Targeting the SphK1/S1P/S1PR1 Axis That Links Obesity, Chronic Inflammation, and Breast Cancer Metastasis
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 01, 2018
- Source ID
- 10.1158/0008-5472.can-17-1423
Entities
People
- Akimitsu Yamada
- Eriko Katsuta
- Jeremy C. Allegood
- Junko Tsuchida
- Kazuaki Takabe
- Kenji Sakimura
- Kizuki Yuza
- Krista P. Terracina
- Manabu Abe
- Masato Nakajima
- Masayuki Nagahashi
- Nitai C. Hait
- Sarah Spiegel
- Sheldon Milstien
- Tomoyoshi Aoyagi
- Toshifumi Wakai
- Wei-ching Huang
Organizations
- Japan Society for the Promotion of Science
- National Cancer Institute
- Niigata University
- Roswell Park Comprehensive Cancer Center
- Susan G. Komen for the Cure
- Takeda Science Foundation
- Tokyo Medical University
- Uehara Memorial Foundation
- United States Department of Defense
- University at Buffalo
- Virginia Commonwealth University
- Virginia Commonwealth University School of Medicine
- Yokohama City University
- Yokohama City University Medical Center