Enhanced hepatocyte growth factor signaling by type II transforming growth factor-beta receptor knockout fibroblasts promotes mammary tumorigenesis.

Cheng N, Chytil A, Shyr Y, Joly A, Moses HL
Cancer Res. 2007 67 (10): 4869-77

PMID: 17495323 · DOI:10.1158/0008-5472.CAN-06-3381

Transforming growth factor-beta (TGF-beta) plays complex dual roles as an inhibitor and promoter of tumor progression. Although the influence of the stromal microenvironment on tumor progression is well recognized, little is known about the functions of TGF-beta signaling in the stroma during tumor progression. Using cre-lox technology, expression of the type II TGF-beta receptor was selectively knocked out in fibroblasts (Tgfbr2(FspKO)). In a co-xenograft model, we show that Tgfbr2(FspKO) fibroblasts enhance mammary carcinoma growth and metastasis in mice while increasing hepatocyte growth factor (HGF) expression and c-Met signaling downstream pathways including signal transducers and activators of transcription 3 (Stat3) and p42/44 mitogen-activated protein kinase (MAPK). Treatment of tumor-bearing mice with a pharmacologic inhibitor (EXEL-7592) of c-Met blocks tumor progression and reduces levels of phospho-Stat3 and phospho-p42/44 MAPK. Similarly, small interfering RNA knockdown of c-Met expression in mammary tumor cells reduces metastasis and c-Met signaling caused by Tgfbr2(FspKO) fibroblasts. The results show that TGF-beta signaling in fibroblasts suppresses tumor metastasis by antagonizing HGF/c-Met signaling within tumor epithelial cells. Furthermore, this co-xenograft model represents a unique context to study stromal TGF-beta and HGF signaling in mammary tumorigenesis.

MeSH Terms (20)

Animals Cell Transformation, Neoplastic Female Fibroblasts Hepatocyte Growth Factor Mammary Neoplasms, Experimental Mice Mice, Inbred C57BL Mice, Knockout Mice, Nude Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Protein-Serine-Threonine Kinases Proto-Oncogene Proteins c-met Receptor, Transforming Growth Factor-beta Type II Receptors, Transforming Growth Factor beta RNA, Small Interfering Signal Transduction STAT3 Transcription Factor Stromal Cells

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