Tanaka Takuji, Kohno Hiroyuki, Suzuki Rikako, Hata Kazuya, Sugie Shigeyuki, Niho Naoko, Sakano Katsuhisa, Takahashi Mami, Wakabayashi Keiji
Department of Oncologic Pathology, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
Int J Cancer. 2006 Jan 1;118(1):25-34. doi: 10.1002/ijc.21282.
The mouse model for familial adenomatous polyposis, Apc(Min/+) mouse, contains a truncating mutation in the Apc gene and spontaneously develops numerous adenomas in the small intestine but few in the large bowel. Our study investigated whether dextran sodium sulfate (DSS) treatment promotes the development of colonic neoplasms in Apc(Min/+) mice. Apc(Min/+) and Apc+/+ mice of both sexes were exposed to 2% dextran sodium sulfate in drinking water for 7 days, followed by no further treatment for 4 weeks. Immunohistochemistry for cyclooxygenase-2, inducible nitric oxide synthase, beta-catenin, p53, and nitrotyrosine, and mutations of beta-catenin and K-ras and loss of wild-type allele of the Apc gene in the colonic lesions were examined. Sequential observation of female Apc(Min/+) mice that received DSS was also performed up to week 5. At week 5, numerous colonic neoplasms developed in male and female Apc(Min/+) mice but did not develop in Apc+/+ mice. Adenocarcinomas developed in Apc(Min/+) mice that received DSS showed loss of heterozygosity of Apc and no mutations in the beta-catenin and K-ras genes. The treatment also significantly increased the number of small intestinal polyps. Sequential observation revealed increase in the incidences of colonic neoplasms and dysplastic crypts in female Apc(Min/+) mice given DSS. DSS treatment increased inflammation scores, associated with high intensity staining of beta-catenin, cyclooxygenase-2, inducible nitric oxide synthase and nitrotyrosine. Interestingly, strong nuclear staining of p53 was specifically observed in colonic lesions of Apc(Min/+) mice treated with DSS. Our results suggest a strong promotion effect of DSS in the intestinal carcinogenesis of Apc(Min/+) mice. The findings also suggest that strong oxidative/nitrosative stress caused by DSS-induced inflammation may contribute to the colonic neoplasms development.
家族性腺瘤性息肉病的小鼠模型，即Apc(Min/+)小鼠，其Apc基因存在截短突变，会在小肠中自发形成大量腺瘤，而在大肠中形成的腺瘤较少。我们的研究调查了硫酸葡聚糖钠（DSS）处理是否会促进Apc(Min/+)小鼠结肠肿瘤的发生。将雌雄Apc(Min/+)和Apc+/+小鼠暴露于饮用水中2%的硫酸葡聚糖钠7天，随后4周不再进行进一步处理。检测了结肠病变中环氧合酶-2、诱导型一氧化氮合酶、β-连环蛋白、p53和硝基酪氨酸的免疫组化，以及β-连环蛋白和K-ras的突变和Apc基因野生型等位基因的缺失。还对接受DSS处理的雌性Apc(Min/+)小鼠进行了长达第5周的连续观察。在第5周时，雌雄Apc(Min/+)小鼠均出现了大量结肠肿瘤，而Apc+/+小鼠未出现。接受DSS处理的Apc(Min/+)小鼠发生的腺癌显示Apc杂合性缺失，β-连环蛋白和K-ras基因无突变。该处理还显著增加了小肠息肉的数量。连续观察发现，给予DSS的雌性Apc(Min/+)小鼠结肠肿瘤和发育异常隐窝的发生率增加。DSS处理增加了炎症评分，与β-连环蛋白、环氧合酶-2、诱导型一氧化氮合酶和硝基酪氨酸的高强度染色相关。有趣的是，在用DSS处理的Apc(Min/+)小鼠的结肠病变中特异性观察到p53的强核染色。我们的结果表明DSS对Apc(Min/+)小鼠肠道致癌作用有很强的促进作用。这些发现还表明，DSS诱导的炎症引起的强烈氧化/亚硝化应激可能有助于结肠肿瘤的发生。
