The effect of adipocyte–macrophage crosstalk in obesity-related breast cancer

Abstract

Adipose tissue is the primary source of many pro-inflammatory cytokines in obesity. Macrophage numbers and pro-inflammatory gene expression are positively associated with adipocyte size. Free fatty acid and tumor necrosis factor-α involve in a vicious cycle between adipocytes and macrophages aggravating inflammatory changes. Thereby, M1 macrophages form a characteristic ‘crown-like structure (CLS)’ around necrotic adipocytes in obese adipose tissue. In obese women, CLSs of breast adipose tissue are responsible for both increase in local aromatase activity and aggressive behavior of breast cancer cells. Interlinked molecular mechanisms between adipocyte–macrophage–breast cancer cells in obesity involve seven consecutive processes: Excessive release of adipocyte- and macrophage-derived inflammatory cytokines, TSC1–TSC2 complex–mTOR crosstalk, insulin resistance, endoplasmic reticulum (ER) stress and excessive oxidative stress generation, uncoupled respiration and hypoxia, SIRT1 controversy, the increased levels of aromatase activity and estrogen production. Considering elevated risks of estrogen receptor (E2R)-positive postmenopausal breast cancer growth in obesity, adipocyte–macrophage crosstalk is important in the aforementioned issues. Increased mTORC1 signaling in obesity ensures the strong activation of oncogenic signaling in E2Rα-positive breast cancer cells. Since insulin and insulin-like growth factors have been identified as tumor promoters, hyperinsulinemia is an independent risk factor for poor prognosis in breast cancer despite peripheral insulin resistance. The unpredictable effects of adipocyte-derived leptin–estrogen–macrophage axis, and sirtuin 1 (SIRT1)–adipose-resident macrophage axis in obese postmenopausal patients with breast cancer are unresolved mechanistic gaps in the molecular links between the tumor growth and adipocytokines.

The Role of Mitochondria in Inflammation: From Cancer to Neurodegenerative Disorders

“…Nevertheless, other molecules are undergoing optimization processes, and these are compounds that can hinder mitochondrial transmembrane potential, such as lipophilic cations [152]; the Krebs cycle, consequently affecting ECT and OXPHOS [166]; inhibitors against the conversion of pyruvate to AcCoA, hindering the Krebs cycle [167]; or inhibitors that interfere with DNA polymerase, which influences mtDNA transcription, with consequent effects on the mitochondrial protein pool [168,169].…”

Macrophages in Tumor-Associated Adipose Microenvironment Accelerate Tumor Progression

“…Likewise, macrophages envelope around phagocytosis of a dead or dying adipocyte, this con guration is termed as crown-like structures (CLS) [36]. Notably, the number and the density of CLS is positively correlated to high body mass index, large adipocyte size, postmenopausal status as well as insulin resistance in obese subjects, suggesting the pathophysiologic role CLS played in adipose tissue in ammation [25,37]. Hence, macrophages in ltration in adipose tissue around tumor seems to have vital clinical signi cance, especially in macrophage polarization, yet it needs further investigation.…”

“…The chemokines such as CCL2 and CCL5 have the pivotal functions in the recruit and polarization of macrophages in both tumor tissues and fatty tissues [7,9,37]. In the case of obesity, the hypertrophic expansion of adipose tissue has many features in common with the growth of solid tumors.…”

Adipocyte of Obese Breast Cancer Patients Is Characterized by The Overexpression of Caveolin-1 Protein/Mediator the Main Constituent of the Plasma Membrane Vesicles Caveolae That Contain Proteins Contribute to Breast Cancer Progression

“…Obesity is identified as over fat accumulation in the adipose tissues (AT) which constitute mainly of cells known as adipocytes (Engin, Engin, & Gonul, 2019). Any dysfunction in AT physiological role can promote excess weight (Chu et al, 2019), which in turn affects BC by releasing certain bioactive proteins collectively termed adipokines that contribute to proliferation and migration of cancer cells that influence the poor prognosis in patients with BC (Guerro-Millo, 2004).…”