Insulin-like growth factor (IGF)-II in gastrointestinal stromal tumors (GIST): expression, secretion, and clinical relevance

Abstract

20504 Background: Non-islet cell tumor induced hypoglycemia (NICTH) has been reported anecdotically in patients with a GIST and is associated with increased plasma levels of ‘big’-IGF-II, a high molecular weight form of IGF-II. The role of IGF-II in GIST is unknown. In non- GIST cancer, it has been suggested to be an autocrine growth factor, mainly acting by its major growth promoting receptors IGF-1 receptor (IGF- 1R) and the isoform A of the insulin receptor (IR). We investigated the clinical and biological relevance of (‘big’-)IGF-II in GIST. Methods: Plasma levels of ‘big’-IGF-II, and their relationship with disease status and NICTH, were determined in 25 consecutive GIST patients treated with imatinib (n=24) or sunitinib (n=1). Plasma samples were collected prior to, 1 week, and median 5 months after start of treatment. The levels of ‘big’-IGF-II were measured by specific radioimmunoassay (RIA). Results were compared with those obtained from healthy subjects and expressed as standard deviation scores (SDS). Paraffin-embedded GISTs (n=69) were analyzed for IGF-II, IGF-1R and IR expression by RNA in situ hybridization and immunohistochemistry (IHC). IGF-II secretion by the GIST882 cell line was analyzed by ELISA and western blotting. Results: Before treatment and/or during follow-up, 4 of 25 patients (16%) showed increased (i.e. SDS >2.0) plasma levels of ‘big’-IGF-II. Three of them developed NICTH. Patients with metastatic disease, high serum LDH, or total tumor size >12 cm had the highest ‘big’-IGF-II levels (for all p<0.05). 87% of GISTs expressed IGF-II mRNA, being excessive in tumors from patients with NICTH. These results were confirmed by IHC. GIST882 cells secreted mainly high molecular weight forms of IGF-II. The various GISTs and GIST882 cells did not express IGF-1R or IR. Conclusions: NICTH seems not to be a rare phenomenon in GIST patients. We showed for the first time that most GISTs express and secrete (‘big’-)IGF-II. Therefore, it is likely that many patients are at risk of developing NICTH, presumably especially in case of high tumor bulk. The exact role of (‘big’-)IGF-II in GIST is still not elucidated, as it does not seem to act as an autocrine growth factor since IGF-IR and IR isoform A are lacking. No significant financial relationships to disclose.