Mechanisms of Prostate Tumorigenesis Using Genetically Engineered Mouse Models

使用基因工程小鼠模型研究前列腺肿瘤发生机制

• 批准号: 8552875
• 负责人: Terry van Dyke
• 金额: $ 65.22万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8552875
• 关键词: Adenocarcinoma; Age-Months; Androgens; Animal Model; Animals; Bladder; Carcinoma; Castration; Cell Cycle; Cells; Colon; Complex; Cytokeratin; Development; Diagnostic tests; Epithelial; Epithelium; Event; Family member; Female; Fibroblasts; Genetically Engineered Mouse; Goals; Growth; Hormones; Human; Immune; K-18 conjugate; KRT19 gene; Lesion; Lung; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Manuscripts; Mesenchyme; Modeling; Molecular Abnormality; Mus; Oncogenic; Other Genetics; Pathway interactions; Patients; Phenotype; Predisposition; Preparation; Process; Prostate; Prostatic Intraepithelial Neoplasias; Prostatic Neoplasms; Refractory Disease; Regulatory Pathway; Role; Solid; Stomach; Testing; Tissues; Transgenic Mice; Tumor Subtype; Tumor Suppression; Withdrawal; Writing; Yang; adenoma; androgen independent prostate cancer; cell type; early onset; effective therapy; in vivo; interest; male; mouse model; pre-clinical; response; tumor; tumor initiation; tumor progression; tumorigenesis

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)

癌发生在复杂的微环境中，由间充质、基质成纤维细胞、脉管系统和免疫细胞包围的实质的多个不同上皮谱系组成。目前还不清楚癌症是由什么细胞引起的。我们依靠小鼠模型来前瞻性地检查早期致癌事件，因为在人类中研究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具有不同的易感性。由于大多数人实体肿瘤在Rb细胞周期调控通路中存在畸变，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（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失活的敏感性是亚型依赖性的。对于膀胱、胃、肺和结肠上皮，K19细胞更容易受到Rb-TS灭活，而对于胸腺上皮，K18细胞更容易受到Rb-TS灭活。此外，当Rb-TS在K19细胞中失活时，与雌性动物相比，雄性动物的膀胱腺瘤发病较早（诱导后9个月vs 14个月），只有小部分动物发生癌/腺癌，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失活的敏感性，我们使用前列腺特异性Cre线（Pb-Cre 4）失活前列腺中K18和K19亚型中的Rb-TS。令我们惊讶的是，小鼠前列腺上皮内瘤变（mPIN）病变在K19细胞中开始，但在2个月大的K18细胞中没有，表明K19细胞对前列腺肿瘤发生更敏感。因此，细胞亚型肿瘤的起始决定了组织病理学表型和肿瘤发展的开始。我们目前正在撰写第一篇论文，并分析在Pten缺失的K18或K19转基因小鼠中产生的小鼠前列腺表型。我们还评估了这些模型中肿瘤对去势的反应。Song Y，Yang C，Pan W，Fathalizadeh A，Lu X，吉尔伯特D，Wang C，O？刘晓波，刘晓波，货车晓波.上皮细胞亚型中Rb的失活：肿瘤发生的不同易感性。(in（编制）