Regulation of hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and angiogenesis by an insulin-like growth factor-I receptor autocrine loop in human pancreatic cancer.

Stoeltzing O, Liu W, Reinmuth N, Fan F, Parikh AA, Bucana CD, Evans DB, Semenza GL, Ellis LM
Am J Pathol. 2003 163 (3): 1001-11

PMID: 12937141 · PMCID: PMC1868239 · DOI:10.1016/s0002-9440(10)63460-8

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-1alpha 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.

MeSH Terms (27)

Adenocarcinoma Apoptosis Autocrine Communication Cell Division Cyclooxygenase 2 Cyclooxygenase 2 Inhibitors Cyclooxygenase Inhibitors Endothelial Growth Factors Humans Insulin-Like Growth Factor I Intercellular Signaling Peptides and Proteins Intracellular Membranes Isoenzymes Ligands Lymphokines Membrane Proteins Mixed Function Oxygenases Neovascularization, Pathologic Pancreatic Neoplasms Prostaglandin-Endoperoxide Synthases Receptor, IGF Type 1 Repressor Proteins Signal Transduction Transcription Factors Tumor Cells, Cultured Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors

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