MOUSE CANCER MODELS VIA TGF-BETA RII LOSS

前列腺癌、结肠癌和乳腺癌占人类实体瘤的大部分。 在这三种人类癌症中已经鉴定了TGF β信号传导的破坏，特别是通过II型TGF β受体（TbetaRII）的衰减或功能丧失。 初步数据表明，在具有广泛表达的金属硫蛋白启动子/增强子显性负性TGF β RII（DNIIR）cDNA的转基因小鼠的前列腺和结肠上皮中发生恶性组织学变化，在表达更受限的MMTV-DNIIR cDNA的小鼠的乳腺中发生恶性组织学变化。 我们现在建议通过器官选择性减少或消除TbetaRII来开发这三种常见癌症的小鼠模型。 这些模型的组织学表征将由小鼠和人前列腺、结直肠和乳腺肿瘤方面的病理学家进行。 通过比较组织病理学分析、cDNA微阵列表达和质谱指纹分析，将能够验证它们的人类对应物。除了破坏TGF β信号传导之外，令人信服的流行病学和实验数据支持环加氧酶-2（考克斯-2）在人类结肠直肠癌发病机制中的作用，并且研究表明COY-2与人类前列腺癌和乳腺癌之间的联系。 将在这三种模型中检测考克斯-2及其代谢产物的表达。预计考克斯-2表达和对NSAIDS的反应性将是这些模型的额外验证者。 将使用选择性考克斯-2抑制剂进行化学预防，以及创新的治疗策略。 这些方法将部分由范德比尔特癌症中心承担，并将利用范德比尔特在小鼠模型开发和利用方面的经验、生长因子研究方面的优势以及类花生酸生物学方面的独特专业知识和分析能力。 在未来的方向，我们提出了一个“财团中的财团”计划，以开发一个小鼠模型的胰腺导管癌，以及一个战略，以确定修饰基因的营养方面的结直肠癌。

Cancers of the prostate, colon and breast comprise a majority of human solid tumors. Disruption of TGFbeta signaling, notably through attenuation or functional loss of the type II TGFbeta receptor (TbetaRII), has been identified in these three human cancers. Preliminary data demonstrate malignant histological changes in prostatic and colonic epithelium of transgenic mice with a widely-expressed metallothionein promoter/enhancer dominant negative TGFbetaRII (DNIIR) cDNA and malignant histological changes in the mammary gland of mice expressing a more restricted MMTV-DNIIR cDNA. We now propose to develop mouse models of these three common cancers by organ selective reduction or elimination of TbetaRII. Histological characterization of these models will be conducted by pathologists expert in mouse and human prostate, colorectal and mammary neoplasia. Validation to their human counterparts will be enabled by comparative histopathological analysis, cDNA microarray expression and mass spectrometric fingerprinting In addition to disrupted TGFbeta signaling, convincing epidemiological and experimental data support a role for cyclooxygenase-2 (COX-2) in the pathogenesis of human colorectal cancer and studies suggest a link between COY-2 and human prostate and breast cancer. Expression of COX-2 and its metabolites will be examined in these three models. It is anticipated that COX-2 expression and responsiveness to NSAIDS will be additional validators of these models. Chemoprevention with selective COX-2 inhibitors, as well as innovative treatment strategies, will be performed. These approaches will be underwritten, in part, by the Vanderbilt Cancer Center and will take advantage of Vanderbilt's experience in development and utilization of mouse models, strengths in growth factor research, and unique expertise and analytical capabilities in eicosanoid biology. In future directions, we propose a "consortium within a consortium" plan to develop a mouse model of ductular pancreatic carcinoma, as well as a strategy to identify modifier genes to nutritional aspects of colorectal cancer.