Obesity-Activated Lung Stromal Cells Promote Myeloid Lineage Cell Accumulation and Breast Cancer Metastasis

SIMPLE SUMMARY: Obese breast cancer patients have an increased risk for metastasis; however, the mechanisms are not well characterized. Here, we show that obesity promotes rapid mammary tumor growth and enhances metastases in mice. Within the lungs of non-tumor-bearing mice, obesity increased recruitment of myeloid lineage cells and elevated deposition of collagen fibers. Lung stromal cells isolated from obese mice demonstrated increased expression of extracellular matrix proteins and inflammatory cytokines, including colony-stimulating factor 2 (CSF2). Conditioned media from lung stromal cells of obese mice promoted the invasion of myeloid lineage cells, which was dependent upon lung stromal cell expression of CSF2. These studies suggest that obesity creates an environment conducive to metastatic growth in the lungs prior to tumor formation. Understanding how obesity promotes metastases may increase therapeutic options for a growing population of obese breast cancer patients. ABSTRACT: Obesity is correlated with increased incidence of breast cancer metastasis; however, the mechanisms underlying how obesity promotes metastasis are unclear. In a diet-induced obese mouse model, obesity enhanced lung metastasis in both the presence and absence of primary mammary tumors and increased recruitment of myeloid lineage cells into the lungs. In the absence of tumors, obese mice demonstrated increased numbers of myeloid lineage cells and elevated collagen fibers within the lung stroma, reminiscent of premetastatic niches formed by primary tumors. Lung stromal cells isolated from obese tumor-naïve mice showed increased proliferation, contractility, and expression of extracellular matrix, inflammatory markers and transforming growth factor beta-1 (TGFβ1). Conditioned media from lung stromal cells from obese mice promoted myeloid lineage cell migration in vitro in response to colony-stimulating factor 2 (CSF2) expression and enhanced invasion of tumor cells. Together, these results suggest that prior to tumor formation, obesity alters the lung microenvironment, creating niches conducive to metastatic growth.