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

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.

The obesity-breast cancer link: a multidisciplinary perspective

“…Several leptin-mediated mechanisms behind this link have been established, including breast cancer invasion, migration, and immune regulation [46,47], as well as cancer stem cell enrichment and mesenchymal stem cell dysregulation in the tumor microenvironment [31,48]. Preclinical models of obesity demonstrate that increased myeloid-derived suppressor cell (MDSC) recruitment, collagen deposition, and changes in fibroblast phenotype in the lungs cooperate to create a favorable premetastatic niche for breast cancer [49].…”

The Reality of Lung Cancer Paradox: The Impact of Body Mass Index on Long-Term Survival of Resected Lung Cancer. A French Nationwide Analysis from the Epithor Database

“…Women had a higher risk of cancer incidence at endometrial, uterine, kidney, and breast sites, but only endometrial cancer mortality was significantly associated with being overweight and centrally obese [ 3 ]. Biological mechanisms behind the major role of obesity in chronic inflammation and carcinogenesis have been extensively assessed [ 4 , 5 , 6 , 7 ]. On the other hand, a population-based cohort study on BMI and the risk of 22 specific cancers in 5.24 million UK adults, showed that BMI was associated with 17 of 22 cancers, but the effect varied substantially by cancer type; each 5 kg/m² increase in BMI was linearly associated with cancers of the uterus, gallbladder, kidney, cervix, thyroid, and leukemia [ 8 ].…”

Obesity Does Not Increase Perioperative Outcomes in Older Patients Undergoing Thoracoscopic Anatomic Lung Cancer Surgery

“…Among these types, an inverse relationship between obesity and lung cancer risk has been reported in previous studies (6)(7)(8)(9). And the biological mechanisms underlying the major role of obesity in chronic inflammation and carcinogenesis have also been extensively evaluated (4,(10)(11)(12).…”