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Small cancer cells don't stray

Cancer cells (top) exposed to TGF-ß grow and elongate as they undergo EMT (bottom).

Wanderlust is what makes cancer cells deadly. On page 437, Lamouille and Derynck show that anticancer drugs already in clinical trials might have an unexpected benefit by turning the rogue cells into homebodies.

Cancer cells often enlarge and crank up protein synthesis, presumably to support their racing metabolism. Before they metastasize, the cells undergo a transformation known as the epithelial–mesenchymal transition (EMT). They reorganize their skeleton, stretch out, and break connections with their neighbors. After they've completed the transition, cells dissolve the extracellular matrix that restrains them and start spreading. EMT is prodded by increased expression of the cytokine TGF-ß via the Smad pathway, which regulates gene transcription.

TGF-ß also acts through a separate pathway that increases protein synthesis, the researchers found while studying cultured breast cancer cells. Dosing the cells with TGF-ß spurred them to get bigger and boost translation while undergoing EMT.

The speed of protein synthesis is controlled by the mTOR pathway, which Lamouille and Derynck found was activated by TGF-ß in these cancer cells. In turn, the researchers discovered, mTOR was under the control of a pathway initiated by PI3 kinase rather than Smads.

The drug rapamycin, which blocks mTOR, prevented cells from bulking up and boosting protein production, but it didn't forestall EMT. It did, however, rein in the cells, probably by loosening the surface attachments that cells use to crawl. These findings indicate that although tumor cells undergo EMT before they move, the two events can be separated.

That distinction suggests a strategy for thwarting metastasis. Researchers have so far focused on blocking TGF-ß to short-circuit EMT. But drugs that shut down mTOR might keep cancer cells at home even if they don't stop EMT. The researchers are now testing whether rapamycin analogues restrain cancer cells in animals. If they do, the good news is that similar compounds are already in clinical trials.

Mitch Leslie

mitchleslie{at}comcast.net

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Related Article

Cell size and invasion in TGF-ß–induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway

Samy Lamouille and Rik Derynck
J. Cell Biol. 2007 178: 437-451. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF, 1020K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Leslie, M. Search for Related Content PubMed Articles by Leslie, M. Related Collections Related Article Social Bookmarking                            What's this?