Hypoxia of the adipose tissue is a
Hypoxia of the adipose tissue is a key step in the inflammatory response linked to obesity and contributes to accelerated tumor progression in the obese population (Rosenow et al., 2013). Intermittent hypoxia exposure induces a 2.2-fold increase in the infiltration of tumor-associated macrophages and phenotypic alterations of adipose tissue macrophages in mice (Almendros et al., 2015). These hypoxia-induced changes contribute to increased tumor proliferation and invasion (Almendros et al., 2015). In the obese state, fat accumulation is associated with compromised adipose tissue vascularization and restricting oxygen availability, leading to hypoxic areas in the adipose tissue. In mice, the hypoxia of adipose tissue can be detected and measured by a reduction in the interstitial partial oxygen pressure (up to 70% reduction) and an elevation in expression of the hypoxia response genes (Ye et al, 2007, Rausch et al, 2008). Macrophages recruited in adipose tissue in obesity are localized in the hypoxic areas of the tissue, further suggesting a direct association between hypoxia and inflammation (Rausch et al., 2008). Hypoxia-inducible factor 1α (HIF-1α), described as the master regulator of oxygen homeostasis, is a subunit of an important transcription factor whose activity is induced by hypoxia and used as an indicator of hypoxic conditions in tissues (Wang et al., 2007). HIF-1α is continually synthesized and rapidly degraded in the presence of oxygen but is stabilized when oxygen levels are low (Liu and Semenza, 2007). HIF-1α is involved in the regulation of gene transcription leading to increased vascularization, such as vascular endothelial growth factor (VEGF) and VEGF receptor 1 (Forsythe et al., 1996). An altered balance between angiogenic factors and inhibitors is typically observed in obese patients, with expansion of the tnf alpha inhibitors in regional adipose depots, possibly contributing to documented increased risk of metastatic disease in obese subjects with cancer (Silha et al., 2005). Increased adipocyte oxygen consumption has also been shown to drive adipose tissue hypoxia in the context of obesity, triggering the induction of HIF-1α (Lee et al., 2014). Furthermore, HIF-1α has been reported to control the transcription of more than 100 genes involved in other important cellular processes including apoptosis, extracellular matrix, glucose utilization and inflammation (Semenza, 2003). Specifically, HIF-1α has been shown to play a pivotal role in the induction of chronic inflammation by being responsible for the increased expression of MCP-1, resulting in a pro-inflammatory environment and macrophage infiltration into the adipose tissue (Kihira et al., 2014). Besides HIF-1α, multiple other transcription factors are sensitive to hypoxia and regulate the expression of hypoxia-sensitive genes; including nuclear factor-κB (NFκB), the key transcription factor in inflammatory response signaling and stimulation of tumor suppressor p53 (Cummins and Taylor, 2005, Kenneth and Rocha, 2008). Macrophage accumulation in adipose tissue is mediated by recruitment of peripheral blood monocytes as well as by in situ proliferation of resident macrophages (Zheng et al., 2016). Additionally, a shift is observed in the phenotype of macrophage subpopulations. In lean animals, a low number of resident macrophages intersperse among adipocytes. They are defined as M2 macrophages, having a non-inflammatory phenotype (Italiani and Boraschi, 2014). During obesity, accumulated macrophages exhibit a pro-inflammatory activated phenotype associated with the secretion of an inflammatory cocktail, including TNF-α, IL-1β, IL-8, IL-6 and PGE2 leading to the propagation of obesity-related inflammation (Subbaramaiah et al, 2012, Lumeng et al, 2007). This adipose inflammatory status is histologically detectable by the identification of characteristic crown-like structures, which are composed of dead or dying adipocytes surrounded by macrophages (Morris et al, 2011, Sun et al, 2012). Within the breast, these crown-like structures are present in nearly 75% of obese patients and are detectable by using immunohistochemical staining for CD68, a macrophage marker (Morris et al., 2011). Given the significant biological consequences of these inflammatory lesions, a crown-like structure index was developed to quantify the severity of adipose inflammation. This index is defined as the number of slides with histologic evidence of CLS-B compared to the number of slides examined, reported on a scale ranging from 0 to 1.0 (Iyengar et al., 2013). Measurement of the number of crown-like structures per cm2 has also yielded informative results. It should be noted that these inflammatory lesions can also be found in lean women (Gomez-Ambrosi et al, 2014, Denis and Palmer, 2017). Recently, breast adipose tissue was collected from 72 women with normal BMI undergoing mastectomy for breast cancer risk reduction or treatment. Severity of inflammation was defined by the presence of crown-like structures and was positively associated with elevated aromatase expression and activity, which increased with severity of inflammation. This study demonstrates the existence of a subclinical inflammatory state associated with elevated aromatase in the breast and systemic metabolic dysfunction occurring in some normal BMI women and which may contribute to the pathogenesis of breast cancer (Iyengar et al., 2017). Also, on the other hand, not all obese individuals develop inflammatory and metabolic perturbations. They are usually called “healthy obese” individuals and apparently do not have elevated risk of cancer (Bluher, 2010).