Obesity and colorectal cancer: Role of adipokines in tumor initiation and progression

Table 1 Role of adipokines in colorectal cancer at the various levels of evidence

Adipokine	In vitro evidence	In vivo animal studies	Translational studies	Proposed mechanism(s)
Adiponectin
Inverse association	Suppression of colon cancer cells by its receptor-mediated AMPK activity[82]	Exogenous adiponectin in ApcMin/+ mice is capable of reducing the growth of intestinal polyps[93]Adiponectin knockout mice are more prone to chronic inflammation-induced colon cancer compared to C57BL/6 wild type mice[94,95]	Inhibition of cell proliferation, adhesion, invasion and colony formation	Reduction of TNF-α levels; regulation of metabolic (AMPK/S6), inflammatory (STAT3/VEGF) and cell cycle (p21/p27/p53/cyclins) signaling pathways[79]
Leptin
Direct association	Stimulation of the invasive capacity of early neoplastic cells by enhancing cell motility through increased formation of lamellipodial structures[83]	Obese C57BL/6J-Lep (ob) male mice do not display increased tumorigenesis as compared to their lean littermates[97]C57BL/KsJ-db/db obese and diabetic mice have a significant increase in the multiplicity of premalignant lesions[98]	Involvement in CRC carcinogenesis only after the tumor initiation stage[99] Direct correlation with cancer progression[111,112]	Regulation of proliferation and apoptosis through PI3K/AKT/ mTOR signaling pathwayEnhanced expression of VEGF and VEGF-R2, via PI3K, JAK2/STAT3, and ERK1/2 signaling pathways[63]
Resistin
Direct association	Overexpression in a human colon cancer cell line, LS174T and in the colonic epithelium of many human colon cancer tissues[88]	None reported	Association with the chronic inflammation that leads to cancer pathogenesis[105] Gradual increase with progression in tumor stage[125]	Interference with adipogenesis
Ghrelin
Conflicting	Induction of apoptosis in human CRC cells[89] Overexpression and enhanced production in malignant intestinal epithelial cells[127]	None reported	Stage-dependent correlation of locally produced autocrine tissue ghrelin with colorectal cancer[127]Gradual decrease with progression in tumor stage[128,129]	Inhibition of the ubiquitin-proteasome system and autophagy activation[90]

AMPK: AMP-activated protein kinase; IL-6: Interleukin-6; IGF-1: Insulin-like growth factor-1; IGFBPs: Insulin-like growth factor binding protein; TNF-α: Tumor necrosis factor-α; VEGF: Vascular endothelial growth factor; STAT3: Signal transducer and activator of transcription 3; PI3K: Phosphoinositide kinase-3; AKT: Serine-threonine-protein kinase; mTOR: Mammalian target of rapamycin; ERK: Extracellular-signal-regulated kinase; CRC: Colorectal cancer.