"Role of carcinoma-associated fibroblasts (CAF) in the acquisition of hormone independence in an experimental mammary carcinoma"

FABRIS, VICTORIA; LAMB, CAROLINE; GOROSTIAGA, MARÍA ALICIA; WARGON, VICTORIA; SOLDATI, ROCÍO; NOVARO, VIRGINIA; MOLINOLO, ALFREDO; LANARI, CLAUDIA

Washington DC, EEUU

Congreso; American Association for Cancer Research: Annual Meeting; 2006

We have developed an experimental model in which murine metastatic ductal mammary carcinomas expressing estrogen and progesterone receptors transit through different stages of hormone dependency. In co-culture studies we have demonstrated that CAF from hormone-independent (HI) tumors (CAF-HI) can stimulate epithelial cell proliferation better than those from hormone-dependent (HD) tumors (CAF-HD). The aim of this study was to investigate whether CAF-HI  inoculated with epithelial purified cells from HD tumors would be able to confer an HI phenotype. The C4-HD transplanted mammary carcinoma tumor, which has a near diploid chromosome number, and the C4-HI with an aneuploid karyotype were chosen for this purpose. Epithelial purified cells (2 x 105) of both tumors were inoculated either alone or together with equal number of CAF-HI or CAF-HD cells (n=8/group). CAFs were also inoculated alone in control groups. The purity of the CAF suspensions was about 95% as checked by cytokeratin staining. In three different experiments, epithelial cells from HD tumors were able to grow only when inoculated together with the CAF-HI cells (i.e: tumor size at day 25 after inoculation:: epithelial HD: 0 mm2; epithelial HD CAF-HI: 126 ± 26,6 mm2, p<0.001). To corroborate the origin of the tumor cells, cytogenetic studies were performed in primary cultures from these tumors. Metaphase analysis of the tumors growing in mice inoculated with epithelial HD together with CAF-HI showed a C4-HI karyotype. This data indicates that the very few HI epithelial contaminant cells were able to grow very fastly in this environment. To investigate if inoculated CAF are really able to grow after syngeneic transplantation, C4-HI purified epithelial cells were inoculated in female mice or in male mice, alone or together with CAF-HI. The tumors obtained in male mice were cultured; cytogenetic studies of the CAF enriched cultures showed a normal male karyotype in 90% of the metaphases. These results were corroborated by Fluorescent in situ Hybridization (FISH) studies using a chromosome Y probe. This data indicates that in our model CAF inoculated together with epithelial tumor cells are able to enhance tumor growth, and that tumor stroma is recruited from the host.