Impact of obesity and white adipose tissue inflammation on the omental microenvironment in endometrial cancer

Abstract

Background A complex relationship between adipose tissue and malignancy, involving an inflammatory response, has been reported. The goal of this work was to assess the prevalence of white adipose tissue (WAT) inflammation in patients with endometrial cancer (EC), and the association with circulating inflammation markers. Furthermore, the aim was to characterize the pathways activated in and the cell type composition of adipose tissue in patients with EC. Methods Adipose tissue and blood samples were prospectively collected from 101 patients with EC at initial surgery. WAT inflammation was determined based on adipocytes surrounded by macrophages forming crown‐like structures. Circulating levels of metabolic syndrome–associated and inflammatory markers were quantified. RNA‐sequencing was performed on adipose samples (n = 55); differential gene expression, pathway, and cellular decomposition analyses were performed using state‐of‐the‐art bioinformatics methods. Results WAT inflammation was identified in 46 (45.5%) of 101 EC patients. Dyslipidemia, hypertension, and diabetes mellitus were significantly associated with WAT inflammation (p < .05). WAT inflammation was associated with greater body mass index (p < .001) and higher circulating levels of leptin, high‐sensitivity C‐reactive protein, and interleukin‐6, as well as lower levels of adiponectin and sex hormone–binding globulin (p < .05). Transcriptomic analysis demonstrated increased levels of proinflammatory and pro‐neoplastic–related gene expression in inflamed omental adipose tissue. Conclusions WAT inflammation is associated with metabolic syndrome, obesity, and inflammatory markers, as well as increased expression of proinflammatory and proneoplastic genes.

The tumor multi-omic landscape of endometrial cancers developed on a germline genetic background of adiposity

“…Antibodies targeting the IL6 receptor and small-molecular inhibitors of JAK1 and STAT3 have been shown to inhibit endometrial cancer growth both in vitro in cell lines and in vivo in mice (41). The published literature also provides clues potentially implicating the obesity-driven pro-inflammatory interferon response in endometrial cancer pathogenesis, and in keeping with this we found that the other top ranked pathways significantly upregulated with higher genetic BMI in our analyses included the inflammatory response and interferon-gamma and -alpha pathways (42, 43).…”

Lipid metabolism and tumor immunotherapy

“…Adipose tissue is categorized into two subtypes, white adipose tissue (WAT) and brown adipose tissue. WAT is the main form of fat storage in the body, while brown adipose tissue primarily plays a role in thermogenesis ( Moukarzel et al, 2022 ). Studies have shown that when WAT turns brown, cancer patients develop cachexia, and fat cells are reshaped.…”

“…Adipocytes produce adipocytokines and adipokines, which are essential for tumour angiogenesis. They stimulate tumour cells and mediate their proliferation and migration to promote tumour progression ( Rathmell, 2021 ; Moukarzel et al, 2022 ).…”

Role of adipocytokines in endometrial cancer progression

“…White adipose tissue (WAT), the most abundant adipose form, secretes numerous adipokines and cytokines to regulate whole-body metabolism. Moreover, WAT inflammation, which increases the expression of proinflammatory and proneoplastic genes, is associated with endometrial cancer ( Moukarzel et al, 2022 ). Additionally, it has become helpful to evaluate biomarkers in relation to cancer risk ( Linkov et al, 2018 ).…”

“…In China, the endometrial cancer incidence rate is approximately 7.74/100 000, and the mortality rate is approximately 1.60/100 000 ( Sun et al, 2022 ). The increasing mortality rates are mainly associated with the increasing incidence of obesity, a leading cause of endometrial cancer ( Ding et al, 2020 ; Larsson.et al, 2022 ; Moukarzel et al, 2022 ). In adjusted mixed linear models, weight loss is strongly related to the levels of cancer-associated biologically active substances, including reduced interleukin-6 (IL-6) levels and increased adiponectin levels ( Linkov et al, 2012 ).…”