Regulation of hypoxia-inducible factor-1α, 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, Corazon D. Bucana, Douglas B. Evans, Gregg L. Semenza, Lee M. Ellis

Research output: Contribution to journalArticle

Abstract

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-1α 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.

Original languageEnglish (US)
Pages (from-to)1001-1011
Number of pages11
JournalAmerican Journal of Pathology
Volume163
Issue number3
DOIs
StatePublished - Sep 1 2003

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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