Fibroblast Activation Protein in the Tumor Microenvironment in Lung Cancer

描述（由申请人提供）：肿瘤转化和肿瘤进展是由肿瘤细胞内在的遗传变化以及外在因素如浸润性先天炎症细胞、适应性免疫细胞、内皮细胞（EC）、细胞外基质（ECM）和间充质来源的基质细胞（MDSCs）介导的。MDSCs（肿瘤相关成纤维细胞（TAFs）和周细胞）通过其在ECM重塑、血管生成和基质形成中的作用，在肿瘤的发生、侵袭性生长和转移中发挥了重要作用。然而，所涉及的机制还没有明确定义。这个项目的长期目标是定义这样的机制。这一建议的重点是间质细胞限制性蛋白酶，成纤维细胞激活蛋白（FAP）在肺癌中的作用。FAP是TAFs和血管相关周细胞的明确标记物，可用于研究这些重要细胞群的生成和功能。FAP的表达仅限于肿瘤、伤口愈合和纤维化的成纤维细胞，并受到严格调控。FAP包含一个结构上确定的催化结构域，介导其蛋白酶活性。我们的初步数据证实，FAP+细胞是人类肺癌的重要组成部分，并且在小鼠模型中，FAP基因缺失间接抑制肿瘤细胞的增殖。此外，我们的研究结果表明，FAP是肿瘤中胶原积累的关键决定因素。这些数据为靶向基质细胞介导的过程可能是治疗上皮源性实体瘤的有效方法提供了原理证明。我们现在提议确定FAP在肺癌小鼠模型中促进肿瘤活性的机制基础（Aim 1），并确定驱动TAFs生成的机制（Aim2）。在Aim 3中，我们将验证FAP通过小鼠和人之间保守的机制促进人肺肿瘤细胞生长的假设。拟议的研究将确定促进肺癌生长的taf依赖机制。然而，由于表达fap的基质细胞是多种肿瘤类型的一个突出特征，这些研究的结果可能对上皮源性肿瘤具有广泛的意义。这些研究可能会导致基质靶向治疗的发展，这些治疗可能与针对肿瘤细胞本身的治疗协同作用。

DESCRIPTION (provided by applicant): Neoplastic transformation and tumor progression is mediated by intrinsic genetic changes in tumor cells, as well as extrinsic factors such as infiltrating innate inflammatory cells, adaptive immune cells, endothelial cells (EC), the extracellular matrix (ECM) and mesenchymal-derived stromal cells (MDSCs). MDSCs (tumor associated fibroblasts (TAFs) and pericytes) have emerged as important players in tumor initiation, invasive growth and metastasis through their roles in ECM remodeling, angiogenesis and stromagenesis. However, the mechanisms involved are not yet well-defined. The long-term goal of this project is to define such mechanisms. This proposal is focused on the role of a stromal cell-restricted protease, Fibroblast Activation Protein (FAP), in lung cancer. FAP is a well defined marker of TAFs and blood vessel associated pericytes that can be exploited to study the generation and function of these important cell populations. FAP expression is restricted to fibroblasts in tumors, wound healing and fibrosis and is tightly regulated. FAP contains a structurally defined catalytic domain that mediates its protease activities. Our preliminary data establish that FAP+ cells are a prominent component of human lung cancers and that genetic deletion of FAP indirectly inhibits tumor cell proliferation in mouse models. In addition, our results indicate that FAP is a critical determinant of collagen accumulation in tumors. These data provide proof-of-principle that targeting stromal cell-mediated processes may be an effective approach to treating epithelial-derived solid tumors. We now propose to define the mechanistic bases of the tumor promoting activity of FAP in mouse models of lung cancer (Aim 1) and to define the mechanisms that drive the generation of TAFs (Aim2). In Aim 3, we will test the hypothesis that FAP promotes the growth of human lung tumor cells through mechanisms conserved between mouse and man. The proposed studies will define TAF-dependent mechanisms that promote the growth of lung cancers. However, as FAP-expressing stromal cells are a prominent feature in a wide variety of tumor types, the results of these studies are likely to have broad implications for epithelial-derived tumors. These studies will likely lead to the development of stroma-targeted therapies that are likely to synergize with therapies directed against tumor cells per se.