Inflammation-Associated Serum and Colon Markers as Indicators of Dietary Attenuation of Colon Carcinogenesis in ob/ob Mice

Abstract

Although inflammatory cytokines and obesity-associated serum proteins have been reported as biomarkers of colorectal adenoma risk in humans, little is known of biomarkers of response to interventions that attenuate tumorigenesis. Dietary navy beans and their fractions attenuate colon carcinogenesis in carcinogen-induced genetically obese mice. We hypothesized that this attenuation would be associated with changes in inflammatory cytokines and obesity-related serum proteins that may serve as measures of efficacy. ob/ob mice (n = 160) were injected with the carcinogen azoxymethane (AOM) to induce colon cancer and randomly placed on one of four diets (control, whole navy bean, bean residue fraction, or bean extract fraction) for 26 to 28 wk. Serum was analyzed for 14 inflammationor obesity-related proteins, and colon RNA was analyzed for expression of 84 inflammationassociated genes. Six of 14 serum proteins were increased [i.e., interleukin (IL)-4, IL-5, IL-6, IL-10, IFNγ, granulocyte macrophage colony-stimulating factor] in hyperplastic/dysplastic stages of colon carcinogenesis. Bean-fed mice had significantly higher monocyte chemoattractant protein-1 and lower IL-6 levels in serum. In colon mucosa, 55 of 84 inflammationassociated genes differed between AOM-induced and noninduced mice. Of the 55 AOM-induced genes, 5 were counteracted by bean diets, including IL-6 whose increase in expression levels was attenuated by bean diets in AOM-induced mice. In summary, IL-6 emerged as a serum protein that was increased in hyperplastic/dysplastic stages of colon carcinogenesis, but attenuated with bean-based diet in serum and colon mucosa. Changes in a subset of inflammation-associated serum proteins and colon gene expression may serve as response indicators of dietary attenuation of colon carcinogenesis.

Effects of diet-induced obesity on colitis-associated colon tumor formation in A/J mice

“…Recent studies have suggested that obesity facilitates colon tumor formation in adiponectin-gene-deficient mice, 34 APC-genedeficient mice 35 and leptin-gene-deficient mice. 36 However, animal models of specific gene-deficient mice may exhibit different molecular mechanisms for developing tumors from those observed in diet-induced obesity. For example, leptin-gene-deficient mice had significantly higher circulating concentrations of inflammatory cytokines, which Obesity accelerates colon carcinogenesis S-Y Park et al may be related to the colon carcinogenesis without involving leptin, 36 whereas our diet-induced obesity created hyperleptinemia.…”

“…36 However, animal models of specific gene-deficient mice may exhibit different molecular mechanisms for developing tumors from those observed in diet-induced obesity. For example, leptin-gene-deficient mice had significantly higher circulating concentrations of inflammatory cytokines, which Obesity accelerates colon carcinogenesis S-Y Park et al may be related to the colon carcinogenesis without involving leptin, 36 whereas our diet-induced obesity created hyperleptinemia. Therefore, we developed the obese colon cancer model using wild-type animals to study the relationship between diet-induced obesity and colon cancer.…”

Obesity and cancer—mechanisms underlying tumour progression and recurrence

“…57 The researchers attributed this observation to the fact that consumption of the bean diet resulted in considerably lower serum levels of IL-6. Treatment of leptin-receptor-deficient Lepr db/db mice with the ch olesterol-lowering drug pitavastatin resulted in decreased levels of circulating inflammatory cytokines, as well as reduced tumour initiation.…”

High-Fat Diet-Induced Complement Activation Mediates Intestinal Inflammation and Neoplasia, Independent of Obesity

“…Supporting a role for diet-induced obesity (DIO) in promoting inflammation and cancer, levels of IL-6 and tumor burden are both reduced following azoxymethane treatment of obese Lep ob / ob mice fed a bean-based diet versus a standard diet (5). Furthermore, medications used to treat hyperlipidemia and hypertension prevent colorectal carcinogenesis by attenuating chronic inflammation (6).…”