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Clinical Cancer Research Vol. 8, 3259-3269, October 2002
© 2002 American Association for Cancer Research

Experimental Therapeutics, Preclinical Pharmacology

Blockade of Insulin-like Growth Factor I Receptor Function Inhibits Growth and Angiogenesis of Colon Cancer1

Niels Reinmuth, Wenbiao Liu, Fan Fan, Young D. Jung, Syed A. Ahmad, Oliver Stoeltzing, Corazon D. Bucana, Robert Radinsky and Lee M. Ellis2

Departments of Cancer Biology [N. R., W. L., F. F., Y. D. J., O. S., C. D. B., R. R., L. M. E.] and Surgical Oncology [S. A. A., L. M. E.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Purpose and Experimental Design: Insulin-like growth factors (IGFs) I and II and their principle receptor, IGF-I receptor (IGF-IR), are frequently expressed in human colon cancers and play a role in preventing apoptosis, enhancing cell proliferation, and inducing expression of vascular endothelial growth factor (VEGF). To elucidate the in vitro and in vivo effects of IGF-IR in human colon cancer growth and angiogenesis, HT29 cells were transfected with a truncated dominant-negative (DN) form of IGF-IR or vector alone.

Results: IGF-I increased VEGF expression in parental and vector-transfected cells, whereas IGF-I induction of VEGF mRNA and protein was abrogated in IGF-IR DN cells. The IGF-IR DN cells demonstrated inhibited growth in both monolayer culture and soft agar (P < 0.05). s.c. injections of IGF-IR DN cells in nude mice led to significantly decreased tumor growth (P < 0.05). Immunohistochemical analyses revealed that IGF-I DN tumors demonstrated decreased tumor cell proliferation, VEGF expression, and vessel count and increased tumor cell apoptosis (P < 0.05 for all parameters compared with controls). Furthermore, IGF-IR DN-transfected cells yielded significantly decreased tumorigenicity and growth in the liver.

Conclusions: These studies demonstrate that the IGF ligand-receptor system plays an important role in multiple mechanisms that mediate human colon cancer growth including regulation of VEGF and angiogenesis.




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Copyright © 2002 by the American Association for Cancer Research.