Mechanisms of Prostate Tumorigenesis Using Genetically Engineered Mouse Models

癌症发生在一个复杂的微环境中，由多个不同的实质上皮谱系组成，周围环绕着间质、间质成纤维细胞、血管系统和免疫细胞。目前还不知道哪种细胞类型的癌症是由什么引起的。我们依靠小鼠模型来前瞻性地检查早期致癌事件，因为研究人类的启动事件是不可行的。然而，大多数转基因小鼠模型并不是特定于细胞类型的。我们假设不同的上皮亚型对肿瘤的发生有不同的敏感性。由于大多数实体人类肿瘤在Rb细胞周期调控途径中存在异常，我们在体内测试了表达细胞角蛋白(K)18或K19的两种上皮亚型对Rb及其家族成员p107和p130肿瘤抑制(统称为Rb-TS)的破坏的敏感性。我们发现，肿瘤发生可以在K18或K19细胞中启动。然而，上皮组织对RB-TS失活的敏感性与亚型有关。对于膀胱、胃、肺和结肠上皮，K19细胞对RB-TS更敏感，而对于胸腺上皮，K18细胞更容易失活。此外，当RB-TS在K19细胞中失活时，雄性比雌性更早发生膀胱腺瘤(诱导后9个月对14个月)，并且只有一小部分动物发生癌症/腺癌，这表明肿瘤的进展需要其他遗传事件(S)。为了进一步评估前列腺上皮对Rb-TS失活的易感性，我们使用前列腺特异性Cre系(Pb-Cre4)灭活了前列腺中K18和K19亚型的Rb-TS。令我们惊讶的是，小鼠前列腺上皮内瘤变(MPIN)在2个月龄的K19细胞中开始发生，但在K18细胞中没有发生，这表明K19细胞更容易发生前列腺癌。因此，细胞亚型肿瘤的发生决定了肿瘤的组织病理表型和发生发展。我们目前正在撰写第一篇手稿，并分析Pten缺失的K18或K19转基因小鼠的前列腺表型。在这些模型中，我们还在评估肿瘤对去势的反应。宋勇，杨晨，潘伟，Fathalizadeh A，Lu X，Gilbert D，Wang C，O？Sullivan N，Haines D，Martin P，Van Dyke T.RB在上皮亚型中的失活：肿瘤启动的不同易感性。(正在准备中)

Carcinomas arise in a complex microenvironment consisting of multiple distinct epithelial lineages of the parenchyma surrounded by the mesenchyme, stromal fibroblasts, vasculature, and immune cells. It is not known what cell type cancers arise from. We rely on mouse models to prospectively examine early oncogenic events since it is not feasible to study initiation events in human. However, most transgenic mouse models are not cell type specific. We hypothesize that different epithelial subtypes have varied susceptibility for tumor initiation. Since most solid human tumors harbor aberrations in the Rb cell cycle regulatory pathway, we tested the susceptibility of two epithelial subtypes expressing cytokeratin (K) 18 or K19 to the disruption of Rb and its family members p107 and p130 tumor suppression (Rb-TS, collectively) in vivo. We found that tumorigenesis could be initiated in either K18 or K19 cells. However, the susceptibility of epithelial tissues to Rb-TS inactivation was subtype-dependent. For bladder, stomach, lung, and colon epithelium, K19 cells were more susceptible to Rb-TS inactivation, while for thymic epithelium, K18 cells. Moreover, when Rb-TS was inactivated in K19 cells, males had early onset of bladder adenoma compared to females (9 vs 14 months post induction), and only small percentage of animals developed carcinoma/adenocarcinoma, indicating that other genetic event(s) is required for tumor progression. To further assess the susceptibility of prostate epithelium to Rb-TS inactivation, we inactivated Rb-TS in K18 and K19 subtypes in prostate using prostate specific Cre line (Pb-Cre4). To our surprise, mouse prostatic intraepithelial neoplasia (mPIN) lesions were initiated in K19 cells, but not in K18 cells at 2 months of age, indicating that K19 cells are more susceptible to prostate tumorigenesis. Thus, cell subtype tumors are initiated in dictates the histopathological phenotype and onset of tumor development. We are currently in the process of writing up the 1st manuscript and analyzing the mouse prostate phenotype developed in K18 or K19 transgenic mice with Pten deletion. We are also assessing the tumors response to castration in these models. Song Y, Yang C, Pan W, Fathalizadeh A, Lu X, Gilbert D, Wang C, O?Sullivan N, Haines D, Martin P, Van Dyke T. Rb inactivation in epithelial subtypes: Differential susceptibility for tumor initiation. (in preparation)