Obesity, Breast cancer, Macrophages, Cancer stem-like cells, Angiogenesis
Obesity is correlated with worsened prognosis and treatment resistance in breast cancer. Macrophage-targeted therapies are currently in clinical trials, however, little is known about how obesity may impact treatment efficacy. Within breast adipose tissue, obesity leads to chronic, macrophage-driven inflammation, suggesting that obese breast cancer patients may benefit from these therapies. Using a high fat diet model of obesity, we orthotopically transplanted cancer cell lines into the mammary glands of obese and lean mice. We quantified changes in tumor invasiveness, angiogenesis and metastasis, and examined the efficacy of macrophage depletion to diminish tumor progression in obese and lean mice. Mammary tumors from obese mice grew significantly faster, were enriched for cancer stem-like cells (CSCs) and were more locally invasive and metastatic. Tumor cells isolated from obese mice demonstrated enhanced expression of stem cell-related pathways including Sox2 and Notch2. Despite more rapid growth, mammary tumors from obese mice had reduced necrosis, higher blood vessel density, and greater macrophage recruitment. Depletion of macrophages in obese tumor-bearing mice resulted in increased tumor necrosis, reduced endothelial cells, and enhanced recruitment of CD8+ T cells compared to IgG-treated controls. Macrophages may be an important clinical target to improve treatment options for obese breast cancer patients.
This research was funded by Susan G. Komen Career Catalyst Grant, grant number CCR1532611 to L.M.A.; NIH grant number R01 CA227542 to L.M.A.; NIH, grant number T32 GM007215 to L.E.H.; NIH grant number T35 OD011078 to R.Q.M. and M.H.; AVMA/AVMF Second Summer Research Opportunity Fellowship to R.Q.M.; NIH Support Grant, grant number P30 CA014520 to University of Wisconsin Carbone Cancer.
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Hillers-Ziemer, L. E.; McMahon, R. Q. ; Hietpas, M.; Paderta, G.; LeBeau, J.; McCready, J.; and Arendt, L. M. (2020). Obesity Promotes Cooperation of Cancer Stem-Like Cells and Macrophages to Enhance Mammary Tumor Angiogenesis. Cancers 12(2): 502. https://doi.org/10.3390/cancers12020502