University of Wisconsin-Madison K4/532 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792.
Cancer Prev Res (Phila). 2014 Jan;7(1):105-13. doi: 10.1158/1940-6207.CAPR-13-0163. Epub 2013 Nov 6.
Colorectal cancer often arises from adenomatous colonic polyps. Polyps can grow and progress to cancer, but may also remain static in size, regress, or resolve. Predicting which polyps progress and which remain benign is difficult. We developed a novel long-lived murine model of colorectal cancer with tumors that can be followed by colonoscopy. Our aim was to assess whether these tumors have similar growth patterns and histologic fates to human colorectal polyps to identify features to aid in risk stratification of colonic tumors. Long-lived Apc(Min/+) mice were treated with dextran sodium sulfate to promote colonic tumorigenesis. Tumor growth patterns were characterized by serial colonoscopy with biopsies obtained for immunohistochemistry and gene expression profiling. Tumors grew, remained static, regressed, or resolved over time with different relative frequencies. Newly developed tumors demonstrated higher rates of growth and resolution than more established tumors that tended to remain static in size. Colonic tumors were hyperplastic lesions (3%), adenomas (73%), intramucosal carcinomas (20%), or adenocarcinomas (3%). Interestingly, the level of β-catenin was higher in adenomas that became intratumoral carcinomas than those that failed to progress. In addition, differentially expressed genes between adenomas and intramucosal carcinomas were identified. This novel murine model of intestinal tumorigenesis develops colonic tumors that can be monitored by serial colonoscopy, mirror growth patterns seen in human colorectal polyps, and progress to colorectal cancer. Further characterization of cellular and molecular features is needed to determine which features can be used to risk-stratify polyps for progression to colorectal cancer and potentially guide prevention strategies.
结直肠癌常起源于腺瘤性结肠息肉。息肉可以生长并进展为癌症，但也可能保持大小不变、消退或消失。预测哪些息肉会进展，哪些会保持良性是困难的。我们开发了一种新型的长寿命结直肠癌小鼠模型，其肿瘤可以通过结肠镜检查进行随访。我们的目的是评估这些肿瘤的生长模式和组织学结局是否与人类结直肠息肉相似，以确定有助于结直肠肿瘤风险分层的特征。长寿命 Apc(Min/+) 小鼠用葡聚糖硫酸钠处理以促进结肠肿瘤发生。通过定期结肠镜检查和活检进行肿瘤生长模式的特征描述，用于免疫组织化学和基因表达谱分析。肿瘤随时间推移而增长、保持稳定、消退或消失，其相对频率不同。新发展的肿瘤比更成熟的肿瘤表现出更高的生长和消退率，后者往往保持大小不变。结肠肿瘤是增生性病变（3%）、腺瘤（73%）、黏膜内癌（20%）或腺癌（3%）。有趣的是，在进展为癌内癌的腺瘤中β-连环蛋白的水平高于那些未能进展的腺瘤。此外，还鉴定了腺瘤和黏膜内癌之间差异表达的基因。这种新型的肠道肿瘤发生小鼠模型可通过定期结肠镜检查监测结肠肿瘤，反映人类结直肠息肉中的生长模式，并进展为结直肠癌。需要进一步研究细胞和分子特征，以确定哪些特征可用于对进展为结直肠癌的息肉进行风险分层，并可能指导预防策略。
