p53 Status in Stromal Fibroblasts Modulates Tumor Growth in an SDF1-Dependent Manner

Abstract

The p53 tumor suppressor exerts a variety of cell-autonomous effects that are aimed to thwart tumor development. In addition, however, there is growing evidence for cell nonautonomous tumor suppressor effects of p53. In the present study, we investigated the impact of stromal p53 on tumor growth. Specifically, we found that ablation of p53 in fibroblasts enabled them to promote more efficiently the growth of tumors initiated by PC3 prostate cancer-derived cells. This stimulatory effect was dependent on the increased expression of the chemokine SDF-1 in the p53-deficient fibroblasts. Notably, fibroblasts harboring mutant p53 protein were more effective than p53-null fibroblasts in promoting tumor growth. The presence of either p53-null or p53-mutant fibroblasts led also to a markedly elevated rate of metastatic spread of the PC3 tumors. These findings implicate p53 in a cell nonautonomous tumor suppressor role within stromal fibroblasts, through suppressing the production of tumor stimulatory factors by these cells. Moreover, expression of mutant p53 by tumor stroma fibroblasts might exert a gain of function effect, further accelerating tumor development. Cancer Res; 70(23); 9650-8.Ó2010 AACR.

The Role of Stromal Myofibroblast and Extracellular Matrix in Tumor Angiogenesis

“…p53 regulates the expression of TSP-1 and SDF-1, two potent regulators of angiogenesis, in stromal fibroblasts. 84,85 As mentioned already, stromal myofibroblasts are a prominent source of VEGF and bFGF, two angiogenic factors regulated by p53. 86,87 Dissecting the functional consequences of specific mutations in stromal myofibroblasts will be an exciting area to watch in cancer biology.…”

Tumor-secreted SDF-1 promotes glioma invasiveness and TAM tropism toward hypoxia in a murine astrocytoma model

“…For example, the expression of relatively high levels of SDF-1 by ALTS1C1 cells could be a direct consequence p53 inactivation. 37,38 The fact that the highest levels of SDF-1 were found in the infiltrating tumor front and invasion islands that were associated with high MVD and TAMs confers on this model suitability for preclinical testing of therapeutic strategies and for study of the roles of the microenvironment in glioma infiltration.…”

Cancer Cells Cue the p53 Response of Cancer-Associated Fibroblasts to Cisplatin

“…Several lines of evidence support the hypothesis that activation of p53 in 1 cell can influence the response of neighboring cells, particularly via transcriptional activation of genes that encode for secreted factors. For instance, in mouse xenograft models as well as in cell culture experiments using conditioned medium, it has been shown that the p53 activity of stromal fibroblasts can reduce growth and enhance apoptosis of epithelial cancer cells (10,11). Therefore, attenuation of the p53 response of carcinoma-associated fibroblasts (CAF) should support tumor growth.…”