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

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 fibroblasts 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.ovarian cancer ͉ Ras ͉ transformation ͉ tumor microenvironment

Profiling influences of senescent and aged fibroblasts on prostate carcinogenesis

“…An important study demonstrating the potential in vivo relevance of these observations focused on the localised regions directly surrounding human ovarian cancers. Increased numbers of senescent stromal cells were enriched in regions juxtaposed to cancer epithelium, a finding that indicates an intimate relationship between the influences and interactions of tumour cells and their attendant microenvironment (Yang et al, 2006). Agingassociated Figure 1 Ageing, senescence, and cellular phenotypic responses.…”

Interleukin 32 promotes hematopoietic progenitor expansion and attenuates bone marrow cytotoxicity

“…Among these, the Gro proteins comprise a family of melanoma growth stimulatory factors. They can support tumor genesis (Gro 1, [35]), angiogenesis and malignant cell proliferation (Gro 2 and 3 [36], also termed MIP-2a and 2b). The GRO genes were originally isolated from transformed fibroblasts.…”

The essence of senescence: Figure 1.

“…In certain settings, pro-oncogenic effects result: The proliferative rate, migration, and invasion of premalignant cells are enhanced when they are cocultured with, or grown in medium conditioned by, senescent fibroblasts (Krtolica et al 2001;Dilley et al 2003;Parrinello et al 2005;Yang et al 2006). For example, a study on ovarian tumorigenesis has revealed that preneoplastic epithelial ovarian cells expressing oncogenic RAS induce expression of GRO1 (a cytokine recognized by CXCR2) (Yang et al 2006).…”