Faculty Collaboration Database

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. Am J Pathol 2003 Sep;163(3):1001-11

Date

08/26/2003

Pubmed ID

12937141

Pubmed Central ID

PMC1868239

DOI

10.1016/s0002-9440(10)63460-8

Scopus ID

2-s2.0-0042926509 (requires institutional sign-in at Scopus site)   146 Citations

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-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.

Author List

Stoeltzing O, Liu W, Reinmuth N, Fan F, Parikh AA, Bucana CD, Evans DB, Semenza GL, Ellis LM

Author

Douglas B. Evans MD Chair, Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

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