Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB

Nature. 2004 Aug 26;430(7003):1034-9. doi: 10.1038/nature02765.

Abstract

Metastasis is a major factor in the malignancy of cancers, and is often responsible for the failure of cancer treatment. Anoikis (apoptosis resulting from loss of cell-matrix interactions) has been suggested to act as a physiological barrier to metastasis; resistance to anoikis may allow survival of cancer cells during systemic circulation, thereby facilitating secondary tumour formation in distant organs. In an attempt to identify metastasis-associated oncogenes, we designed an unbiased, genome-wide functional screen solely on the basis of anoikis suppression. Here, we report the identification of TrkB, a neurotrophic tyrosine kinase receptor, as a potent and specific suppressor of caspase-associated anoikis of non-malignant epithelial cells. By activating the phosphatidylinositol-3-OH kinase/protein kinase B pathway, TrkB induced the formation of large cellular aggregates that survive and proliferate in suspension. In mice, these cells formed rapidly growing tumours that infiltrated lymphatics and blood vessels to colonize distant organs. Consistent with the ability of TrkB to suppress anoikis, metastases--whether small vessel infiltrates or large tumour nodules--contained very few apoptotic cells. These observations demonstrate the potent oncogenic effects of TrkB and uncover a specific pro-survival function that may contribute to its metastatic capacity, providing a possible explanation for the aggressive nature of human tumours that overexpress TrkB.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anoikis*
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / metabolism
  • Caspases / metabolism
  • Cell Adhesion
  • Cell Line
  • Cell Movement
  • Cell Survival
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Cell Transplantation
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Epithelial Cells / transplantation
  • Gene Library
  • Intestinal Mucosa / metabolism
  • Intestines / cytology
  • Intestines / pathology
  • Mice
  • Mice, Nude
  • Neoplasm Metastasis* / pathology
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Oncogenes / genetics
  • Oncogenes / physiology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Rats
  • Receptor, trkB / genetics
  • Receptor, trkB / metabolism*
  • Survival Rate
  • Transduction, Genetic

Substances

  • Brain-Derived Neurotrophic Factor
  • Proto-Oncogene Proteins
  • Phosphatidylinositol 3-Kinases
  • Receptor, trkB
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Caspases