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Carcinogenesis Advance Access originally published online on October 8, 2008
Carcinogenesis 2009 30(1):20-27; 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
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Modulated expression of WFDC1 during carcinogenesis and cellular senescence

Shalom Madar{dagger}, Ran Brosh{dagger}, Yosef Buganim, Osnat Ezra, Ido Goldstein, Hilla Solomon, Ira Kogan, Naomi Goldfinger, Helmut Klocker1 and Varda Rotter*

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

* To whom correspondence should be addressed. Tel: +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 proportion 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 with prostate NAFs. Microarray analysis revealed a set of 161 genes that were altered in CAFs compared with NAFs. We focused on whey acidic protein four-disulfide core domain 1 (WFDC1), a known secreted protease inhibitor, and found it to be downregulated in the CAFs. WFDC1 expression was also dramatically downregulated 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 upregulated 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 downregulation of WFDC1 might serve as a biomarker for cellular transformation.

Abbreviations: CAFs, cancer-associated fibroblasts; cDNA, complementary DNA; ECM, extracellular matrix; IL, interleukin; mRNA, messenger RNA; NAF, normal-associated fibroblast; PDL, population doubling; PF, prostate fibroblast; ps20, prostate-specific 20; QRT-PCR, quantitative real-time polymerase chain reaction; SKY, spectral karyotyping; {alpha}SMA, {alpha}-smooth muscle actin; WFDC1, whey acidic protein four-disulfide core domain 1

{dagger} These authors contributed equally to this work.

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


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