Obesity and Breast Cancer: The Role of Crown-Like Structures in Breast Adipose Tissue in Tumor Progression, Prognosis, and Therapy

Faria, Sara Socorro; Corrêa, Luís Henrique; Heyn, Gabriella Simões; Sant’Ana, Lívia Pimentel de; Almeida, Rafael; Magalhães, Kelly Grace

doi:10.4048/jbc.2020.23.e35

Cited by 40 publications

(45 citation statements)

References 106 publications

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“…In obesity, there is an exacerbated presence of CLS in WAT ( 24 ). It has been described that CLS can promote the survival and proliferation of breast cancer in patients with obesity, influencing the tumor microenvironment ( 25 ).…”

Section: Adipose Tissue and Macrophagesmentioning

confidence: 99%

The Impact of Adipose Tissue–Derived miRNAs in Metabolic Syndrome, Obesity, and Cancer

2020

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Obesity is a multifactorial and complex condition that is characterized by abnormal and excessive white adipose tissue accumulation, which can lead to the development of metabolic diseases, such as type 2 diabetes mellitus, nonalcoholic fatty liver disease, cardiovascular diseases, and several types of cancer. Obesity is characterized by excessive adipose tissue accumulation and associated with alterations in immunity, displaying a chronic low-grade inflammation profile. Adipose tissue is a dynamic and complex endocrine organ composed not only by adipocytes, but several immunological cells, which can secrete hormones, cytokines and many other factors capable of regulating metabolic homeostasis and several critical biological pathways. Remarkably, adipose tissue is a major source of circulating microRNAs (miRNAs), recently described as a novel form of adipokines. Several adipose tissue–derived miRNAs are deeply associated with adipocytes differentiation and have been identified with an essential role in obesity-associated inflammation, insulin resistance, and tumor microenvironment. During obesity, adipose tissue can completely change the profile of the secreted miRNAs, influencing circulating miRNAs and impacting the development of different pathological conditions, such as obesity, metabolic syndrome, and cancer. In this review, we discuss how miRNAs can act as epigenetic regulators affecting adipogenesis, adipocyte differentiation, lipid metabolism, browning of the white adipose tissue, glucose homeostasis, and insulin resistance, impacting deeply obesity and metabolic diseases. Moreover, we characterize how miRNAs can often act as oncogenic and tumor suppressor molecules, significantly modulating cancer establishment and progression. Furthermore, we highlight in this manuscript how adipose tissue–derived miRNAs can function as important new therapeutic targets.

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Section: Adipose Tissue and Macrophagesmentioning

confidence: 99%

The Impact of Adipose Tissue–Derived miRNAs in Metabolic Syndrome, Obesity, and Cancer

2020

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“…Crown like structures (CLSs) are a histological feature of dead or dying adipocytes surrounded by macrophages and they are increased in obesity associated adipose tissue [ 37 ]. CLS are associated with free fatty acid (FFA) release, NF-κB activation and the generation of a proinflammatory microenvironment [ 106 ]. They are best characterized for their role in the initiation and progression of breast cancer [ 106 ] but they are also reported to play a role in endometrial cancer [ 107 ], prostate cancer [ 108 ] and non-alcoholic steatohepatitis (NASH)—a major risk factor for HCC [ 109 ].…”

Section: Mechanisms Linking Adipose Tissue To the Metastatic Cascamentioning

confidence: 99%

“…CLS are associated with free fatty acid (FFA) release, NF-κB activation and the generation of a proinflammatory microenvironment [ 106 ]. They are best characterized for their role in the initiation and progression of breast cancer [ 106 ] but they are also reported to play a role in endometrial cancer [ 107 ], prostate cancer [ 108 ] and non-alcoholic steatohepatitis (NASH)—a major risk factor for HCC [ 109 ]. In breast adipose tissue CLS are not only associated with inflammation but they also drive aromatase activity resulting in an increased ratio of estrogen:androgen in blood and local tissues [ 110 ].…”

