4485

MST1

macrophage stimulating 1;MST1;macrophage stimulating 1

hepatocyte growth factor-like protein|hepatocyte growth factor-like protein homolog|macrophage stimulating 1 (hepatocyte growth factor-like)|macrophage-stimulating protein

3p21

protein-coding

A better understanding of tumor metastasis requires development of animal models that authentically reproduce the metastatic process. By modifying an existing mouse model of breast cancer, we discovered that macrophage-stimulating protein promoted breast tumor growth and metastasis to several organs. A special feature of our findings was the occurrence of osteolytic bone metastases, which are prominent in human breast cancer. To explore the clinical relevance of our model, we examined expression levels of three genes involved in activation of the MSP signaling pathway (MSP, MT-SP1, and MST1R) in human breast tumors. We found that overexpression of MSP, MT-SP1, and MST1R was a strong independent indicator of both metastasis and death in human breast cancer patients and significantly increased the accuracy of an existing gene expression signature for poor prognosis. These data suggest that signaling initiated by MSP is an important contributor to metastasis of breast cancer and introduce an independent biomarker for assessing the prognosis of humans with breast cancer.

The organ microenvironment significantly affects the processes of cancer metastasis. Elucidating the molecular mechanisms of interaction between tumor cells and the organ microenvironment is crucial for the development of effective therapeutic strategies to eradicate cancer metastases. Macrophage stimulating protein (MSP), an activator of macrophages, regulates a pleiotropic array of effects, including proliferation, cellular motility, invasiveness, angiogenesis, and resistance to anoikis. However, the role of MSP in cancer metastasis is still largely unknown. In this study, the action of MSP on the production of metastases was determined in a multiple-organ metastasis model. The murine MSP gene was transfected into two human SCLC cell lines, SBC-5 and H1048, to establish transfectants secreting biologically active MSP. MSP gene transduction did not affect cell proliferation and motility in vitro. Intravenously inoculated MSP transfectants produced significantly larger numbers of liver metastases than parental cells or vector control clones, while there were no significant differences in bone or lung metastases among them. Immunohistochemical analyses of liver metastases revealed that tumor-associated microvessel density and tumor-infiltrating macrophages were significantly increased in lesions produced by MSP transfectants. MSP could stimulate the migration of murine macrophages and endothelial cells in vitro. Consequently, MSP may be one of the major determinants that affects the properties of tumor stroma and that produces a permissive microenvironment to promote cancer metastasis.