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(American Journal of Pathology. 2003;163:1001-1011.)
© 2003 American Society for Investigative Pathology

Regulation of Hypoxia-Inducible Factor-1{alpha}, Vascular Endothelial Growth Factor, and Angiogenesis by an Insulin-Like Growth Factor-I Receptor Autocrine Loop in Human Pancreatic Cancer

Oliver Stoeltzing*, Wenbiao Liu*, Niels Reinmuth*, Fan Fan*, Alexander A. Parikh{dagger}, Corazon D. Bucana*, Douglas B. Evans{dagger}, Gregg L. Semenza{ddagger} and Lee M. Ellis*{dagger}

From the Departments of Cancer Biology*and Surgical Oncology,{dagger}The University of Texas M. D. Anderson Cancer Center, Houston, Texas; and the Departments of Pediatrics and Medicine and McKusick-Nathans Institute of Genetic Medicine,{ddagger}The Johns Hopkins University School of Medicine, Baltimore, Maryland

Activation of the insulin-like growth factor-I receptor (IGF-IR) was recently shown to modulate angiogenesis by up-regulating the expression of vascular endothelial growth factor (VEGF). We hypothesized that inhibiting IGF-IR function would inhibit angiogenesis and growth of pancreatic cancer in vivo and sought to identify major signaling pathways regulated by IGF-IR in pancreatic cancer cells. Human pancreatic cancer cells (L3.6pl) were stably transfected with a dominant-negative form of IGF-IR (IGF-IR DN) or an empty vector (pcDNA). In vitro, IGF-IR DN cells exhibited a decrease in both constitutive and inducible phosphorylation of IGF-IR and Erk1/2. Constitutive expression of nuclear hypoxia-inducible factor-1{alpha} and secreted VEGF (P < 0.01) protein levels also were significantly lower in IGF-IR DN cells than in pcDNA cells. In vivo, IGF-IR inhibition led to decreases in pancreatic tumor volume and weight, vessel density, and tumor cell proliferation (P < 0.01 for all) and increases in tumor cell apoptosis (P < 0.02). Our results suggest that autocrine activation of the IGF-IR system significantly affects VEGF expression and angiogenesis in human pancreatic cancer. Thus, IGF-IR may be a valid target in the treatment of pancreatic cancer.




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