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

Speaker : 林純羽                            Time: 11/03/04

Commentator: 湯銘哲 教授                   Place: 601 Room

Abstract:

It is well known that the living of cells depends on communications between cells and matrix, and the cell-cell interactions. The process of 'anoikis' (from the Greek for 'homelessness') refers to cell death when they lose contact with the neighboring. Nevertheless, cancer cells are not lethally homesick even if taken apart from their homeland. As a result, the ability of cancer cells in avoiding anoikis appears indispensable to invade and metastasize. In this study, an unbiased, genome-wide functional screening was performed in attempt to identify metastasis-associated genes related to suppressed anoikis. The TrkB, a neurotrophic tyrosine kinase receptor, was found to be a potent and specific suppressor of caspase-associated anoikis of non-malignant epithelial cells. Through activating phosphatidylinositol-3-OH kinase/protein kinase B pathway, activation of TrkB induces the formation of large cellular aggregates that can survive and proliferate in the suspension. Moreover, these cells form rapidly growing tumors and infiltrate in the lymphatics and blood vessels followed by colonization in the distant organs in vivo. Consistent with the capability of TrkB to suppress the anoikis, there were very few apoptotic cells at site of metastasis or in large tumors. The results substantiate the oncogenic effect and pro-survival function of TrkB that may contribute to the metastatic potential of tumor cells. Activation of TrkB thus may represent one of early events in the multi-step tumorigenesis. By using anoikis suppression as a functional property of cancer cells, the authors successfully identify the metastasis-associated oncogenes.

References:

1.     Asim Khwaja, Pablo Rodriguez-Viciana, Stefan Wennstro¨ m, Patricia H. Warne and Julian Downward.1997.Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway.EMBO.16:2783-2793.

2.     Sirith Douma, Theo van Laar, John Zevenhoven, Ralph Meuwissen,Evert van Garderen & Daniel S. Peeper.2004. Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB. Nature.430: 1034-1040.