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

Sirith Douma, Theo van Laar, John Zevenhoven, Ralph Meuwissen, Evert van Garderen and Daniel S. Peeper ()
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Sirith Douma: Division of Molecular Genetics
Theo van Laar: Division of Molecular Genetics
John Zevenhoven: Division of Molecular Genetics
Ralph Meuwissen: Division of Molecular Genetics
Evert van Garderen: The Netherlands Cancer Institute
Daniel S. Peeper: Division of Molecular Genetics

Nature, 2004, vol. 430, issue 7003, 1034-1039

Abstract: 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 organs1,2,3. 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 receptor4,5, 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.

Date: 2004
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DOI: 10.1038/nature02765

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