MOUSE CANCER MODELS VIA TGF-BETA RII LOSS

前列腺癌、结肠癌和乳腺癌占人类实体肿瘤的大多数。在这三种人类癌症中，已经发现TGFbeta信号的中断，特别是通过II型TGFbeta受体(TbetaRII)的衰减或功能丧失。初步数据显示，广泛表达金属硫蛋白启动子/增强子显性负TGFbetaRII(DNIIR)基因的转基因小鼠的前列腺和结肠上皮发生了恶性组织学变化，而表达限制性更强的MMTV-DNIIR基因的小鼠的乳腺发生了恶性组织学变化。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。这些模型的组织学特征将由研究小鼠和人类前列腺、结直肠和乳腺肿瘤的病理学家进行。除了干扰的TGFbeta信号外，将通过比较组织病理学分析、cDNA微阵列表达和质谱学指纹图谱来验证它们与人类同行的有效性，令人信服的流行病学和实验数据支持环氧合酶-2(COX-2)在人类结直肠癌发病机制中的作用，研究表明COY-2与人类前列腺癌和乳腺癌之间存在联系。将在这三个模型中检测COX-2及其代谢物的表达。预计COX-2的表达和对NSAID的反应性将是这些模型的额外验证因素。将采用选择性COX-2抑制剂以及创新的治疗策略进行化学预防。这些方法将部分由范德比尔特癌症中心提供担保，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二十烷类生物学方面的独特专业知识和分析能力。在未来的发展方向中，我们提出了一个“联合体内的联合体”计划，以发展一种小鼠导管状胰腺癌模型，以及一种确定结直肠癌营养方面的修饰基因的策略。

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.