The chemokine growth-regulated oncogene 1 (Gro-1) links RAS signaling to the senescence of stromal fibroblasts and ovarian tumorigenesis

Gong Yang, Daniel G. Rosen, Zhihong Zhang, Robert C. Bast, Gordon B. Mills, Justin A. Colacino, Imelda Mercado-Uribe, Jinsong Liu

Research output: Contribution to journalArticle

230 Scopus citations

Abstract

Epithelial-stromal interactions play a critical role in tumor initiation and progression; cancer-associated stroma, but not normal stroma, is known to be tumor-promoting. However, the molecular signal used by epithelial cancer cells to reprogram normal stroma to a tumorigenic stroma is not known. Here, we present evidence to suggest that the chemokine growth-regulated oncogene 1 (Gro-1) may be one such signaling molecule. We showed that the expression of Gro-1 is activated by RAS and is vital for cell survival and the malignant transformation of ovarian epithelial cells. Surprisingly, we found that Gro-1 is a potent inducer of senescence in stromal fibroblasts and that this effect depends on functional p53. Senescent iibroblasts induced by Gro-1 can promote tumor growth whereas abrogation of senescence through immortalization results in loss of such tumor promoting activity. We also demonstrated that stromal fibroblasts adjacent to epithelial cancer cells are senescent in human ovarian cancer specimens and in heterografts from RAS-transformed human ovarian epithelial cells and ovarian cancer cells. Moreover, Gro-1 was expressed at significantly higher amounts in ovarian cancer than in normal tissues and was higher in serum samples from women with ovarian cancer than in serum from women without ovarian cancer. These findings provide strong evidence that RAS-induced Gro-1 can reprogram the stromal microenvironment through the induction of senescence of fibroblasts and thus can promote tumorigenesis. Therefore, Gro-1 may be a therapeutic target as well as a diagnostic marker in ovarian cancer.

Original languageEnglish (US)
Pages (from-to)16472-16477
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number44
DOIs
StatePublished - Oct 31 2006
Externally publishedYes

Keywords

  • Ovarian cancer
  • Ras
  • Transformation
  • Tumor microenvironment

ASJC Scopus subject areas

  • General

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