Table 1.
Cancer site | Adiposity-associated pathogenic mechanisms | Proposed adiposity-associated molecular mechanisms for carcinogenesis |
---|---|---|
Esophageal adenocarcinoma [[124], [125], [126], [127]] |
Abdominal adiposity predisposes to gastroesophageal reflux disease, increasing the risk of Barrett's esophagus and esophageal adenocarcinoma. Additional contributors: chronic inflammation and hyperinsulinemia. | Increased expression of leptin receptors in patients with obesity and esophageal adenocarcinoma could stimulate proliferation and inhibit apoptosis in esophageal adenocarcinoma cells, promoting progression of the disease. |
Hyperinsulinemia in vivo leads to IGF-1 receptor upregulation and promotion of esophageal carcinogenesis through cell growth and proliferation. | ||
Gastric cardia [[128], [129], [130], [131], [132]] |
Chronic inflammation and hyperinsulinemia. | Malignant gastric cells have higher expression of IGF-1, which could promote cell proliferation. |
There is correlation between leptin levels and leptin tissue expression and clinicopathological variables in gastric cancer, suggesting its carcinogenic role. | ||
IL-mediated chronic inflammation could contribute to cell proliferation and invasion. | ||
Colorectal [[133], [134], [135], [136], [137]] |
Chronic inflammation and hyperinsulinemia. | Chronic inflammation related to visceral adiposity may participate tumorigenesis and immune escape, leading to cancer development and progression. |
Leptin and other adipokines potentially induce growth of neoplastic colorectal cells. | ||
Insulin and IGF-1 signaling favors mitogenic and proangiogenic signals in colorectal. | ||
Liver [[138], [139], [140], [141]] |
Chronic inflammation, hyperinsulinemia, and alterations in the gut microbiome. | Adiposity induced proinflammatory cytokines, such as TNFα and IL-6 might contribute to liver tumorigenesis. |
Obesity-associated alterations in gut microbiome metabolites might contribute to DNA damage and activation of a senescence-associated secretory phenotype in hepatic stellate cells, essential for liver tumorigenesis. | ||
Insulin and IGF-1 signaling in the liver might contribute to liver tumorigenesis. | ||
Gallbladder [142,143] |
Chronic inflammation from gallstones, which patients with obesity are at risk of. | Not widely studied. |
Pancreas [[144], [145], [146], [147], [148], [149]] |
Chronic inflammation and hyperinsulinemia. | Adipokines and other adiposity-associated inflammatory mediators activate oncogenic downstream pathways. |
Insulin and IGF-1 stimulate pancreatic duct acinar cell proliferation through mTOR signaling. | ||
Breast (post-menopausal), Endometrium and Ovary [16,[150], [151], [152], [153], [154], [155], [156], [157], [158], [159], [160]] |
Hyperestrogenism, chronic inflammation, oxidative stress, and hyperinsulinemia. | Excess adiposity and its associated inflammatory environment increase adipose-tissue aromatase expression and activity, leading to androgen conversion to estrogen. |
Estrogen and insulin/IGF-1 are major synergistic mitogens for epithelial cells, inducing cell cycle progression. | ||
Excess adiposity promotes oxidative stress, which denatures cell structures leading to genetic instability and tumorigenesis. | ||
Leptin stimulates breast, endometrial, and ovarian cancer cell growth and impairs apoptosis through activation of multiple signaling pathways. In addition, leptin increases the expression of aromatase, further contributing to hyperestrogenism. | ||
Clear Cell Renal cell carcinoma (ccRCC) [[161], [162], [163], [164]] |
Microenvironment alterations, metabolic reprogramming, and chronic inflammation. | Genes associated with an increased risk of ccRCC are associated with metabolic stress pathways. |
Lipidomic signatures of ccRCC contributes to cell proliferation. | ||
Expression of different adipokines has been suggested to modify the risk for ccRCC. | ||
Meningioma [[165], [166], [167], [168], [169]] |
Hyperestrogenism. | Excess adiposity and its associated inflammatory environment increase adipose-tissue aromatase expression and activity, leading to androgen conversion to estrogen. Most meningiomas express progesterone, estrogen, or androgen receptors, and estrogen is a potent enhancer of meningioma cell proliferation in vitro. |
Thyroid [[170], [171], [172], [173], [174], [175], [176], [177]] |
Chronic inflammation. Possibly hyperinsulinemia and hyperestrogenism, although their roles are less well defined. | Increased adipokines and oxidative stress promote malignancy. |
In vitro, insulin promotes thyroid cell proliferation and migration, and insulin resistance correlates with thyroid nodule vascularity. | ||
There is increased estrogen α-receptor expression in thyroid cancer cells, especially in post-menopausal women. Its role is unclear. | ||
Multiple myeloma [[178], [179], [180], [181], [182]] |
Chronic inflammation. Possibly hyperinsulinemia although its role is less well defined. | Increase in bone marrow adipose tissue leads to increased circulating adipokines. |
In vivo and in vitro studies show increased adipocyte-secreted cytokine angiotensin II promotes tumorigenesis. | ||
Insulin is a potent growth factor for multiple myeloma cells in vitro. |