'Big'-insulin-like growth factor-II signaling is an autocrine survival pathway in gastrointestinal stromal tumors

Am J Pathol. 2012 Jul;181(1):303-12. doi: 10.1016/j.ajpath.2012.03.028. Epub 2012 May 29.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Piperazines / pharmacology
  • Protein Precursors / metabolism
  • Protein Precursors / physiology*
  • Pyrimidines / pharmacology
  • Receptor, IGF Type 1 / metabolism
  • Receptor, Insulin / metabolism
  • Tumor Cells, Cultured
  • Young Adult


  • Antineoplastic Agents
  • Benzamides
  • IGF2 protein, human
  • Neoplasm Proteins
  • Piperazines
  • Protein Precursors
  • Pyrimidines
  • proinsulin-like growth factor II
  • Insulin-Like Growth Factor II
  • Imatinib Mesylate
  • Receptor, IGF Type 1
  • Receptor, Insulin