Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB.
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.
Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands.
Sirith
S
Douma
Theo
T
Van Laar
John
J
Zevenhoven
Ralph
R
Meuwissen
Evert
E
Van Garderen
Daniel S
DS
Peeper
D000818:Animals; D023102:Anoikis; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D017690:Cell Transplantation; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D015723:Gene Library; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000473:pathology; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D009857:Oncogenes / Q000235:genetics / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate; D014161:Transduction, Genetic
D019208:Brain-Derived Neurotrophic Factor; D020169:Caspases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D020813:Receptor, trkB