Table 1.

Mechanisms of carcinogenesis for obesity-associated cancers.

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.