DEFICIENT TRANSFORMING-GROWTH-FACTOR-BETA-1 ACTIVATION AND EXCESSIVE INSULIN-LIKE-GROWTH-FACTOR-II (IGFII) EXPRESSION IN IGFII-RECEPTOR-MUTANT TUMORS

The insulin-like growth factor II receptor (IGFIIR) gene has been iden tified as a coding region target of microsatellite instability in huma n gastrointestinal (GI) tumors. IGFIIR normally has two growth-suppres sive functions: it binds and stimulates the plasmin-mediated cleavage and activation of the latent transforming growth factor-beta 1 (LTGF-b eta 1) complex, and it mediates the internalization and degradation of IGFII ligand, a mitogen. We used an immunohistochemical approach to d etermine whether IGFIIR mutation affected expression of these proteins in GI tumors. Four highly specific antibodies were used: LC(1-30), wh ich recognizes the active form of TGF-beta 1; anti-LTGF-beta 1, which detects the LTGF-beta 1 precursor protein; anti-IGFIIR; and anti-IGFII ligand. Twenty GI tumors either with (6 of 20) or without (14 of 20) known IGFIIR mutation were examined, along with matching normal tissue s. Results were statistically significant in the following categories: (a) decreased active TGF-beta 1 protein expression in IGFIIR-mutant t umor tissues versus matching normal tissues or IGFIIR-wild-type tumor tissues; (b) increased LTGF-beta 1 protein expression in IGFIIR-mutant tumor tissues versus matching normal tissues or IGFIIR-wild-type tumo r tissues; and (c) increased IGFII ligand protein expression in IGFIIR -mutant tumor tissues versus matching normal tissues or IGFIIR-wild-ty pe tumor tissues. These data suggest that in genetically unstable GI t umors, mutation of a microsatellite within the coding region of IGFIIR functionally inactivates this gene, causing both diminished growth su ppression (via decreased activation of TGF-beta 1) and augmented growt h stimulation (via decreased degradation of the IGFII ligand).