1. ¹Oncology Department, Cancer Research Center, Chaim Sheba Medical Center, Tel-Hashomer, Israel
2. ²Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel
3. ³Cancer Research Center, Chaim Sheba Medical Center, Tel-Hashomer, Israel
4. ⁴The Beatson Institute for Cancer Research, Glasgow, UK
5. ⁵Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
6. ⁶Department of Thoracic Surgery, Chaim Sheba Medical Center, Tel-Hashomer, Israel
7. ⁷Institute of Pathology, Chaim Sheba Medical Center, Tel-Hashomer, Israel
8. ⁸Department of Surgery 'C', Chaim Sheba Medical Center, Tel-Hashomer, Israel
9. ⁹Paediatric Haematology-Oncology, Cancer Research Center, Chaim Sheba Medical Center, Tel-Hashomer, Israel

Correspondence: Dr J Bar, Division of Medical Oncology, The Ottawa Hospital Cancer Center, General Campus, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6. E-mail: bar.jair@gmail.com

Received 9 September 2008; Revised 29 September 2008; Accepted 1 November 2008; Published online 8 December 2008.

Abstract

The p53 tumor suppressor serves as a crucial barrier against cancer development. In tumor cells and their progenitors, p53 suppresses cancer in a cell-autonomous manner. However, p53 also possesses non-cell-autonomous activities. For example, p53 of stromal fibroblasts can modulate the spectrum of proteins secreted by these cells, rendering their microenvironment less supportive of the survival and spread of adjacent tumor cells. We now report that epithelial tumor cells can suppress p53 induction in neighboring fibroblasts, an effect reproducible by tumor cell-conditioned medium. The ability to suppress fibroblast p53 activation is acquired by epithelial cells in the course of neoplastic transformation. Specifically, stable transduction of immortalized epithelial cells by mutant H-Ras and p53-specific short inhibitory RNA endows them with the ability to quench fibroblast p53 induction. Importantly, human cancer-associated fibroblasts are more susceptible to this suppression than normal fibroblasts. These findings underscore a mechanism whereby epithelial cancer cells may overcome the non-cell-autonomous tumor suppressor function of p53 in stromal fibroblasts.