McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
Cancer Prev Res (Phila). 2010 Dec;3(12):1534-41. doi: 10.1158/1940-6207.CAPR-10-0086. Epub 2010 Oct 6.
Human anal cancers are associated with high-risk human papillomaviruses (HPV) that cause other anogenital cancers and head and neck cancers. As with other cancers, HPV16 is the most common high-risk HPV in anal cancers. We describe the generation and characterization of a mouse model for human anal cancer. This model makes use of K14E6 and K14E7 transgenic mice in which the HPV16 E6 and E7 genes are directed in their expression to stratified squamous epithelia. HPV16 E6 and E7 possess oncogenic properties including, but not limited to, their capacity to inactivate the cellular tumor suppressors p53 and pRb, respectively. Both E6 and E7 were found to be functionally expressed in the anal epithelia of K14E6/K14E7 transgenic mice. To assess the susceptibility of these mice to anal cancer, mice were treated topically with dimethylbenz[a]anthracene (DMBA), a chemical carcinogen that is known to induce squamous cell carcinomas in other sites. Nearly 50% of DMBA-treated HPV16 E6/E7 transgenic mice showed overt signs of tumors, whereas none of the like-treated nontransgenic mice showed tumors. Histopathologic analyses confirmed that the HPV16 transgenic mice were increased in their susceptibility to anal cancers and precancerous lesions. Biomarker analyses demonstrated that these mouse anal cancers exhibit properties that are similar to those observed in HPV-positive precursors to human anal cancer. This is the first mouse model for investigating the contributions of viral and cellular factors in anal carcinogenesis, and should provide a platform for assessing new therapeutic modalities for treating and/or preventing this type of cancer.
人类肛门癌与高危型人乳头瘤病毒（HPV）有关，高危型 HPV 可引起其他肛门生殖器癌症和头颈部癌症。与其他癌症一样，HPV16 是肛门癌中最常见的高危 HPV。我们描述了一种用于人类肛门癌的小鼠模型的生成和特征。该模型利用 K14E6 和 K14E7 转基因小鼠，其中 HPV16 E6 和 E7 基因在其表达中被定向到分层鳞状上皮。HPV16 E6 和 E7 具有致癌特性，包括但不限于分别使细胞肿瘤抑制因子 p53 和 pRb 失活的能力。在 K14E6/K14E7 转基因小鼠的肛门上皮中发现 E6 和 E7 均具有功能性表达。为了评估这些小鼠对肛门癌的易感性，用二甲基苯并[a]蒽（DMBA）对小鼠进行局部处理，DMBA 是一种已知可在其他部位诱导鳞状细胞癌的化学致癌物。在接受 DMBA 处理的 HPV16 E6/E7 转基因小鼠中，近 50%的小鼠出现明显的肿瘤迹象，而接受类似处理的非转基因小鼠中无一例出现肿瘤。组织病理学分析证实，HPV16 转基因小鼠对肛门癌和癌前病变的易感性增加。生物标志物分析表明，这些小鼠肛门癌表现出与 HPV 阳性人类肛门癌前体相似的特性。这是研究病毒和细胞因素在肛门癌发生中的作用的第一个小鼠模型，应该为评估治疗和/或预防这种癌症的新治疗方法提供一个平台。
