Steroids and Stem Cell in Carcinogenesis

描述(由申请人提供)： 器官培养是一种组织培养模型，通过操纵细胞外基质内和细胞外基质上的上皮细胞和基质细胞来模拟体内组织结构。这些模型包含了在单层培养中无法评估的细胞-基质和上皮-基质相互作用的各个方面。它们可以用来评估单克隆克隆，而动物的单个异种移植瘤是从数百万个细胞建立起来的。因此，器官培养中的菌落比动物异种移植更准确地模拟肿瘤的发生。与动物模型相比，器官类型培养可以更容易地在基因和化学上进行操纵，从而允许更多的实验数量和更低的成本。然而，它们不能取代动物模型，因为它们不包括新陈代谢、生理和免疫影响。因此，在动物模型试验之前，器官类型培养有可能被用于筛选和改进化学防腐剂。此外，它们还提供了评估假说驱动的致癌和化学预防研究的机会。 我们建立了人正常子宫内膜、良性卵巢组织和交界性低恶性潜能卵巢肿瘤(LMP)的器官模型。该项目的目标是将这些器官模型进一步发展成为可用于研究致癌和化学预防过程的致癌模型。建议的实验将评估芳香烃、雌激素、孕酮、他莫昔芬、分化和成体干细胞在子宫内膜癌和卵巢癌发生中的相互作用。我们未来的目标将是验证这些模型，并将它们用于我们努力开发低毒的维甲酸类化合物，杂芳烃类化合物，用于化学预防。 这项研究将加深我们对癌症发生和化学预防过程的理解，最终可能转化为预防癌症的策略和药物。

DESCRIPTION (provided by applicant): Organotypic cultures are tissue culture models that mimic in vivo tissue architecture through manipulation of epithelial and stromal cells within and on top of an extracellular matrix. These models incorporate aspects of cell-matrix and epithelial-stromal interactions that cannot be evaluated in monolayer cultures. They can be used to evaluate monoclonal colonies, whereas individual xenograft tumors in animals are established from millions of cells. Colonies in organotypic culture therefore, more accurately mimic tumorigenesis than animal xenografts. Organotypic cultures can be more readily genetically and chemically manipulated than animal models, allowing increased numbers of experiments and less cost. They cannot replace animal models however, because they do not incorporate metabolic, physiologic and immunologic effects. Thus organotypic cultures can potentially be used to screen and improve chemoprevention agents prior to testing in animal models. In addition, they provide opportunities to evaluated hypothesis driven research on carcinogenesis and chemoprevention. We developed organotypic models of normal human endometrium, benign human ovarian tissue, and human borderline ovarian tumors of low malignant potential (LMP). The objective of this project is to further develop these organotypic models into models of carcinogenesis that can be used to study the processes of carcinogenesis and chemoprevention. The experiments proposed will evaluate the interaction of aromatic hydrocarbons, estrogen, progesterone, tamoxifen, differentiation and adult stem cells in endometrial and ovarian carcinogenesis. Our future goals will be to validate these models and to use them in our efforts to develop low-toxicity retinoids, heteroarotinoids, for chemoprevention. This research will enhance our understanding of the process of carcinogenesis and chemoprevention, which could ultimately translate into strategies and pharmaceuticals for prevention of cancer.