Obesity-Associated Extracellular Matrix Remodeling Promotes a Macrophage Phenotype Similar to Tumor-Associated Macrophages

Springer, Nora L.; Iyengar, Neil M.; Bareja, Rohan; Verma, Akanksha; Jochelson, Maxine S.; Giri, Dilip; Zhou, Xi Kathy; Elemento, Olivier; Dannenberg, Andrew J.; Fischbach, Claudia

doi:10.1016/j.ajpath.2019.06.005

Cited by 70 publications

(55 citation statements)

References 111 publications

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“…Importantly, we found that the expression of CD206 is characteristic of the M1D and M2A populations (Fig EV2E and G). Recently, macrophages present in the breast of obese women were shown to express the same marker and to resemble more M2 than M1 subtype, bearing also similarities to tumour‐associated macrophages (Springer et al , ). Macrophages in the breast have also been reported to reprogramme during obesity, become metabolically activated and different from M1 macrophages due to their pro‐tumourigenic activity (Tiwari et al , ).…”

Section: Discussionmentioning

confidence: 99%

Macrophages induce malignant traits in mammary epithelium via IKKε/TBK1 kinases and the serine biosynthesis pathway

et al. 2020

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During obesity, macrophages infiltrate the breast tissue leading to low-grade chronic inflammation, a factor considered responsible for the higher risk of breast cancer associated with obesity. Here, we formally demonstrate that breast epithelial cells acquire malignant properties when exposed to medium conditioned by macrophages derived from human healthy donors. These effects were mediated by the breast cancer oncogene IKKe and its downstream target-the serine biosynthesis pathway as demonstrated by genetic or pharmacological tools. Furthermore, amlexanox, an FDA-approved drug targeting IKKe and its homologue TBK1, delayed in vivo tumour formation in a combined genetic mouse model of breast cancer and high-fat diet-induced obesity/inflammation. Finally, in human breast cancer tissues, we validated the link between inflammation-IKKe and alteration of cellular metabolism. Altogether, we identified a pathway connecting obesity-driven inflammation to breast cancer and a potential therapeutic strategy to reduce the risk of breast cancer associated with obesity.

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Section: Discussionmentioning

confidence: 99%

Macrophages induce malignant traits in mammary epithelium via IKKε/TBK1 kinases and the serine biosynthesis pathway

et al. 2020

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“…In addition, very interesting studies are emerging that reveal important relationships between obesity, inflammation, and matrix remodeling, especially in the context of breast cancer. 53 However, some of the interactions may lead to matrix degradation [54][55][56][57][58] and others to enhanced cross-links. 6 In fact, a recent study showed that levels of collagen fiber alignment, macrophages, and inflammatory markers are predictors of overall survival for breast cancer patients.…”

Section: Conclusion and Discussionmentioning

confidence: 99%

Factors associated with obesity alter matrix remodeling in breast cancer tissues

et al. 2020

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Obesity is associated with a higher risk of developing breast cancer and with worse disease outcomes for women of all ages. The composition, density, and organization of the breast tissue stroma are also known to play an important role in the development and progression of the disease. However, the connections between obesity and stromal remodeling are not well understood. We sought to characterize detailed organization features of the collagen matrix within healthy and cancerous breast tissues acquired from mice exposed to either a normal or high fat (obesity inducing) diet. We performed second-harmonic generation and spectral two-photon excited fluorescence imaging, and we extracted the level of collagen-associated fluorescence (CAF) along with metrics of collagen content, three-dimensional, and two-dimensional organization. There were significant differences in the CAF intensity and overall collagen organization between normal and tumor tissues; however, obesity-enhanced changes in these metrics, especially when three-dimensional organization metrics were considered. Thus, our studies indicate that obesity impacts significantly collagen organization and structure and the related pathways of communication may be important future therapeutic targets. © The Authors. Published by SPIE under a Creative Commons Attribution 4.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.

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“…TAMs cluster within areas exhibiting a high level of angiogenic activity and are therefore suspected to promote vascularization (18,19). Characterization of breast tissue macrophages showed that macrophages from obese women were similar to TAMs (20). A recent study found that fatty breast tissue combined with a high level of TAMs increased the risk of breast cancer recurrence and mortality (21).…”

Section: Introductionmentioning

confidence: 99%

Breast Adipocyte Co-culture Increases the Expression of Pro-angiogenic Factors in Macrophages

et al. 2020

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Obese individuals with breast cancer have a poorer prognosis and higher risk of metastatic disease vs. non-obese patients. Adipose tissue in obese individuals is characterized by an enhanced macrophage infiltration, creating a microenvironment that favors tumor progression. Here, we demonstrate a role for adipocyte-macrophage interactions in the regulation of angiogenesis. Co-culture of THP-1 macrophages with human breast adipocytes led to increased expression of the pro-angiogenic growth factor, vascular endothelial growth factor A (VEGFA). Several adipocyte-derived proteins including leptin, insulin, IL-6, and TNF-α were each capable of increasing VEGFA expression in THP-1 macrophages, identifying these as possible mediators of the changes that were observed with co-culture. Furthermore, analysis of THP-1 culture media by antibody array revealed that THP-1 secrete several other pro-angiogenic signals in response to adipocyte co-culture, including interleukin 8 (IL-8), matrix metalloproteinase 9 (MMP9), pentraxin 3 (PTX3), and serpin E1 (plasminogen activator inhibitor 1, PAI1) after co-culture with human adipocytes. We used an in vitro endothelial tube formation assay with human vascular endothelial cells to evaluate the effects of THP-1 culture media on angiogenesis. Here, culture media from THP-1 cells previously exposed to human adipocytes stimulated endothelial tube formation more significantly than THP-1 cells cultured alone. In summary, we find that adipocyte co-culture stimulates the expression of pro-angiogenic mediators in macrophages and has pro-angiogenic effects in vitro, thus representing a possible mechanism for the enhanced risk of breast cancer progression in obese individuals.

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Obesity-Associated Extracellular Matrix Remodeling Promotes a Macrophage Phenotype Similar to Tumor-Associated Macrophages

Cited by 70 publications

References 111 publications

Macrophages induce malignant traits in mammary epithelium via IKKε/TBK1 kinases and the serine biosynthesis pathway

Macrophages induce malignant traits in mammary epithelium via IKKε/TBK1 kinases and the serine biosynthesis pathway

Factors associated with obesity alter matrix remodeling in breast cancer tissues

Breast Adipocyte Co-culture Increases the Expression of Pro-angiogenic Factors in Macrophages

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