Arendt, L. M. | Search bioRxiv

bioRxiv2023

Alterations in the Mammary Gland and Tumor Microenvironment of Formerly Obese Mice

Obesity is a risk factor for breast cancer, and women with obesity that develop breast cancer have a worsened prognosis. Within the mammary gland, obesity causes chronic, macrophage-driven inflammation and adipose tissue fibrosis. To examine the impact of weight loss on the mammary microenvironment, mice were fed high-fat diet to induce obesity, then switched to a low-fat diet. In formerly obese mice, we observed reduced numbers of crown-like structures and fibrocytes in mammary glands, while collagen deposition was not resolved with weight loss. Following transplant of TC2 tumor cells into the mammary glands of lean, obese, and formerly obese mice, diminished collagen deposition and cancer-associated fibroblasts were observed in tumors from formerly obese mice compared to obese mice. When TC2 tumor cells were mixed with CD11b+CD34+ myeloid progenitor cells, collagen deposition within the tumors was significantly greater compared to when tumor cells were mixed with CD11b+CD34- monocytes, suggesting that fibrocytes contribute to early collagen deposition in mammary tumors of obese mice. Overall, these studies show that weight loss resolved some of the microenvironmental conditions within the mammary gland that may contribute to tumor progression.

cancer biology↗

bioRxiv2020

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

Obesity is correlated with increased incidence of breast cancer metastasis, however the mechanisms underlying how obesity promotes metastasis are unclear. In a diet-induced obesity mouse model, obesity enhanced lung metastases 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 pre-metastatic niches formed by primary tumors. Lung stromal cells isolated from obese non-tumor-bearing mice showed increased proliferation, contractility, and expression of extracellular matrix, inflammatory markers, and TGF{beta}1. Conditioned media from lung stromal cells from obese mice promoted myeloid lineage cell migration in vitro in response to 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 for metastatic growth.

cancer biology↗