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.
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Acknowledgements
We thank Dr J Schachter and Dr B Kaufman for helpful discussions. This work was supported in part by a Center of Excellence grant from the Flight Attendant Medical Research Institute (FAMRI), and by grant R37 CA40099 from the National Cancer Institute. JB was supported also by the Koschitzky family donation to the breast cancer unit of CSMC, and by a Van Bates grant from the Tel Aviv University Cancer Biology Research Center.
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Bar, J., Feniger-Barish, R., Lukashchuk, N. et al. Cancer cells suppress p53 in adjacent fibroblasts. Oncogene 28, 933ā936 (2009). https://doi.org/10.1038/onc.2008.445
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DOI: https://doi.org/10.1038/onc.2008.445
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