Impact of insulin-like growth factor receptor-I function on angiogenesis, growth, and metastasis of colon cancer

Lab Invest. 2002 Oct;82(10):1377-89. doi: 10.1097/01.lab.0000032411.41603.c2.


Insulin-like growth factors and their principal receptor, IGF-I receptor (IGF-IR), are frequently expressed in human colon cancers and play a role in preventing apoptosis, enhancing cell proliferation, and inducing expression of vascular endothelial growth factor (VEGF). The role of IGF-IR in regulating angiogenesis and metastases of human colon cancer has not been elucidated. To determine the in vitro and in vivo effects of IGF-IR in human colon cancer growth and angiogenesis, human KM12L4 colon cancer cells were transfected with a truncated dominant-negative form of IGF-IR (IGF-IR dom-neg). IGF-IR dom-neg-transfected cells demonstrated markedly decreased constitutive expression of VEGF mRNA and protein. Subcutaneous injections of IGF-IR dom-neg-transfected cells in nude mice led to significantly decreased tumor growth (p < 0.05) that was associated with decreased tumor cell proliferation, VEGF expression, and vessel count and with increased tumor cell apoptosis (p < 0.05 for all parameters compared with controls). In addition, pericyte coverage of endothelial cells was significantly decreased in tumors from IGF-IR dom-neg-transfected cells. Following this observation, we demonstrated in vitro that vascular smooth muscle cells migrated significantly less in conditioned medium derived from IGF-IR dom-neg-transfected cells compared with medium from control cells. After splenic injections, IGF-IR dom-neg transfectants failed to produce liver metastases, in contrast to parental cells and mock transfectants (p < 0.05). In addition, IGF-IR dom-neg-transfected cells failed to form liver tumors after direct injection into the liver. These studies demonstrate that the IGF-IR plays an important role in multiple mechanisms that mediate the growth, angiogenesis, and metastasis of human colon cancer. IGF-IR is a valid target for the therapy of human colon cancer.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Division / genetics
  • Cell Movement / drug effects
  • Colonic Neoplasms / blood supply*
  • Colonic Neoplasms / pathology*
  • Colonic Neoplasms / physiopathology
  • Endothelial Growth Factors / genetics
  • Endothelial Growth Factors / pharmacology
  • Humans
  • Insulin-Like Growth Factor I / pharmacology
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / pharmacology
  • Lymphokines / genetics
  • Lymphokines / pharmacology
  • Neoplasm Metastasis
  • Neovascularization, Pathologic / genetics*
  • RNA, Messenger / genetics
  • Receptor, IGF Type 1 / genetics
  • Receptor, IGF Type 1 / physiology*
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / pharmacology
  • Transcription, Genetic
  • Transfection
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors


  • Endothelial Growth Factors
  • Intercellular Signaling Peptides and Proteins
  • Lymphokines
  • RNA, Messenger
  • Recombinant Proteins
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1