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Obesity is associated with adipose inflammation, defined by macrophages encircling dead adipocytes, as well as extracellular matrix (ECM) remodeling and increased risk of breast cancer. Whether ECM affects macrophage phenotype in obesity is uncertain. A better understanding of this relationship could be strategically important to reduce cancer risk or improve outcomes in the obese. Using clinical samples, computational approaches, and in vitro decellularized ECM models, this study quantified the relative abundance of pro-inflammatory (M1) and anti-inflammatory (M2) macrophages in human breast adipose tissue, determined molecular similarities between obesity and tumor-associated macrophages, and assessed the regulatory effect of obese versus lean ECM on macrophage phenotype. Our results suggest that breast adipose tissue contains more M2- than M1-biased macrophages across all body mass index categories. Obesity further increased M2-biased macrophages but did not affect M1-biased macrophage density. Gene Set Enrichment Analysis suggested that breast tissue macrophages from obese versus lean women are more similar to tumor-associated macrophages. These changes positively correlated with adipose tissue interstitial fibrosis, and in vitro experiments indicated that obese ECM directly stimulates M2-biased macrophage functions. However, mammographic density cannot be used as a clinical indicator of these changes. Collectively, these data suggest that obesity-associated interstitial fibrosis promotes a macrophage phenotype similar to tumor-associated macrophages, which may contribute to the link between obesity and breast cancer., (Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Obesity has been associated with increased severity of diagnoses for several types of cancer, and recent evidence suggests that the mechanism by which obese tissues contribute to cancer progression involves the extracellular matrix (ECM). Understanding the physicochemical differences between lean and obese ECM, and how cancer cells respond to these differences, promises therapeutic insight., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Obesity and extracellular matrix (ECM) density are considered independent risk and prognostic factors for breast cancer. Whether they are functionally linked is uncertain. We investigated the hypothesis that obesity enhances local myofibroblast content in mammary adipose tissue and that these stromal changes increase malignant potential by enhancing interstitial ECM stiffness. Indeed, mammary fat of both diet- and genetically induced mouse models of obesity were enriched for myofibroblasts and stiffness-promoting ECM components. These differences were related to varied adipose stromal cell (ASC) characteristics because ASCs isolated from obese mice contained more myofibroblasts and deposited denser and stiffer ECMs relative to ASCs from lean control mice. Accordingly, decellularized matrices from obese ASCs stimulated mechanosignaling and thereby the malignant potential of breast cancer cells. Finally, the clinical relevance and translational potential of our findings were supported by analysis of patient specimens and the observation that caloric restriction in a mouse model reduces myofibroblast content in mammary fat. Collectively, these findings suggest that obesity-induced interstitial fibrosis promotes breast tumorigenesis by altering mammary ECM mechanics with important potential implications for anticancer therapies., (Copyright © 2015, American Association for the Advancement of Science.)

Obesity increases the risk and worsens the prognosis for breast cancer due, in part, to altered adipose stromal cell (ASC) behavior. Whether ASCs from obese individuals increase migration of breast cancer cells relative to their lean counterparts, however, remains unclear. To test this connection, multicellular spheroids composed of MCF10A‐derived tumor cell lines of varying malignant potential and lean or obese ASCs are embedded into collagen scaffolds mimicking the elastic moduli of interstitial breast adipose tissue. Confocal image analysis suggests that tumor cells alone migrate insignificantly under these conditions. However, direct cell‐cell contact with either lean or obese ASCs enables them to migrate collectively, whereby obese ASCs activate tumor cell migration more effectively than their lean counterparts. Time‐resolved optical coherence tomography imaging suggests that obese ASCs facilitate tumor cell migration by mediating contraction of local collagen fibers. Matrix metalloproteinase (MMP)‐dependent proteolytic activity significantly contributes to ASC‐mediated tumor cell invasion and collagen deformation. However, ASC contractility is also important, as co‐inhibition of both MMPs and contractility is necessary to completely abrogate ASC‐mediated tumor cell migration. These findings imply that obesity‐mediated changes of ASC phenotype may impact tumor cell migration and invasion with potential implications for breast cancer malignancy in obese patients. [ABSTRACT FROM AUTHOR]

Extracellular Matrix Remodelling: Obesity-Associated Adipose Stromal Cells Promote Breast Cancer Invasion through Direct Cell Contact and ECM Remodeling (Adv. Funct. Keywords: collagen; extracellular matrix remodeling; obesity; optical coherence tomography; tumor invasion EN collagen extracellular matrix remodeling obesity optical coherence tomography tumor invasion 1 1 1 11/27/20 20201125 NES 201125 In article number 1910650, Claudia Fischbach and co-workers combine collagen-embedded multicellular spheroids and advanced imaging to investigate the effect of adipose stromal cells (ASCs) on tumor cell invasion as a function of obesity. Obese ASCs increase collective tumor cell migration relative to lean ASCs by stimulating proteolytic and contractility-dependent collagen remode ling, providing insights into how obesity promotes breast cancer malignancy. [Extracted from the article]