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Deficient Transforming Growth Factor-ß1 Activation and Excessive Insulin-like Growth Factor II (IGFII) Expression in IGFII Receptor-Mutant Tumors¹

Department of Medicine (GI Division) [S. W., R. F. S., D. K., J. Y., K. N. S., T-T. Z., J. M. A., S. J. M.], Greenebaum Cancer Center [S. J. M.], Molecular Biology Graduate Program [K. N. S., S. J. M.], and Department of Pathology [D. K., S. J. M.], University of Maryland School of Medicine and Baltimore Veterans Affairs Hospital, Baltimore, Maryland 21201; University of Michigan, Ann Arbor, Michigan [T. F.]; Glaxo Conjoint Gastroenterology Laboratory, Royal Brisbane Hospital, Herston, Q4029, Australia [J. Y.]; Laboratory of Chemoprevention, National Cancer Institute, NIH, Bethesda, Maryland [K. C. F.]; and First Department of Pathology, Hamamatsu University of Medicine, Hamamatsu 431-31, Japan [H. S.]

The insulin-like growth factor II receptor (IGFIIR) gene has been identified as a coding region target of microsatellite instability in human gastrointestinal (GI) tumors. IGFIIR normally has two growth-suppressive functions: it binds and stimulates the plasmin-mediated cleavage and activation of the latent transforming growth factor-ß1 (LTGF-ß1) complex, and it mediates the internalization and degradation of IGFII ligand, a mitogen. We used an immunohistochemical approach to determine whether IGFIIR mutation affected expression of these proteins in GI tumors. Four highly specific antibodies were used: LC(1–30), which recognizes the active form of TGF-ß1; anti-LTGF-ß1, which detects the LTGF-ß1 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 tissues. Results were statistically significant in the following categories: (a) decreased active TGF-ß1 protein expression in IGFIIR-mutant tumor tissues versus matching normal tissues or IGFIIR-wild-type tumor tissues; (b) increased LTGF-ß1 protein expression in IGFIIR-mutant tumor tissues versus matching normal tissues or IGFIIR-wild-type tumor tissues; and (c) increased IGFII ligand protein expression in IGFIIR-mutant tumor tissues versus matching normal tissues or IGFIIR-wild-type tumor tissues. These data suggest that in genetically unstable GI tumors, mutation of a microsatellite within the coding region of IGFIIR functionally inactivates this gene, causing both diminished growth suppression (via decreased activation of TGF-ß1) and augmented growth stimulation (via decreased degradation of the IGFII ligand).

¹ Supported by Grants DK47717, CA67497, and ES 07120, NASA Grant 9307-0502, American Cancer Society Grant CCE 74525, the Robert and Sally D. Funderburg Award in Gastric Cancer Biology, and the Office of Medical Research, Department of Veterans Affairs.

² To whom requests for reprints should be addressed, at University of Maryland, 22 South Greene Street, Room N3W62, Baltimore, MD 21201. Phone: (410) 706-3375; Fax: (410) 328-6559; E-mail: smeltzer@umabnet.ab.umd.edu.

Received 3/28/97. Accepted 5/ 9/97.

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