Editors' ChoiceCell Biology

Axon Guiders Control Proliferation and Angiogenesis

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Science's STKE  20 Jun 2006:
Vol. 2006, Issue 340, pp. tw203
DOI: 10.1126/stke.3402006tw203

Two reports this week expand the functions of signaling proteins originally associated with axon guidance and cell migration. Holmberg et al. studied the role of ephrins and their receptors, the EphB proteins, in control of epithelial stem cells in the intestine. These stem cells undergo orderly and spatially restricted development in folds or crypts formed in the intestinal epithelium. Ephrins and their EphB receptor proteins regulate migration of cells out of the crypts, but Holmberg et al. explored a further role in control of cell proliferation, an effect not previously attributed to these regulators. In fact, they found that mutant animals lacking the receptor proteins EphB2 and EphB3 had about 50% fewer proliferating cells in their colon crypts than did control animals. Acute disruption of ephrin signaling with agents that prevented ephrin clustering and signaling similarly decreased the number of proliferating cells in crypts, and overexpression of EphB2 in cultured explants increased stem cell proliferation. The effects of ephrins and their receptors are thus complex, and it can be difficult to distinguish their effects on proliferation or cell migration. Indeed, EphB proteins have been implicated as tumor suppressors in adenomas, but Holmberg et al. show that loss of EphB signaling reduced the number of proliferating cells in adenomas. Thus the authors propose that the tumor-suppressive functions are likely mediated by restriction of invasion rather than suppression of proliferation.

That may still be an oversimplification though, if one takes into account new results from Basile et al. These authors detected the gene encoding Semaphorin 4D (Sema4D) (another molecule that acts with its receptor plexin-B1 to regulate axonal growth) as one that was selectively overexpressed in head and neck squamous cell carcinomas (HNSCCs) and also in prostate, colon, breast, and lung carcinomas. In culture, HNSCC cells shed soluble Sema4d molecules and caused attraction of endothelial cells present in the same cultures. The authors used RNA interference to limit expression of Sema4D in cultured HNSCC cells, and this blocked their chemotactic effect on endothelial cells. Similarly, when expression of Sema4D was limited by expression of shRNA in HNSCC cells before they were transferred as xenografts to immunocompromised mice, the size of resulting tumors and amount of associated angiogenesis was decreased. Thus although class III semaphorins have been implicated, like ephrins, as tumor suppressors, Sema4D appears to promote angiogenesis and could thus be a target for anticancer therapies directed at certain malignancies.

J. Holmberg, M. Genander, M. M. Halford, C. Annerén, M. Sondell, M. J. Chumley, R. E. Silvany, M. Henkemeyer, J. Frisén, EphB receptors coordinate migration and proliferation in the intestinal stem cell niche. Cell 125, 1151-1163 (2006). [Online Journal]

J. R. Basile, R. M. Castilho, V. P. Williams, J. S. Gutkind, Semaphorin 4D provides a link between axon guidance processes and tumor-induced angiogenesis. Proc. Natl. Acad. Sci. U.S.A. 103, 9017-9022 (2006). [Abstract] [Full Text]

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