Section: Mechanisms Linking Adipose Tissue To the Metastatic Cascamentioning

confidence: 99%

Obesity and Cancer Metastasis: Molecular and Translational Perspectives

Annett

Moore

Robson

2020

Cancers

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Obesity is a modern health problem that has reached pandemic proportions. It is an established risk factor for carcinogenesis, however, evidence for the contribution of adipose tissue to the metastatic behavior of tumors is also mounting. Over 90% of cancer mortality is attributed to metastasis and metastatic tumor cells must communicate with their microenvironment for survival. Many of the characteristics observed in obese adipose tissue strongly mirror the tumor microenvironment. Thus in the case of prostate, pancreatic and breast cancer and esophageal adenocarcinoma, which are all located in close anatomical proximity to an adipose tissue depot, the adjacent fat provides an ideal microenvironment to enhance tumor growth, progression and metastasis. Adipocytes provide adipokines, fatty acids and other soluble factors to tumor cells whilst immune cells infiltrate the tumor microenvironment. In addition, there are emerging studies on the role of the extracellular vesicles secreted from adipose tissue, and the extracellular matrix itself, as drivers of obesity-induced metastasis. In the present review, we discuss the major mechanisms responsible for the obesity–metastatic link. Furthermore, understanding these complex mechanisms will provide novel therapies to halt the tumor–adipose tissue crosstalk with the ultimate aim of inhibiting tumor progression and metastatic growth.

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“…The relationship between adipocytes in adipose tissue of obese BC patients and macrophages has been well documented in recent years (34,45). However, our study did not focus on adipose tissue due to obesity nor did we include obese patients only -it aimed to analyze the role of the adipose tissue right in the breast that is also present in lean BC patients.…”

Section: Discussionmentioning

confidence: 99%

“…A further feature found in adipose tissue, which is considered to be a hallmark of the proin ammatory process in adipose tissue, are the so-called crown-like structures (CLS, recently reviewed by Faria et.al (34)) CLS consist of hypertrophied, necrotic adipocytes (that need to be resorbed) surrounded by adipose tissue M1 macrophages (35)(36)(37)(38). CLS might promote BC and might contribute to the fact that obese women are more likely to be diagnosed with larger and higher-grade BC and have higher incidence of metastases than lean individuals (39).…”

Section: Introductionmentioning

confidence: 99%

Breast Adipose Tissue Macrophages (BATMs) have a Stronger Correlation with Breast Cancer Survival than Breast Tumor Stroma Macrophages (BTSMs)

Lin

Kühn

Ditsch

et al. 2020

Preprint

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Background: An abundance of tumor-associated macrophages has been shown to be an independent prognostic factor for a poor prognosis of human breast cancer (BC). Adipose tissue accounts for the largest proportion of the breast and has also been identified as an independent indicator of poor survival in BC. This study aims to elucidate, if the influence of adipose tissue in BC might be mediated by macrophages. The roles of macrophages in the breast tumor-stroma (breast tumor stroma macrophages, BTSM) and macrophages in the surrounding adipose tissue (breast adipose tissue macrophages, BATM) were explored separately.Methods: 298 BC tissue samples were analyzed immunohistochemically. The number of macrophages was detected by CD68+ staining. The quantity of BATMs and BTSMs was correlated to clinical and pathological parameters as well as to disease free survival (DFS) and overall survival (OS). Results: The amounts of BATMs and BTSMs strongly correlated with each other (r = 0.5, p < 0.001). The quantity of BTSMs, but not of BATMs, was significantly associated with the BC molecular subtype (p < 0.001) and all triple negative BC tumors contained high amounts of BTSMs. BATMs were negatively associated with DFS (p = 0.0332). Both BATMs (p < 0.001) and BTSMs (p = 0.021) were negatively associated with OS in the Kaplan-Meier analysis, but only BATMs remained an independent factor in the multivariate Cox-regression analysis (HR = 4.464, p = 0.004). Combining prostaglandin E2 receptor 3 (EP3)-expression and the quantity of BATMs, a subgroup with an extremely poor prognosis could be identified (median OS 2.31 years in the “high BATMs/low EP3” subgroup compared to 11.42 years in the most favorable “low BATMs/high EP3” subgroup, p < 0.001).Conclusion: Our findings suggest that BTSMs and BATMs seem to be involved differently in BC. Breast adipose tissue might contribute to the aggressiveness of BC via BATMs, which were independently associated with BC survival. BATMs’ role and occurrence might be functionally dependent on EP3, as a combination of both factors was strongly associated with survival. Targeting BATMs – eventually in combination with targeting the EP3-pathway – might be promising for future therapies.

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Obesity and Breast Cancer: The Role of Crown-Like Structures in Breast Adipose Tissue in Tumor Progression, Prognosis, and Therapy

Cited by 40 publications

References 106 publications

The Impact of Adipose Tissue–Derived miRNAs in Metabolic Syndrome, Obesity, and Cancer

The Impact of Adipose Tissue–Derived miRNAs in Metabolic Syndrome, Obesity, and Cancer

Obesity and Cancer Metastasis: Molecular and Translational Perspectives

Breast Adipose Tissue Macrophages (BATMs) have a Stronger Correlation with Breast Cancer Survival than Breast Tumor Stroma Macrophages (BTSMs)

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