A^y allele promotes azoxymethane‐induced colorectal carcinogenesis by macrophage migration in hyperlipidemic/diabetic KK mice

Abstract

The incidence of colorectal cancer has been increasing and is associated with obesity and diabetes. We have found that type 2 diabetes model KK-A y ⁄ TaJcl (KK-A y ) mice develop tumors within a short period after treatment with azoxymethane (AOM). However, factors that contribute to the promotion of carcinogenesis have not been clarified. Therefore, we looked at the genetic background of KK-A y , including two genetic characteristics of KK ⁄ TaJcl (KK) mice and C57BL ⁄ 6J-Ham-A y ⁄ + (A y ) mice, compared with other non-obese and non-diabetic mouse strains C57BL ⁄ 6J and ICR, and induced colorectal premalignant lesions, aberrant crypt foci (ACF), and tumors using AOM (150 lg ⁄ mouse ⁄ week for 4 weeks and 200 lg ⁄ mouse ⁄ week for 6 weeks, respectively). The mice with a diabetes feature, KK-A y and KK, developed significantly more ACF, 67 and 61 per mouse, respectively, whereas ICR, A y , and C57BL ⁄ 6J mice developed 42, 24, and 18 ACF ⁄ mouse, respectively, at 17 weeks of age. Serum insulin and triglyceride levels in KK-A y and KK mice were quite high compared with other non-diabetic mouse strains. Interestingly, KK-A y mice developed more colorectal tumors (2.7 AE 2.3 tumor ⁄ mouse) than KK mice (1.2 AE 1.1 tumor ⁄ mouse) at 25 weeks of age, in spite of similar diabetic conditions. The colon cancers that developed in both KK-A y and KK mice showed similar activation of bcatenin signaling. However, mRNA levels of inflammatory factors related to the activation of macrophages were significantly higher in colorectal cancer of KK-A y mice than in KK. These data indicate that factors such as insulin resistance and dyslipidemia observed in obese and diabetic patients could be involved in susceptibility to colorectal carcinogenesis. In addition, increase of tumor-associated macrophages may play important roles in the stages of promotion of colorectal cancer. (Cancer Sci 2013; 104: 835-843)

Fatty pancreas: A possible risk factor for pancreatic cancer in animals and humans

“…Interlobular fat is observed in C57BL/6J-A y and ICR mice 36 and high-fat diet-induced obese C57BL/6 mice, 37 but is rare in lean C57BL/6J mice. 36 Apc Min mice, a model of familial adenomatous polyposis, are insulin-resistant and develop hypertriglyceridemia with age. 38 Despite having high serum triglyceride levels, Apc Min mice are lean, and scattered intralobular FI is not observed in the mouse pancreas (data not shown).…”

“…On the other hand, C57BL/6J-A y mice, an obesity model, had fewer intralobular adipocytes in the pancreas ( Figure 1H) and ICR mice had only small adipocytes in the pancreas ( Figure 1I). 36 Scattered FI is rarely observed in the pancreas of C57BL/6J mice ( Figure 1J). Interlobular fat is observed in C57BL/6J-A y and ICR mice 36 and high-fat diet-induced obese C57BL/6 mice, 37 but is rare in lean C57BL/6J mice.…”

“…Pancreatic fatty infiltration ( FI ) in humans and animals. Hematoxylin and eosin‐stained sections of the pancreas with intralobular FI and/or interlobular fat of pancreatic ductal adenocarcinoma ( PDAC ) patients (A‐D), Syrian golden hamsters at 24 wk of age (E), KK ‐ A y (F), KK (G), C57 BL /6J‐ A y (H), ICR (I) and C57 BL /6J mice (J) at 17 wk of age, and OLETF (K) and LETO rats (L) at 65 wk of age that were obtained from our previous studies . Bar, 500 μm…”

“…Scattered FI is rarely observed in the pancreas of C57BL/6J mice (Figure J). Interlobular fat is observed in C57BL/6J‐ A y and ICR mice and high‐fat diet‐induced obese C57BL/6 mice, but is rare in lean C57BL/6J mice . Apc Min mice, a model of familial adenomatous polyposis, are insulin‐resistant and develop hypertriglyceridemia with age .…”

Rohitukine inhibits in vitro adipogenesis arresting mitotic clonal expansion and improves dyslipidemia in vivo

“…Many natural compounds like EGCG, genistein, and kaempferol, which show antiadipogenic potential, have also been found to be anticancer agents (21)(22)(23). Recently, there have been reports that establish an association between obesity and cancer (24)(25)(26). The phosphoinositide 3-kinase/protein kinase B/ mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is the key signaling pathway that links both obesity and cancer.…”