Expression of connective tissue growth factor mRNA in the fibrous stroma of mammary tumors.

Desmoplasia, the formation of highly cellular, excessive connective tissue stroma associated with some cancers, shares many features with the wound healing response. Since connective tissue growth factor (CTGF) has previously been demonstrated to play a role in wound repair, we wanted to determine if it might be involved in the pathogenesis of stromal demoplasia in mammary cancer. We assayed 11 human invasive mammary ductal carcinomas by Northern blot and 7 out of 11 were positive for both CTGF expression and transforming growth factor-beta 1 (TGF-beta 1, a principal CTGF inducer). One specimen was positive only for TGF-beta 1. The remaining 3 tumors lacked significant stromal involvement and were negative for either factor. In every case we assayed, in which there was marked connective tissue involvement, both CTGF and TGF-beta 1 messages were found. We also assayed 3 murine mammary tumor models. The GI-101 xenograft model had marked stroma and was positive for both factors in-vivo, but positive for only TGF-beta 1 mRNA expression in culture where fibroblasts were absent. The DMBA murine tumor lacked significant stroma and was negative for CTGF and TGF-beta 1 expression by Northern blot, while the stromal rich DMBA-MMTV tumor contained multifocal desmoplasia and was positive for both factors. We performed in-situ hybridization for CTGF and TGF-beta 1 on the GI-101 and DMBA-MMTV tumors. CTGF message was observed only in the fibroblasts of the stroma, while TGF-beta 1 mRNA hybridization was present in tumor epithelial cells and leukocytes. These results suggest that cancer stroma formation involves induction of similar fibroproliferative growth factors (TGF-beta 1 and CTGF) as wound repair.