Correlation of Leptin, Proinflammatory Cytokines and Oxidative Stress with Tumor Size and Disease Stage of Endometrioid (Type I) Endometrial Cancer and Review of the Underlying Mechanisms

Abstract

Endometrioid endometrial cancer is associated with increased BMI and obesity through multiple pathogenetic mechanisms involving hyperestrogenism, hyperinsulinemia, altered adipokine secretion, inflammation, and oxidative stress. In the present study, we aimed to investigate the correlation between BMI, leptin, the proinflammatory cytokines IL-6 and TNFα, reactive oxygen species (ROS), and the traditional prognostic factors T, G, N and M status among type I endometrioid and type II endometrial cancer patients. We enrolled 305 consecutive endometrial cancer patients prospectively. We found that BMI, leptin, and IL-6 significantly correlated with T status, N status, and M status among endometrioid type I endometrial cancer patients. Among type II endometrial cancer patients, BMI and leptin did not correlate with any of the prognostic parameters, whereas there was a positive correlation between IL-6 and the presence of distant metastases. In the multivariate regression analysis, BMI, leptin, and IL-6 were independent predictive variables of T, N, and M status in endometrioid type I endometrial cancer patients. Our study demonstrates that weight gain, adiposity-related adipokines, inflammation, and oxidative stress correlate with the prognostic factors of endometrioid endometrial cancer. Knowledge of the role of obesity-related biological pathways and mediators in the pathogenesis and prognosis of endometrioid endometrial malignancies may offer new perspectives on combined therapeutic strategies that have not been explored to date, both in the advanced disease and in the adjuvant setting.

Models including preoperative plasma levels of angiogenic factors, leptin and IL-8 as potential biomarkers of endometrial cancer

“…Leptin is among the most important adipokines during EC development, and numerous recent studies have already proposed it as a new candidate marker in determining the potential risk of EC ( 42 – 45 ). In accordance with the literature ( 46 – 50 ), our study showed higher leptin levels in EC patients, particularly in Type I EC, at higher stages and in patients with present metastasis or MI and LVI.…”

“…observed that BMI and diabetes appeared to affect the association between leptin levels and EC risk ( 43 ). Some other studies found a strong positive correlation between patients’ BMI and serum leptin levels ( 46 , 50 ), while a recent Mendelian randomization analysis showed a causal effect of BMI on EC but failed to find evidence for leptin to be causally implicated in EC risk ( 59 ).…”

The roles and clinical applications of interleukins in endometrial carcinoma

“…Elevated levels of IL-1α ( 22 ), IL-11 ( 57 ), IL-31 ( 27 ) and IL-33 ( 27 ) were observed in poor differentiated EC, while low level of IL-27 ( 20 ) and infiltration of IL-9 + lymphocyte ( 47 ) was recorded with the decrease of EC differentiation degree. Moreover, IL-6 ( 56 , 146 ), IL-8 ( 117 ), IL-31 ( 27 , 29 ) and IL-33 ( 27 , 29 ) were positively correlated with poor clinical characteristics including advanced stage, myoinvasion, and node or distant metastases. Therefore, in the future, these interleukins may be useful as the indicators for the management of EC, for example for the evaluation of whether lymph node dissection is necessary.…”

Role of adipocytokines in endometrial cancer progression

“…Adipokines, a diverse group of biologically active substances, are characterized by adipose tissue secretion ( Trayhurn and Wood 2004 ). The levels of various adipokines, such as leptin ( Madeddu et al, 2022 ), visfatin ( Wang et al, 2019 ), galectin ( Boutas et al, 2021 ), resistin ( Ozgor et al, 2019 ), adiponectin ( Ellis et al, 2020 ), and vaspin ( Erdogan et al, 2013 ), are increased or decreased in endometrial cancer and significantly correlated with cancer progression ( Ray et al, 2022 ).…”