'Big'-insulin-like growth factor-II signaling is an autocrine survival pathway in gastrointestinal stromal tumors.
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.
Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Bart
B
Rikhof
Winette T A
WT
van der Graaf
Albert J H
AJ
Suurmeijer
Jaap
J
van Doorn
Gert Jan
GJ
Meersma
Patricia J T A
PJ
Groenen
Ed M D
EM
Schuuring
Coby
C
Meijer
Steven
S
de Jong
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D019898:Autocrine Communication / Q000187:drug effects / Q000502:physiology; D001549:Benzamides; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D000068877:Imatinib Mesylate; D007335:Insulin-Like Growth Factor II / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011498:Protein Precursors / Q000378:metabolism / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D014407:Tumor Cells, Cultured; D055815:Young Adult
D000970:Antineoplastic Agents; D001549:Benzamides; C035170:IGF2 protein, human; D009363:Neoplasm Proteins; D010879:Piperazines; D011498:Protein Precursors; D011743:Pyrimidines; C066038:proinsulin-like growth factor II; D007335:Insulin-Like Growth Factor II; D000068877:Imatinib Mesylate; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin