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Carcinogenesis Advance Access published online on October 8, 2008
Carcinogenesis, doi:10.1093/carcin/bgn232
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Modulated expression of WFDC1 during carcinogenesis and cellular senescence

Shalom Madar1,*, Ran Brosh1,*, Yosef Buganim1, Osnat Ezra1, Ido Goldstein1, Hilla Solomon1, Ira Kogan1, Naomi Goldfinger1, Helmut Klocker2 and Varda Rotter1,3

1 Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
2 Department of Urology, Innsbruck Medical University, Innsbruck, Austria

3 Corresponding author: Varda Rotter, Ph.D. Phone: 972-8-9344070; Fax: 972-8-9465265; Email: varda.rotter{at}weizmann.ac.il.

Fibroblasts located adjacent to the tumor (Cancer Associated Fibroblasts – CAFs) that constitute a large propotion of the cancer associated stroma facilitate the transformation process. In this study we compared the biological behavior of CAFs that were isolated from a prostate tumor to their Normal Associated Fibroblast (NAF) counterparts. CAFs formed more colonies when seeded at low cell density, exhibited a higher proliferation rate and were less prone to contact inhibition. In contrast to the general notion that high levels of alpha smooth muscle actin serve as a marker for CAFs, we found that prostate CAFs express it at a lower level compared to prostate NAFs. Microarray analysis revealed a set of 161 genes that were altered in CAFs compared to NAFs. We focused on Wap-four disulfide domain 1 (WFDC1), a known secreted protease inhibitor, and found it to be down-regulated in the CAFs. WFDC1 expression was also dramatically down-regulated in highly prolific mesenchymal cells and in various cancers including fibrosarcomas and in tumors of the lung, bladder and brain. Overexpression of WFDC1 inhibited the growth rate of the fibrosarcoma HT1080 cell line. Furthermore, WFDC1 level was up-regulated in senescent fibroblasts. Taken together, our data suggest an important role for WFDC1 in inhibiting proliferation of both tumors and senescent cells. Finally, we suggest that the down-regulation of WFCD1 might serve as a biomarker for cellular transformation.

Key Words: Cancer associated fibroblasts • stroma • prostate cancer • senescence • {alpha}SMA

* These authors contributed equally to this study

Received June 19, 2008; revised September 21, 2008; accepted September 30, 2008.


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