Fibroblast Activation Protein in the Tumor Microenvironment in Lung Cancer

描述(申请人提供)：肿瘤转化和肿瘤进展是由肿瘤细胞的内在遗传变化以及外在因素，如渗透的先天炎症细胞、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和周细胞)通过其在ECM重塑、血管生成和间质形成中的作用，在肿瘤的发生、侵袭、生长和转移中发挥重要作用。然而，其中涉及的机制尚未得到很好的定义。该项目的长期目标是确定这样的机制。这项建议的重点是一种基质细胞限制的蛋白酶，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体的生成和功能。FAP在肿瘤、伤口愈合和纤维化中的表达仅限于成纤维细胞，并且受到严格的调控。FAP含有一个结构上定义的催化结构域，它介导了FAP的蛋白酶活性。我们的初步数据证实，FAP+细胞是人类肺癌的重要组成部分，在小鼠模型中，FAP基因缺失间接抑制了肿瘤细胞的增殖。此外，我们的结果表明，FAP是肿瘤中胶原堆积的关键决定因素。这些数据提供了靶向间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据。我们现在建议在小鼠肺癌模型中确定FAP促肿瘤活性的机制基础(目标1)，并定义驱动TAFs产生的机制(AIM2)。在目标3中，我们将验证FAP通过人和鼠之间的保守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FAP表达的间质细胞是多种肿瘤类型的显著特征，这些研究的结果可能对上皮源性肿瘤具有广泛的意义。这些研究可能导致间质靶向治疗的发展，这些治疗可能与针对肿瘤细胞本身的治疗协同作用。 与公共卫生相关：癌症是第二大致死原因，是一个重大的公共卫生问题。肺癌是第二常见的癌症，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。我们已经获得证据表明，靶向一种仅限于间充质来源的基质细胞的蛋白酶可以抑制肿瘤的生长，这种基质细胞普遍存在于各种实体肿瘤中。拟议中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。这些研究可能导致针对基质细胞的新的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.