‘Big’-Insulin-Like Growth Factor–II Signaling Is an Autocrine Survival Pathway in Gastrointestinal Stromal Tumors

• Published in: The American journal of pathology Vol. 181; no. 1; pp. 303 - 312
• Main Authors: Rikhof, Bart, van der Graaf, Winette T.A, Suurmeijer, Albert J.H, van Doorn, Jaap, Meersma, Gert Jan, Groenen, Patricia J.T.A, Schuuring, Ed M.D, Meijer, Coby, de Jong, Steven
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2012
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Agents - pharmacology; Autocrine Communication - drug effects; Autocrine Communication - physiology; Benzamides; Cell Death - drug effects; Cell Death - physiology; Cell Survival - physiology; Down-Regulation - physiology; Female; Gastrointestinal Stromal Tumors - metabolism; Gastrointestinal Stromal Tumors - pathology; Gastrointestinal Stromal Tumors - physiopathology; Humans; Imatinib Mesylate; Insulin-Like Growth Factor II - metabolism; Insulin-Like Growth Factor II - physiology; Male; Middle Aged; Neoplasm Proteins - metabolism; Pathology; Piperazines - pharmacology; Protein Precursors - metabolism; Protein Precursors - physiology; Pyrimidines - pharmacology; Receptor, IGF Type 1 - metabolism; Receptor, Insulin - metabolism; Tumor Cells, Cultured; Young Adult
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/j.ajpath.2012.03.028

New treatment targets need to be identified in gastrointestinal stromal tumors (GISTs) to extend the treatment options for patients experiencing failure with small-molecule tyrosine kinase inhibitors, such as imatinib. Insulin-like growth factor (IGF)–II acts as an autocrine factor in several tumor types by binding to IGF receptor type 1 (IGF-1R) and/or the insulin receptor (IR) isoform A. The aim of the present study was to investigate the putative role of unprocessed pro-IGF-II, called ‘big’-IGF-II, in GISTs. The imatinib-sensitive GIST882 and imatinib-resistant GIST48 cell lines secrete high levels of big-IGF-II as demonstrated by ELISA and Western blotting analyses. IR isoform A mRNA and protein expression, but not that of IGF-1R, was found in these KIT mutant cell lines and in KIT and platelet-derived growth factor receptor α-mutant GIST specimens. Down-regulation of either big-IGF-II or IR affected AKT and MAPK signaling and reduced survival in both cell lines. Disruption of big-IGF-II signaling in combination with imatinib had additive cytotoxic effects on GIST882 cells. IGF-II mRNA as determined by in situ hybridization was present in 91% of 60 primary GISTs. Immunohistochemical analysis of big-IGF-II protein expression was associated with moderate- to high-risk tumors compared with tumors with a lower risk classification ( P < 0.028). Our data put forth the big-IGF-II/IR isoform A axis as an autocrine survival pathway and potential therapeutic target in GISTs.