TY - JOUR
T1 - p53 status in stromal fibroblasts modulates tumor growth in an SDF1-dependent manner
AU - Addadi, Yoseph
AU - Moskovits, Neta
AU - Granot, Dorit
AU - Lozano, Guillermina
AU - Carmi, Yaron
AU - Apte, Ron N.
AU - Neeman, Michal
AU - Oren, Moshe
PY - 2010/12/1
Y1 - 2010/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=78649930457&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-10-1146
DO - 10.1158/0008-5472.CAN-10-1146
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C2 - 20952507
AN - SCOPUS:78649930457
SN - 0008-5472
VL - 70
SP - 9650
EP - 9658
JO - Cancer Research
JF - Cancer Research
IS - 23
ER -