Cancer Associated Fibroblasts and Basal Cell Carcinoma Allografts

描述(由申请人提供)据估计，每三个有欧洲血统的美国人中就有一个会在有生之年患上基底细胞癌。虽然患者死亡率很低，但这些肿瘤是局部侵袭性的，可能会导致严重的组织破坏和发病率，特别是因为80%的肿瘤发生在头和颈部。去调节的Sonic hedgehog(HH)信号与多种癌症有关，是BCC发生的最重要的(如果不是排他性的)遗传致病因素。作为研究最深入的体系，BCC的发生、生长和发展都归因于HH的异常激活。这些知识导致了BCC小鼠模型的发展，这反过来又显著地提高了我们对BCC和HH信号的理解。过去，对致癌的研究主要集中在肿瘤细胞本身。然而，越来越多的证据有力地证明，肿瘤微环境，统称为肿瘤间质，在肿瘤形成的不同过程中发挥着至关重要的作用。在含有多种细胞类型的基质复合体中，成纤维细胞，又称癌症相关成纤维细胞(CAF)，是主要的成分，并积极支持肿瘤的生长。BCC CAF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被直接解决。缺乏数据的部分原因是过去的肿瘤移植实验的成功有限，相比之下，这些实验大大推进了其他癌症类型的间质研究。基于我们以前的发现以及文献中的一些见解，该项目的目标是开发一种简单但健壮的同种异体移植模型，利用差异标记的肿瘤细胞和来自转基因小鼠的CAF，直接评估CAF对肿瘤生长的影响。作为原则证明，我们将使用此模型在根本层面上解决1)是否 CAF是肿瘤生长所必需的；2)ptch1+/-皮肤成纤维细胞是否起CAF作用；3)照射后的皮肤成纤维细胞是否起CAF作用。与NIAMS的使命一致，我的研究的长期目标是在我们之前的发现的基础上，实现对基底细胞癌致癌的全面了解，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信号的基本机制，这有望开发出更好的策略来检测、治疗甚至预防癌症。 公共卫生相关性：我们的目标是开发一种改进的实验模型系统，该系统不仅可以直接评估成纤维细胞在最常见的皮肤癌-基底细胞癌(BCC)中的关键作用，还将导致发现治疗基底细胞癌以及其他癌症的新药物靶点。

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.