Insulin-like Growth Factor Receptor Expression Is Associated With Aggressive Phenotypes and Has Therapeutic Activity in Biliary Tract Cancers

Cancer Sci. 2012 Feb;103(2):252-61. doi: 10.1111/j.1349-7006.2011.02138.x. Epub 2011 Dec 13.

Abstract

Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling is required for carcinogenicity and progression of several cancers but the function of this pathway and its utility as a therapeutic target have not been studied comprehensively in biliary tract carcinomas (BTC). We investigated the immunohistochemical expression of elements of the IGF axis, matrilysin, overexpression of p53 and the methylation status of the IGFBP-3 promoter in 80 surgically resected BTC. We also assessed the effect of IGF-IR blockade on signal transduction, proliferation and survival in three BTC cell lines using a new tyrosine kinase inhibitor, BMS-536924, and dominant negative IGF-IR (IGF-IR/dn). The effects of IGF-IR blockade was also studied in nude mouse xenograft models. IGF-I was expressed in 60% and IGF-II in 50% of tumors. High expression was associated with tumor size. IGF-IR was expressed in 69% of the cases and was associated with advanced stage and matrilysin expression. Hypermethylation of the IGFBP-3 promoter was detected in 41% of BTC and was inversely correlated with p53 expression. BMS-536924 blocked autophosphorylation of IGF-IR and both Akt and ERK activation by both IGF-I and insulin. BMS-536924 suppressed proliferation and tumorigenicity in vitro in a dose-dependent fashion. This inhibitor upregulated chemotherapy-induced apoptosis in a dose-dependent fashion. Moreover, IGF-IR blockade was effective against tumors in mice. IGF-IR might identify a subset of BTC with a particularly aggressive phenotype and is a candidate therapeutic target in this disease. BMS-536924 might have significant therapeutic utility.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Benzimidazoles / pharmacology
  • Biliary Tract Neoplasms / metabolism*
  • Biliary Tract Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival
  • DNA Methylation
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Humans
  • Insulin / metabolism
  • Insulin-Like Growth Factor Binding Protein 3 / genetics*
  • Matrix Metalloproteinase 7 / biosynthesis
  • Mice
  • Mice, Nude
  • Oncogene Protein v-akt / metabolism
  • Promoter Regions, Genetic
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Pyridones / pharmacology
  • Receptors, Somatomedin / biosynthesis
  • Receptors, Somatomedin / metabolism*
  • Signal Transduction
  • Somatomedins / biosynthesis
  • Tumor Suppressor Protein p53 / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • BMS 536924
  • Benzimidazoles
  • Insulin
  • Insulin-Like Growth Factor Binding Protein 3
  • Protein Kinase Inhibitors
  • Pyridones
  • Receptors, Somatomedin
  • Somatomedins
  • Tumor Suppressor Protein p53
  • Protein-Tyrosine Kinases
  • Oncogene Protein v-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Matrix Metalloproteinase 7