Ay allele promotes azoxymethane-induced colorectal carcinogenesis by macrophage migration in hyperlipidemic/diabetic KK mice
Ay allele promotes azoxymethane-induced colorectal carcinogenesis by macrophage migration in hyperlipidemic/diabetic KK mice
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DOI：
10.1111/cas.12162
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发表时间：
2013-07-01
期刊：
影响因子：
5.7
通讯作者：
Takahashi, Mami
中科院分区：
文献类型：
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作者：
Ito, Kumiko;Ishigamori, Rikako;Takahashi, Mami
结直肠癌的发病率一直在上升，并与肥胖和糖尿病有关。我们发现，2型糖尿病模型KK-A(Y)/TaJCL(KK-A(Y))小鼠在接受偶氮甲烷(AOM)治疗后的短时间内发生肿瘤。然而，促进癌症发生的因素还没有被阐明。因此，我们观察了KK-A(Y)的遗传背景，包括KK/TaJCL(KK)小鼠和C57BL/6J-Ham-A(Y)/+(A(Y))小鼠的两个遗传特征，并与其他非肥胖和非糖尿病小鼠品系C57BL/6J和ICR进行了比较，并用AOM(分别为150mU/只/鼠/周和200mU/只鼠/周6周)诱发结直肠癌前病变、异常隐窝病灶和肿瘤。具有糖尿病特征的KK-A(Y)和KK小鼠在17周龄时分别发生了显著更多的ACF，每只小鼠分别为67和61，而ICR、A(Y)和C57BL/6J小鼠分别发生了42、24和18只ACF。与其他非糖尿病小鼠品系相比，KK-A(Y)和KK小鼠的血清胰岛素和甘油三酯水平相当高。有趣的是，KK-A(Y)小鼠在25周龄时发生结直肠癌(2.7+/-2.3个肿瘤/只)比KK-A(1.2+/-1.1个肿瘤/只)多，尽管有相似的糖尿病情况。在KK-A(Y)和KK小鼠身上发生的结肠癌表现出类似的β-连环蛋白信号的激活。然而，与巨噬细胞激活相关的炎性因子在KK-A(Y)小鼠结直肠癌中的表达水平显著高于KK。这些数据表明，肥胖和糖尿病患者中观察到的胰岛素抵抗和血脂异常等因素可能与结直肠癌的易感性有关。此外，肿瘤相关巨噬细胞的增多可能在结直肠癌的推进阶段起重要作用。
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 mu g/mouse/week for 4 weeks and 200 mu g/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 +/- 2.3 tumor/mouse) than KK mice (1.2 +/- 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 beta-catenin 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.