Background: We have reported previously on the occurrence of paraneoplastic hypoglycemias in patients with a gastrointestinal stromal tumor (GIST) as a result of the secretion of unprocessed forms of pro-insulin-like growth factor-II (IGF-II), also called \#8216;big\#8217;-IGF-II, by the tumor. IGF-II has been shown to act as an autocrine growth and survival factor in several tumor types by binding to the IGF receptor type 1 (IGF-1R) and/or the insulin receptor isoform A. The aim of this study was to investigate the role of IGF-II in GIST. Materials and Methods: The expression of IGF-II was analyzed in 57 primary GISTs by RNA in situ hybridization and immunohistochemistry (IHC). The expression levels of IGF-1R and insulin receptor (isoform A) were assessed by IHC, western blotting and RT-PCR. The secretion of IGF-II by the GIST cell lines GIST882 and GIST48 was analyzed by ELISA and western blotting. The effects of tyrosine kinase inhibitors against the insulin receptor in these cell lines were assessed with cytotoxicity and apoptosis assays. Results: IGF-II mRNA was present in 52 of 57 (91%) primary GISTs and absent in all four very-low-risk tumors. IGF-II protein was expressed in the majority of GISTs, far most in high-risk tumors, and in tumors localized in the small bowel and in those with a relatively high mitotic count (i.e. >5/50 HPF; for all parameters p<0.05). IGF-1R was neither expressed in (KIT mutant) GISTs nor in GIST cell lines, in contrast to insulin receptor isoform A. The GIST882 and GIST48 cell lines secreted both high levels of IGF-II, predominantly as \#8216;big\#8217;-IGF-II, but no IGF-I or insulin. Both rhIGF-II and insulin treatment induced phosphorylation of the insulin receptor and AKT in these cells. Inhibitors of the insulin receptor reduced survival of both cell lines in normal (serum containing) media and, in case of GIST882, also under serum-free conditions and caused apoptosis in a time- and concentration-dependent manner. Conclusions: IGF-II is commonly expressed in GIST, predominantly in aggressive tumors. Our in vitro studies suggest that \#8216;big\#8217;-IGF-II might act as an autocrine survival factor in GIST by interacting with the insulin receptor isoform A.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4289.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO