Crossroad between Obesity and Cancer: A Defective Signaling Function of Heavily Lipid-Laden Adipocytes

Abstract

Obesity and its comorbidities exhibit a gender-related dimorphism. Obese males tend to accrue more visceral fat leading to abdominal adiposity, which shows a strong correlation with serious obesity-associated comorbidities, cardiovascular diseases and cancers. In contrast, obese females accumulate excessive fatty tissue predominantly subcutaneously enjoying strong protection from the obesity-related diseases. The health advantage of obese women as compared with obese men may be attributed to their higher estrogen production and an increased transactivation of estrogen receptors (ERs). The recently clarified intracrine, paracrine, and endocrine functions of adipose tissue illuminate that concentrations of estrogens and the suitable expression and activity of ERs strongly define all regulatory functions in both men and women. All well-known cancer risk factors are in correlation with defects of estrogen signaling in partnership with glucose intolerance as estrogen regulates all steps of glucose uptake. In central obesity, increased secretions of cytokines and growth factors are not causal factors of developing insulin resistance, and unrestrained cell proliferation, but rather, they are compensatory processes so as to increase estrogen synthesis and ER transactivation. In conclusion, a causal therapy against obesity and obesity-related diseases aims to improve estrogen signaling in both men and women.

DNA Damage Responses in Tumors Are Not Proliferative Stimuli, but Rather They Are DNA Repair Actions Requiring Supportive Medical Care

“…Proinflammatory cytokines and low-grade inflammation: Proinflammatory cytokines are regulatory proteins which have a great role in the maintenance of genomic and metabolic stability. In obese fatty tissue, low-grade inflammatory reactions and abundantly expressed cytokines are counteractions to genomic deregulation via increasing estrogen synthesis [114]. The insulin resistance of obese estrogen deficient adipose tissue leads to further regulatory disorders in the adjacent organs, resulting in serious co-morbidities, such as fatty degeneration and malignancies [115,116].…”

“…Pro-inflammatory cytokines stimulate aromatase activity, estrogen synthesis and ER expression in the estrogen responsive peritumoral cellular infiltration. When estrogen concentration reaches an appropriately high concentration, the accumulation of anti-inflammatory cytokines will quench the inflammatory reaction parallel with the decreasing estrogen level [114].…”

Rosetta Stone for Cancer Cure: Comparison of the Anticancer Capacity of Endogenous Estrogens, Synthetic Estrogens and Antiestrogens

“…Abdominally located fatty tissue is a hub of the signaling network providing energy and ER signal to the work of visceral organs. Fatty tissue in the pericardium regulates heart, while fat positioned along great vessels drives and controls the function of arteries and veins ( 54 ). Increasing estrogen level in adipocytes activates ERs driving the expression of numerous genes and the synthesis of signaling molecules such as sex steroid hormones, adipokines, growth factors and cytokines ( 49 ).…”

Compensatory Estrogen Signal Is Capable of DNA Repair in Antiestrogen-Responsive Cancer Cells via Activating Mutations

“…At cellular level, activated ERs are the hubs of signaling networks driving the whole genomic machinery through regulatory circuits [32]. At tissue level, the central adipose tissue is the hub of the signaling network controlling and regulating visceral organs and cardiovascular structures through its estrogen synthesis and estrogen receptor activation [45]. Molecular players of all cellular mechanisms are recruited into regulatory circuits receiving their activating signals from ERs and, in turn, sending their signaling reports back to ERs.…”

“…Visceral obesity is a high-risk for overall breast cancer in both young and postmenopausal women as it is strongly associated with a deficient estrogen signaling and defective glucose uptake [ 35 , 45 ]. Circumference measures of abdominal fat mass (waist, hip, and waist/hip ratio) were linearly associated with increased risks for ER-negative and triple-negative breast cancers (TNBCs) in both premenopausal and postmenopausal women [ 88 , 89 ].…”