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由肿瘤细胞的内在遗传变化以及外在因素（如浸润性先天性炎性细胞、适应性免疫细胞、内皮细胞（EC）、细胞外基质（ECM）和间充质源性基质细胞（MDSC））介导。 MDSC（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而成为肿瘤起始、侵袭性生长和转移的重要参与者。 然而，所涉及的机制尚未明确界定。该项目的长期目标是确定这种机制。该提案的重点是基质细胞限制性蛋白酶，成纤维细胞活化蛋白（FAP），在肺癌中的作用。 FAP是TAF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产生和功能。 FAP表达仅限于肿瘤、伤口愈合和纤维化中的成纤维细胞，并且受到严格调控。 FAP含有一个结构确定的催化结构域，介导其蛋白酶活性。 我们的初步数据表明，FAP+细胞是人类肺癌的重要组成部分，并且FAP的基因缺失间接抑制了小鼠模型中的肿瘤细胞增殖。此外，我们的研究结果表明，FAP是胶原蛋白在肿瘤中积累的关键决定因素。 这些数据提供了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的原理证明。 我们现在提出定义FAP在肺癌小鼠模型中的肿瘤促进活性的机制基础（Aim 1），并定义驱动TAF产生的机制（Aim 2）。 在目标3中，我们将检验FAP通过小鼠和人之间保守的机制促进人肺癌细胞生长的假设。拟议的研究将确定TAF依赖的促进肺癌生长的机制。 然而，由于表达FAP的基质细胞是多种肿瘤类型的突出特征，这些研究的结果可能对上皮来源的肿瘤具有广泛的意义。 这些研究可能会导致基质靶向疗法的发展，这些疗法可能与针对肿瘤细胞本身的疗法协同作用。 公共卫生相关性：作为第二大死亡原因，癌症是一个主要的公共卫生问题。 肺癌是第二大常见癌症，也是癌症死亡的主要原因。 因此，迫切需要开发新的肺癌治疗方法。 我们现在知道，肿瘤微环境在驱动肿瘤转化和肿瘤进展中起着关键作用。 我们已经获得的证据表明，靶向限制于间充质来源的基质细胞的蛋白酶抑制肿瘤生长，所述间充质来源的基质细胞在多种实体瘤中普遍存在。 拟议的实验将确定导致这种蛋白酶在肿瘤中表达的机制以及它促进肿瘤生长的机制。 这些研究可能会导致针对基质细胞的新型抗肿瘤疗法的临床开发。

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. PUBLIC HEALTH RELEVANCE: As the second leading cause of death, cancer presents a major public health problem. Lung cancer is the second most common cancer and the leading cause of cancer deaths. Therefore, there is an urgent need to develop new treatments for lung cancer. We now know that the tumor microenvironment plays a critical role in driving neoplastic transformation and tumor progression. We have obtained evidence that targeting a protease restricted to mesenchymal derived stromal cells, which are prevalent in a wide variety of solid tumors, inhibits tumor growth. The proposed experiments will define the mechanisms that lead to the expression of this protease in tumors and the mechanisms by which it promotes tumor growth. These studies are likely to lead to the clinical development of new anti-tumor therapies that target stromal cells.