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的美国人将在其一生中发展BCC。虽然患者死亡率低，但这些肿瘤是局部侵袭性的，可能导致显著的组织破坏和发病率，特别是因为80%的肿瘤发生在头颈部。失调的Sonic hedgehog（HH）信号转导与多种癌症有关，并且是BCC致癌作用的最重要（如果不是唯一的话）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HH的异常激活。这些知识导致了BCC小鼠模型的发展，这反过来又显着提高了我们对BCC和HH信号传导的理解。在过去，致癌作用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，统称为肿瘤基质，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物中，成纤维细胞（又称癌症相关成纤维细胞（CAF））是主要组分并且积极支持肿瘤生长。BCC CAFs的关键作用已经被基因表达研究所暗示，但到目前为止还没有直接解决。这种数据的缺乏部分是由于过去的肿瘤移植实验成功有限，相反，这极大地推进了其他癌症类型的基质研究。基于我们先前的发现以及文献中的一些见解，本项目的目标是开发一种简单而稳健的同种异体移植模型，该模型利用来自转基因小鼠的差异标记的肿瘤细胞和CAFs，提供CAFs对肿瘤生长的影响的直接评估。作为原理证明，我们将使用该模型在基本层面上解决以下问题：1）是否 CAF是肿瘤生长所必需的; 2）Ptch 1 +/-皮肤成纤维细胞是否充当CAF;以及3）经辐照的皮肤成纤维细胞是否充当CAF。根据NIAMS的使命，我的研究的长期目标是建立在我们以前的研究结果，以实现对BCC致癌作用的全面了解，并发现新的药物靶点。此外，我们将使用BCC作为模型系统来阐明HH信号传导的基本机制，这对于开发更好的策略来检测，治疗甚至预防癌症具有很大的希望。

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.