title: High-fat Western diet-induced obesity contributes to increased tumor growth in mouse models of human colon cancer.
abstract: Strong epidemiologic evidence links colon cancer to obesity. The increasing worldwide incidence of colon cancer has been linked to the spread of the Western lifestyle, and in particular consumption of a high-fat Western diet. In this study, our objectives were to establish mouse models to examine the effects of high-fat Western diet-induced obesity on the growth of human colon cancer tumor xenografts, and to examine potential mechanisms driving obesity-linked human colon cancer tumor growth. We hypothesize that mice rendered insulin resistant due to consumption of a high-fat Western diet will show increased and accelerated tumor growth. Homozygous Rag1tm1Mommice were fed either a low-fat Western diet or a high-fat Western diet (HFWD), then human colon cancer xenografts were implanted subcutaneously or orthotopically. Tumors were analyzed to detect changes in receptor tyrosine kinase-mediated signaling and expression of inflammatory-associated genes in epididymal white adipose tissue. In both models, mice fed an HFWD weighed more and had increased intra-abdominal fat, and tumor weight was greater compared with in the low-fat Western diet-fed mice. They also displayed significantly higher levels of leptin; however, there was a negative correlation between leptin levels and tumor size. In the orthotopic model, tumors and adipose tissue from the HFWD group displayed significant increases in both c-Jun N-terminal kinase activation and monocyte chemoattractant protein 1 expression, respectively. In conclusion, this study suggests that human colon cancer growth is accelerated in animals that are obese and insulin resistant due to the consumption of an HFWD.
authors.affiliation: Department of Nutrition, Auburn University, Auburn, AL 36849, USA; Auburn University Research Initiative in Cancer (AURIC), Auburn University, Auburn, AL 36849, USA.
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: O'Neill
authors.affiliation: Bassett Research Institute, Bassett Medical Center, Cooperstown, NY 13326-1301, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Burrington
authors.affiliation: Department of Surgery, Bassett Medical Center, Cooperstown, NY 13326-1301, USA.
authors.forename: Erin A
authors.initials: EA
authors.lastname: Gillaspie
authors.affiliation: Bassett Research Institute, Bassett Medical Center, Cooperstown, NY 13326-1301, USA.
authors.forename: Darin T
authors.initials: DT
authors.lastname: Lynch
authors.affiliation: Bassett Research Institute, Bassett Medical Center, Cooperstown, NY 13326-1301, USA.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Horsman
authors.affiliation: Department of Nutrition, Auburn University, Auburn, AL 36849, USA; Auburn University Research Initiative in Cancer (AURIC), Auburn University, Auburn, AL 36849, USA. Electronic address: mwgreene@auburn.edu.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Greene
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D003110:Colonic Neoplasms / Q000209:etiology / Q000473:pathology; D059305:Diet, High-Fat / Q000009:adverse effects*; D066273:Diet, Western / Q000009:adverse effects*; D004041:Dietary Fats / Q000009:adverse effects*; D004195:Disease Models, Animal; D004822:Epididymis / Q000378:metabolism; D064593:Heterografts / Q000254:growth & development; D006801:Humans; D007249:Inflammation / Q000235:genetics; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020738:Leptin / Q000097:blood; D008297:Male; D008815:Mice, Inbred Strains; D009765:Obesity / Q000097:blood / Q000150:complications* / Q000378:metabolism; D010766:Phosphorylation; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D018932:Chemokine CCL2; D004041:Dietary Fats; D007328:Insulin; D020738:Leptin; D020794:Receptor Protein-Tyrosine Kinases; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Colon cancer; Diet, Western; Insulin resistance; Mice; Models, animal; Obesity