Editors' ChoiceCancer Metastasis

Cracking the Metastatic Code

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Science Translational Medicine  27 Aug 2014:
Vol. 6, Issue 251, pp. 251ec148
DOI: 10.1126/scitranslmed.3010128

Like explorers charting and selecting new territory to take over, cancer cells travel the bloodstream and land in distant organs, developing distant metastases. Although much is known about how these cells metastasize, the molecular mechanisms that determine which organs become colonized with tumor cells remain unclear. Sevenich and colleagues evaluated tumor interactions with surrounding stroma in a human breast cancer model and identified cathepsin S as the molecule that mediates brain metastasis.

Tumors with a high propensity for metastasis, including breast cancers, often seek out bone, lung, and brain tissue in which to drop anchor. The metastatic process relies not only on selecting the distant organ, but also on changing the local microenvironment for tumor cell extravasation (leaving the blood vessels), colonization, and growth. On the basis of this requirement, the authors focused on enzymatic activities that drive metastasis. Using a microarray approach, the authors screened the tumor and stroma of xenografted breast cancer cells that metastasized to the bone, lungs, and brain in mice. Cathespin S was elevated in brain metastases, and the presence of this molecule correlated with poor patient prognosis only in brain and not in bone or lung metastases. Turning to genetic analyses, Sevenich et al. determined that both tumor cells and macrophages produced cathepsin S; furthermore, metastasis was prevented when cathepsin S was reduced in both populations of cells. The cathepsin S produced by tumor cells helped facilitate transmigration across the blood–brain barrier by cleaving tight junction proteins. Importantly for translation of this mechanism to treatment for patients, a pharmacological inhibitor of cathepsin S inhibited the metastasis of human breast cancer cells to the mouse brain.

This study demonstrated that organ-specific metastatic mechanisms can be identified. Future studies should expand on these findings to crack the metastatic code from a variety of advanced cancers. Knowing the molecular mechanism will facilitate the translation of targeted therapies into the clinical setting.

L. Sevenich et al., Analysis of tumour- and stroma-supplied proteolytic networks reveals a brain-metastasis-promoting role for cathepsin S. Nat. Cell Biol. 10.1038/ncb3011 (2014 ). [Abstract]

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