Cancer Associated Fibroblasts and Basal Cell Carcinoma Allografts

描述（由申请人提供）据估计，三分之一的欧洲血统美国人将在其一生中患上BCC。虽然患者死亡率很低，但这些肿瘤是局部侵袭性的，可能导致严重的组织破坏和发病率，特别是因为80%的肿瘤发生在头部和颈部。不受调控的Sonic hedgehog （HH）信号与多种癌症有关，并且是BCC癌变的最重要的（如果不是唯一的）遗传致病因素。作为研究最多的系统，BCC的发生、生长和进展都归因于异常的HH激活。这一知识导致了BCC小鼠模型的发展，这反过来又显著促进了我们对BCC和HH信号传导的理解。在过去，对癌变的研究主要集中在肿瘤细胞本身。然而，越来越多的证据表明，肿瘤微环境，统称为肿瘤间质，在肿瘤形成的不同过程中起着至关重要的作用。在含有多种细胞类型的基质复合体中，成纤维细胞，又称癌相关成纤维细胞（CAFs），是主要成分，并积极支持肿瘤生长。基因表达研究暗示了BCC CAFs的关键作用，但到目前为止还没有直接解决。这种缺乏数据的部分原因是由于过去的肿瘤移植实验成功有限，相比之下，在其他癌症类型的基质研究方面取得了显著进展。基于我们之前的研究结果以及文献中的一些见解，本项目的目标是开发一种简单而强大的同种异体移植模型，利用来自转基因小鼠的差异标记肿瘤细胞和CAFs，直接评估CAFs对肿瘤生长的影响。作为一个原则的证明，我们将使用这个模型来解决，在基本层面上，1)是否

DESCRIPTION (Provided by the applicant) It is estimated that one of three Americans of European ancestry will develop a BCC during their lifetime. Although patient mortality is low, these tumors are locally invasive and may cause significant tissue destruction and morbidity, particularly because 80% of tumors occur on the head and neck. Deregulated Sonic hedgehog (HH) signaling has been implicated in various cancers and is the foremost, if not exclusive, genetic causative factor for BCC carcinogenesis. Being the best studied system, BCC's initiation, growth and progression have all been attributed to abnormal HH activation. This knowledge has led to the development of BCC mouse models, which in turn has markedly boosted our understanding of BCC and HH signaling. In the past, studies of carcinogenesis have focused primarily on the tumor cells themselves. However, accumulating evidence argues strongly that the tumor microenvironment, collectively referred to as the tumor stroma, plays crucial roles throughout different process of tumor formation. Within the multiple cell type- containing stromal complex, fibroblasts, aka cancer associated fibroblasts (CAFs), are the predominant component and actively support tumor growth. The pivotal roles of BCC CAFs have been implied by gene expression studies, but so far have not been directly addressed. This lack of data is partly due to limited success in past tumor grafting experiments, which in contrast has dramatically advanced stroma research in other cancer types. Based on our prior findings as well as on some insights from the literature, the goal of this project is to develop a simple yet robust allograft model that offers direct assessment of CAFs' influence on tumor growth, utilizing differentially marked tumor cells and CAFs derived from transgenic mice. As a proof-of- principle, we will use this model to address, at the fundamental level, 1) whether or not CAFs are required for tumor growth; 2) whether or not Ptch1+/- skin fibroblasts act as CAFs; and 3) whether or not irradiated skin fibroblasts act as CAFs. In line with the mission of NIAMS, the long-term goal of my research is to build upon our prior findings to achieve comprehensive understanding of BCC carcinogenesis and to discover new drug targets. Additionally, we will use BCC as a model system to elucidate the basic mechanisms of HH signaling, which holds great promises of developing better strategies to detect, treat and even prevent cancers in general. PUBLIC HEALTH RELEVANCE: We aim to develop an improved experimental model system, which not only will allow direct assessment of the crucial roles of fibroblasts in basal cell carcinoma (BCC), the most common skin cancer, but also will lead to discovery of novel drug targets for BCC as well as for other cancers in general.