Transforming growth factor-beta signaling-deficient fibroblasts enhance hepatocyte growth factor signaling in mammary carcinoma cells to promote scattering and invasion.

Cheng N, Chytil A, Shyr Y, Joly A, Moses HL
Mol Cancer Res. 2008 6 (10): 1521-33

PMID: 18922968 · PMCID: PMC2740918 · DOI:10.1158/1541-7786.MCR-07-2203

Fibroblasts are major cellular components of the tumor microenvironment, regulating tumor cell behavior in part through secretion of extracellular matrix proteins, growth factors, and angiogenic factors. In previous studies, conditional deletion of the type II transforming growth factor-beta (TGF-beta) receptor in fibroblasts (Tgfbr2FspKO) was shown to promote mammary tumor metastasis in fibroblast-epithelial cell cotransplantation studies in mice, correlating with increased expression of hepatocyte growth factor (HGF). Here, we advance our findings to show that Tgfbr2(FspKO) fibroblasts enhance HGF/c-Met and HGF/Ron signaling to promote scattering and invasion of mammary carcinoma cells. Blockade of c-Met and Ron by small interfering RNA silencing and pharmacologic inhibitors significantly reduced mammary carcinoma cell scattering and invasion caused by Tgfbr2FspKO fibroblasts. Moreover, neutralizing antibodies to c-Met and Ron significantly inhibited HGF-induced cell scattering and invasion, correlating with reduced Stat3 and p42/44MAPK phosphorylation. Investigation of the signal transducer and activator of transcription 3 (Stat3) and mitogen-activated protein kinase (MAPK) signaling pathways by pharmacologic inhibition and small interfering RNA silencing revealed a cooperative interaction between the two pathways to regulate HGF-induced invasion, scattering, and motility of mammary tumor cells. Furthermore, whereas c-Met was found to regulate both the Stat3 and MAPK signaling pathways, Ron was found to regulate Stat3 but not MAPK signaling in mammary carcinoma cells. These studies show a tumor-suppressive role for TGF-beta signaling in fibroblasts, in part by suppressing HGF signaling between mammary fibroblasts and epithelial cells. These studies characterize complex functional roles for HGF and TGF-beta signaling in mediating tumor-stromal interactions during mammary tumor cell scattering and invasion, with important implications in the metastatic process.

MeSH Terms (22)

Animals Cell Line, Tumor Cell Movement Culture Media, Conditioned Female Fibroblasts Hepatocyte Growth Factor Mammary Neoplasms, Experimental MAP Kinase Signaling System Mice Mice, Knockout Mitogen-Activated Protein Kinase 1 Models, Biological Neoplasm Invasiveness Protein-Serine-Threonine Kinases Proto-Oncogene Proteins c-met Receptor, Transforming Growth Factor-beta Type II Receptor Protein-Tyrosine Kinases Receptors, Transforming Growth Factor beta Signal Transduction STAT3 Transcription Factor Transforming Growth Factor beta

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