Targeting the SphK1/S1P/S1PR1 Axis That Links Obesity, Chronic Inflammation, and Breast Cancer Metastasis.

Autor:	Nagahashi M; Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata City, Niigata, Japan. mnagahashi@med.niigata-u.ac.jp kazuaki.takabe@roswellpark.org.; Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia.; Departments of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia., Yamada A; Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia.; Departments of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia.; Breast and Thyroid Surgery, Yokohama City University Medical Center, Kanagawa, Japan., Katsuta E; Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia.; Division of Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York.; Departments of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia., Aoyagi T; Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia.; Departments of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia., Huang WC; Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia.; Departments of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia., Terracina KP; Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia.; Departments of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia., Hait NC; Departments of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia.; Division of Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York.; Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York., Allegood JC; Departments of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia., Tsuchida J; Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata City, Niigata, Japan., Yuza K; Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata City, Niigata, Japan., Nakajima M; Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata City, Niigata, Japan., Abe M; Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata City, Niigata, Japan., Sakimura K; Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata City, Niigata, Japan., Milstien S; Departments of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia., Wakai T; Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata City, Niigata, Japan., Spiegel S; Departments of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia., Takabe K; Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata City, Niigata, Japan. mnagahashi@med.niigata-u.ac.jp kazuaki.takabe@roswellpark.org.; Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia.; Departments of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia.; Division of Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York.; Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New York, Buffalo, New York.; Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan.; Department of Surgery, Yokohama City University, Yokohama, Japan.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2018 Apr 01; Vol. 78 (7), pp. 1713-1725. Date of Electronic Publication: 2018 Jan 19.
DOI:	10.1158/0008-5472.CAN-17-1423
Abstrakt:	Although obesity with associated inflammation is now recognized as a risk factor for breast cancer and distant metastases, the functional basis for these connections remain poorly understood. Here, we show that in breast cancer patients and in animal breast cancer models, obesity is a sufficient cause for increased expression of the bioactive sphingolipid mediator sphingosine-1-phosphate (S1P), which mediates cancer pathogenesis. A high-fat diet was sufficient to upregulate expression of sphingosine kinase 1 (SphK1), the enzyme that produces S1P, along with its receptor S1PR1 in syngeneic and spontaneous breast tumors. Targeting the SphK1/S1P/S1PR1 axis with FTY720/fingolimod attenuated key proinflammatory cytokines, macrophage infiltration, and tumor progression induced by obesity. S1P produced in the lung premetastatic niche by tumor-induced SphK1 increased macrophage recruitment into the lung and induced IL6 and signaling pathways important for lung metastatic colonization. Conversely, FTY720 suppressed IL6, macrophage infiltration, and S1P-mediated signaling pathways in the lung induced by a high-fat diet, and it dramatically reduced formation of metastatic foci. In tumor-bearing mice, FTY720 similarly reduced obesity-related inflammation, S1P signaling, and pulmonary metastasis, thereby prolonging survival. Taken together, our results establish a critical role for circulating S1P produced by tumors and the SphK1/S1P/S1PR1 axis in obesity-related inflammation, formation of lung metastatic niches, and breast cancer metastasis, with potential implications for prevention and treatment. Significance: These findings offer a preclinical proof of concept that signaling by a sphingolipid may be an effective target to prevent obesity-related breast cancer metastasis. Cancer Res; 78(7); 1713-25. ©2018 AACR . (©2018 American Association for Cancer Research.)
Databáze:	MEDLINE
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