Mechanisms of Prostate Tumorigenesis Using Genetically Engineered Mouse Models

癌发生在复杂的微环境中，由间质、间质成纤维细胞、脉管系统和免疫细胞包围的多种不同上皮细胞系的薄壁组织组成。目前尚不清楚癌症是由哪种细胞类型引起的。我们依靠小鼠模型来前瞻性地检查早期致癌事件，因为研究人类的起始事件是不可行的。然而，大多数转基因小鼠模型不是细胞类型特异性的。我们假设不同的上皮亚型对肿瘤的发生有不同的易感性。由于大多数实体人肿瘤在Rb细胞周期调节途径中存在畸变，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（Rb- ts，统称）的破坏的易感性。我们发现肿瘤发生可以在K18或K19细胞中开始。然而，上皮组织对Rb-TS失活的易感性是亚型依赖的。对于膀胱、胃、肺和结肠上皮，K19细胞更容易受到Rb-TS失活的影响，而对于胸腺上皮，K18细胞更容易受到Rb-TS失活的影响。此外，当K19细胞中的Rb-TS失活时，与雌性相比，雄性的膀胱腺瘤发病早（诱导后9个月vs 14个月），只有一小部分动物发展为癌/腺癌，这表明肿瘤进展需要其他遗传事件。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）灭活前列腺K18和K19亚型的Rb-TS。令我们惊讶的是，2月龄时，小鼠前列腺上皮内瘤变（mPIN）病变在K19细胞中开始，而在K18细胞中没有发生，这表明K19细胞更容易发生前列腺肿瘤。因此，细胞亚型肿瘤的启动决定了组织病理表型和肿瘤发展的开始。我们目前正在撰写第一篇论文，并对Pten缺失的K18或K19转基因小鼠的前列腺表型进行分析。我们也在评估这些模型中肿瘤对去势的反应。宋勇，杨超，潘伟，Fathalizadeh A，陆鑫，Gilbert D，王超，O？苏立文，李建平，李建平，等。细胞上皮细胞Rb失活对肿瘤发生的影响。(准备)

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)