Obesity-associated inflammation and vascular integrity in breast cancer metastasis
Sheri McDowell1, Valérie Breton1, Daniela Quail1 1Goodman Cancer Research Centre, Department of Physiology, McGill University Metastasis is the leading cause of breast cancer-related mortality. Metastatic efficiency is regulated in part by inflammatory factors within the primary tumor microenvironment, the circulation, and/or within secondary organs1. Thus a better understanding of the relationship between cancer, inflammation and the tumor microenvironment is crucial to further clinical advances in immune-targeted therapies. Obesity is characterized by chronic systemic inflammation, and is a major risk factor for cancer development and mortality2, 3. Previous studies have shown that obesity enhances breast cancer metastasis to the lung, and that this is regulated in a neutrophil-dependent manner4. This effect was evident 48-hours following tail vein injection of breast cancer cells into obese and lean mice, suggesting that differences in extravasation may be at play. Supporting this, we have determined that serum isolated from obese mice enhances transendothelial migration of breast cancer cells in vitro, compared to serum isolated from lean mice. Furthermore, using an in vivo vascular integrity assay, we have confirmed that blood vessels in the lungs of obese mice are leakier relative to that of lean mice, and have additionally assessed this phenotype in response to antibody-based neutrophil depletion. Mechanistically, we are now exploring whether there are differences in endothelial junctional proteins and/or secreted proteases by immune cells within the lung microenvironment. As obesity is a global rapidly expanding epidemic, understanding how obesity-associated inflammation contributes to a microenvironment, to assist cancer progression is of great clinical importance.
References 1.Quail, D.F. & Joyce, J.A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423-1437 (2013). 2.Calle, E.E., Rodriguez, C., Walker-Thurmond, K. & Thun, M.J. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N. Engl. J. Med. 348, 1625-1638 (2003). 3.Olson, O.C., Quail, D.F. & Joyce, J.A. Obesity and the tumor microenvironment. Science 358, 1130-1131 (2017). 4.Quail, D.F. et al. Obesity alters the lung myeloid cell landscape to enhance breast cancer metastasis through IL5 and GM-CSF. Nat. Cell Biol. 19, 974-987 (2017).
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