Abstract
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.
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Abbreviations
- MSP:
-
Macrophage stimulating protein
- RON:
-
The recepteur d’origine nantais
- SCLC:
-
Small cell lung cancer
- NK:
-
Natural killer
- SCID:
-
Severe combined immunodeficient
- MEM:
-
Minimum essential medium
- FBS:
-
Fetal bovine serum
- GFP:
-
Green fluorescent protein
- RT-PCR:
-
Reverse transcription-polymerase chain reaction
- GAPDH:
-
Glyceraldehyde 3-phosphate dehydrogenase
- HGFA:
-
Hepatocyte growth factor activator
- MTT:
-
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium
- TAM:
-
Tumor-associated macrophage
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Acknowledgments
We greatly appreciate Dr. A. L. Welm (University of Utah, Salt Lake City, UT) for providing the replication-defective mouse stem cell viruses, pMIG and pMIG-MSP. This study was supported in part by a Grant-in-aid for Cancer Research from the Ministry of Education, Science, Sports, and Culture of Japan.
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The authors declare that we have no conflict of interest.
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Sato, S., Hanibuchi, M., Kuramoto, T. et al. Macrophage stimulating protein promotes liver metastases of small cell lung cancer cells by affecting the organ microenvironment. Clin Exp Metastasis 30, 333–344 (2013). https://doi.org/10.1007/s10585-012-9540-y
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DOI: https://doi.org/10.1007/s10585-012-9540-y