity was increased when treated with 1 nM ETC but was reduced after treatment with 100 nM of AG1478, an EGF receptor tyrosine kinase inhibitor. ETC has thus a significant growth stim ulatory effect on pancreatic cancer cells and might function as an autocrin e and paracrine growth factor. ETC expression in pancreatic cancer cells is , at least in part, controlled by an auto-induction mechanism.