P53 Status in Stromal Fibroblasts Modulates Tumor Growth in an SDF1-dependent Manner

Overview

Journal Cancer Res

Specialty Oncology

Date 2010 Oct 19

PMID 20952507

Citations 70

Authors

Yoseph Addadi

Neta Moskovits

Dorit Granot

Guillermina Lozano

Yaron Carmi

Ron N Apte

Michal Neeman

Moshe Oren

Affiliations

Soon will be listed here.

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.

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References

Eng C, Leone G, Orloff M, Ostrowski M . Genomic alterations in tumor stroma. Cancer Res. 2009; 69(17):6759-64. DOI: 10.1158/0008-5472.CAN-09-0985. View

Hill R, Song Y, Cardiff R, Van Dyke T . Selective evolution of stromal mesenchyme with p53 loss in response to epithelial tumorigenesis. Cell. 2005; 123(6):1001-11. DOI: 10.1016/j.cell.2005.09.030. View

Zhang S, Qi L, Li M, Zhang D, Xu S, Wang N . Chemokine CXCL12 and its receptor CXCR4 expression are associated with perineural invasion of prostate cancer. J Exp Clin Cancer Res. 2008; 27:62. PMC: 2596092. DOI: 10.1186/1756-9966-27-62. View

Bar J, Feniger-Barish R, Lukashchuk N, Shaham H, Moskovits N, Goldfinger N . Cancer cells suppress p53 in adjacent fibroblasts. Oncogene. 2008; 28(6):933-6. PMC: 2727601. DOI: 10.1038/onc.2008.445. View

Paterson R, Ulbright T, MacLennan G, Zhang S, Pan C, Sweeney C . Molecular genetic alterations in the laser-capture-microdissected stroma adjacent to bladder carcinoma. Cancer. 2003; 98(9):1830-6. DOI: 10.1002/cncr.11747. View

Augsten M, Hagglof C, Olsson E, Stolz C, Tsagozis P, Levchenko T . CXCL14 is an autocrine growth factor for fibroblasts and acts as a multi-modal stimulator of prostate tumor growth. Proc Natl Acad Sci U S A. 2009; 106(9):3414-9. PMC: 2651265. DOI: 10.1073/pnas.0813144106. View

Olive K, Tuveson D, Ruhe Z, Yin B, Willis N, Bronson R . Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome. Cell. 2004; 119(6):847-60. DOI: 10.1016/j.cell.2004.11.004. View

Dudley A, Shih S, Cliffe A, Hida K, Klagsbrun M . Attenuated p53 activation in tumour-associated stromal cells accompanies decreased sensitivity to etoposide and vincristine. Br J Cancer. 2008; 99(1):118-25. PMC: 2453010. DOI: 10.1038/sj.bjc.6604465. View

Yang G, Rosen D, Zhang Z, Bast Jr R, Mills G, Colacino J . The chemokine growth-regulated oncogene 1 (Gro-1) links RAS signaling to the senescence of stromal fibroblasts and ovarian tumorigenesis. Proc Natl Acad Sci U S A. 2006; 103(44):16472-7. PMC: 1637606. DOI: 10.1073/pnas.0605752103. View

10.

Jacks T, Remington L, Williams B, Schmitt E, Halachmi S, Bronson R . Tumor spectrum analysis in p53-mutant mice. Curr Biol. 1994; 4(1):1-7. DOI: 10.1016/s0960-9822(00)00002-6. View

11.

Patocs A, Zhang L, Xu Y, Weber F, Caldes T, Mutter G . Breast-cancer stromal cells with TP53 mutations and nodal metastases. N Engl J Med. 2007; 357(25):2543-51. DOI: 10.1056/NEJMoa071825. View

12.

Singh S, Singh U, Grizzle W, Lillard Jr J . CXCL12-CXCR4 interactions modulate prostate cancer cell migration, metalloproteinase expression and invasion. Lab Invest. 2004; 84(12):1666-76. DOI: 10.1038/labinvest.3700181. View

13.

Wernert N, Locherbach C, Wellmann A, Behrens P, HUGEL A . Presence of genetic alterations in microdissected stroma of human colon and breast cancers. Anticancer Res. 2001; 21(4A):2259-64. View

14.

Orimo A, Gupta P, Sgroi D, Arenzana-Seisdedos F, Delaunay T, Naeem R . Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005; 121(3):335-48. DOI: 10.1016/j.cell.2005.02.034. View

15.

Taniwaki K, Fukamachi H, Komori K, Ohtake Y, Nonaka T, Sakamoto T . Stroma-derived matrix metalloproteinase (MMP)-2 promotes membrane type 1-MMP-dependent tumor growth in mice. Cancer Res. 2007; 67(9):4311-9. DOI: 10.1158/0008-5472.CAN-06-4761. View

16.

Hasebe T, Tamura N, Okada N, Hojo T, Akashi-Tanaka S, Shimizu C . p53 expression in tumor-stromal fibroblasts is closely associated with the nodal metastasis and outcome of patients with invasive ductal carcinoma who received neoadjuvant therapy. Hum Pathol. 2009; 41(2):262-70. DOI: 10.1016/j.humpath.2009.07.021. View

17.

Campbell I, Polyak K, Haviv I . Clonal mutations in the cancer-associated fibroblasts: the case against genetic coevolution. Cancer Res. 2009; 69(17):6765-8. DOI: 10.1158/0008-5472.CAN-08-4253. View

18.

Zindy F, Quelle D, Roussel M, Sherr C . Expression of the p16INK4a tumor suppressor versus other INK4 family members during mouse development and aging. Oncogene. 1997; 15(2):203-11. DOI: 10.1038/sj.onc.1201178. View

19.

Allinen M, Beroukhim R, Cai L, Brennan C, Lahti-Domenici J, Huang H . Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell. 2004; 6(1):17-32. DOI: 10.1016/j.ccr.2004.06.010. View

20.

Mitsuyama K, Tsuruta O, Tomiyasu N, Takaki K, Suzuki A, Masuda J . Increased circulating concentrations of growth-related oncogene (GRO)-alpha in patients with inflammatory bowel disease. Dig Dis Sci. 2006; 51(1):173-7. DOI: 10.1007/s10620-006-3104-4. View