Mechanisms of Prostate Tumorigenesis Using Genetically Engineered Mouse Models

癌发生在复杂的微环境中，由多种不同的上皮谱系组成，周围有各种基质细胞类型。了解癌症病因需要评估疾病开始和进展过程中细胞类型之间的关系。基因工程小鼠（GEM）模型有助于对早期致癌事件进行前瞻性检查，这在人类中是不可能的。由于大多数实体瘤在pRb网络中具有畸变，我们开发了一种诱导性GEM方法，用于在pRb介导的肿瘤抑制（Rb-TS）失活后在各种上皮组织和亚型中建立和评估癌起始。该系统允许对表达细胞角蛋白（K）18或19的上皮亚型进行独立评估。通过Cre依赖性表达一种主要使pRb失活的蛋白和功能冗余蛋白p107和p130，可在许多组织的K18或K19表达细胞中引发瘤形成。通过设计，因为只有一个单一的通路畸变被工程化，癌症只有在长时间的潜伏期后才能发展成随机的。因此，允许定向细胞类型特异性癌起始的该系统有助于进一步定义可通过工程化、致癌物诱导和/或自发演变使肿瘤进展为侵袭性癌症的事件。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-Cre4）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）病变开始于K19细胞，但不是在K18细胞在2个月大。在前列腺上皮中添加PTEN缺失加速了K19动物中mPIN向腺癌的转化并转移至肺和其他器官，而K18动物由于胸腺上皮细胞中强K18表达和低PbCre4活性而在6 - 10月龄时全部死于胸腺增大，从而排除了终末期前列腺表型的分析。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K19模型中评估肿瘤对去势的反应。宋，Y.，吉尔伯特，D.，O 'Sullivan，T.N.，杨，C.，潘，W.，Fathalizadeh，A.，卢，L.，Haines，D.，马丁，P.，货车戴克，T.通过Rb肿瘤抑制因子失活的癌发生：一种评估不同组织中上皮亚型依赖性癌发生的通用方法，正在PLoS One上进行综述。08-2013. y.宋角，澳-地Yang，杨氏D.吉尔伯特奥沙利文湖Lu，P.L. Martin和T.货车戴克。在基因工程小鼠模型中，转移性前列腺癌起始于K19前列腺上皮细胞。准备中。

Carcinomas arise in a complex microenvironment consisting of multiple distinct epithelial lineages surrounded by a variety of stromal cell types. Understanding cancer etiologies requires evaluating the relationship among cell types during disease initiation and through progression. Genetically engineered mouse (GEM) models facilitate the prospective examination of early oncogenic events, which is not possible in humans. Since most solid tumors harbor aberrations in the pRb network, we developed an inducible GEM approach for the establishment and assessment of carcinoma initiation in a diverse range of epithelial tissues and subtypes upon inactivation of pRb-mediated tumor suppression (Rb-TS). The system allows independent assessment of epithelial subtypes that express either cytokeratins (K) 18 or 19. By Cre-dependent expression of a protein that dominantly inactivates pRb and functionally redundant proteins p107 and p130, neoplasia could be initiated in either K18 or K19 expressing cells of numerous tissues. By design, because only a single pathway aberration was engineered, carcinomas developed stochastically only after long latency. Hence, this system, which allows for directed cell-type-specific carcinoma initiation, facilitates further definition of events that can progress neoplasms to aggressive cancers via engineered, carcinogen-induced and/or spontaneous evolution. 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. Addition of PTEN deletion in prostate epithelium accelerated the mPIN to adenocarcinoma and metastasized to lung and other organs in K19 animals, while K18 animals all died from enlarged thymus at 6-10 months of age due to strong K18 expression and low PbCre4 activity in thymic epithelial cells, precluding the analysis of end stage prostate phenotype. Thus, cell subtype tumors are initiated in dictates the histopathological phenotype and onset of tumor development. We are currently assessing the tumors' response to castration in K19 models. Song, Y., Gilbert, D., O'Sullivan, T.N., Yang, C., Pan,W., Fathalizadeh, A., Lu, L., Haines, D., Martin, P., Van Dyke, T. Carcinoma Initiation via Rb Tumor Suppressor Inactivation: A Versatile Approach to Evaluating Epithelial Subtype-Dependent Cancer Initiation in Diverse Tissues, Under review at PLoS One. 08-2013. Y. Song, C. Yang, D. Gilbert, T.N. O'Sullivan, L. Lu, P.L. Martin, and T. Van Dyke. Metastatic Prostate Cancer Initiated in K19 Prostate Epithelial Cells in Genetically Engineered Mouse Model. In Preparation.