Insulin-like growth factor 1 receptor activates c-SRC and modifies transformation and motility of colon cancer in vitro

Anticancer Res. Mar-Apr 2003;23(2B):1517-24.

Abstract

Colorectal carcinomas have been found to express increased levels of IGF1 and IGF1-R, as compared to normal or adenomatous colonic mucosa, and it has been postulated that a subset of colorectal cancers are under the autocrine regulation of the IGF1/IGF1-R system. In this study, we selected human colorectal carcinoma cell lines with high (SW620, HT29, L4A) and low (CaCo2, and HCT 116) expression of IGF1-R by flow cytometry. Compared to the IGF1-R(-) cells, the IGF1-R(+) cells revealed a more aggressive phenotype as demonstrated by a higher proliferation rate (approximately 2-fold increase) in response to IGF1, higher degree of transformation (approximately 5-to-15-fold increase in colony formation in soft agar), increased resistance to serum deprivation-induced apoptosis [1-7 apoptotic cells/5 microscopic fields, as compared to 37 to 101 apoptotic cells/5 microscopic fields of the IGF1-R(-) cells], and higher migratory capability measured by a wounding assay [IGF1-R(+) cells migrated a distance of up to 15 millimeters from the cut edge of the monolayer, while the IGF1-R(-) cells were able to migrate only 2-3 millimeters away from the same reference point]. While the cell lines overexpressing the IGF1-R had higher levels of Src activation, the use of a Src inhibitor reduced the IGF1-R protein expression, slowed down the proliferation of IGF1-R(+) cells, and reduced their colony formation in soft agar. Based on the above observations, we conclude that an overexpressed and activated IGF1-R may increase the degree of transformation and motility of colon cancer cells by activating c-Src.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / pathology*
  • Apoptosis / drug effects
  • Cell Division
  • Cell Movement / drug effects
  • Cell Transformation, Neoplastic / genetics*
  • Colonic Neoplasms / pathology*
  • Culture Media, Serum-Free / pharmacology
  • Disease Progression
  • Enzyme Induction / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / physiology*
  • Genes, src*
  • Humans
  • Insulin-Like Growth Factor I / pharmacology*
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics*
  • Pyridones / pharmacology
  • Pyrimidines / pharmacology
  • Receptor, IGF Type 1 / drug effects
  • Receptor, IGF Type 1 / physiology*
  • Tumor Cells, Cultured / cytology
  • Tumor Cells, Cultured / drug effects
  • Tumor Stem Cell Assay
  • src-Family Kinases / antagonists & inhibitors
  • src-Family Kinases / biosynthesis*

Substances

  • Culture Media, Serum-Free
  • Neoplasm Proteins
  • Pyridones
  • Pyrimidines
  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1
  • src-Family Kinases
  • PD 180970