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p53 Attenuates Cancer Cell Migration and Invasion through Repression of SDF-1/CXCL12 Expression in Stromal Fibroblasts

Departments of ¹ Molecular Cell Biology and ² Immunology, The Weizmann Institute of Science, Rehovot, Israel and ³ Department of Oncology, Sheba Medical Center, Tel Hashomer, Israel

Requests for reprints: Moshe Oren, Department of Molecular Cell Biology, The Weizmann Institute, P.O. Box 26, Rehovot 76100, Israel. Phone: 972-8-934-2358; Fax: 972-8-934-6004; E-mail: moshe.oren{at}weizmann.ac.il.

The p53 tumor suppressor acts as a major barrier against cancer. To a large extent, this is due to its ability to maintain genome stability and to eliminate cancer cells from the replicative pool through cell-autonomous mechanisms. However, in addition to its well-documented functions within the malignant cancer cell, p53 can also exert non-cell-autonomous effects that contribute to tumor suppression. We now report that p53 can suppress the production of the chemokine SDF-1 in cultured fibroblasts of both human and mouse origin. This is due to a p53-mediated down-regulation of SDF-1 mRNA, which can be exacerbated on activation of p53 by the drug Nutlin-3. SDF-1 promotes the migration and invasiveness of cells that express its cognate receptor CXCR4. Indeed, medium conditioned by p53-deficient fibroblasts induces cancer cells towards increased directional migration and invasiveness, which are largely reversed by CXCR4 antagonist peptides. Because SDF-1 produced by stromal fibroblasts plays an important role in cancer progression and metastasis, our findings suggest that the ability of p53 to suppress stromal SDF-1 production may be an important mechanism whereby it does its non-cell-autonomous tumor suppressor function. (Cancer Res 2006; 66(22): 10671-6)

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