The role of endothelial cells in the formation of early metastatic niches in the lung

摘要 转移性疾病是一个多步骤的级联过程，是癌症相关死亡的主要原因。许多研究 正在研究肿瘤细胞是如何获得转移到远处器官并从 主要位置。然而，人们对Normal的殖民机制知之甚少 通过扩散和循环的肿瘤细胞感染器官，可以说是转移进展中的限速步骤。这个 肺是最常见的转移部位之一，因此在这项建议中，我们将调查 正常肺内的内皮细胞在循环癌细胞从血管腔外渗出过程中的变化 并定植到正常肺以建立肺转移。播散性肿瘤细胞经历了显著的 循环中的压力，以至于在渗入正常肺的过程中，它们需要一个保护性的壁龛 由细胞外基质组成，提供物理锚定，防止细胞失巢和细胞凋亡。这个保护性的 NICE使播散的肿瘤细胞有机会恢复、存活并最终在肺内扩张 成为大转移的病变。我们正在研究激活肺内皮细胞转换正常的过程 肺组织进入好客的“土壤”或早期转移的壁龛(EMN)，以促进循环肿瘤的定植 细胞。我们发表的研究和初步数据表明，肺内皮细胞在肿瘤到来之前就被激活了。 小鼠肺转移模型中的细胞。我们的数据还表明，基质细胞糖蛋白， 凝血酶敏感蛋白-1(TSP1)在血管内皮细胞转移过程中起着重要的调节作用。 特异性转移到肺的肿瘤细胞和肿瘤条件培养液下调肺中TSP1的表达 ECS促进EC激活。我们的初步研究发现基质金属蛋白水解酶表达增加 (MMPs)3在TSP1中低ECs。我们的初步数据表明，MMP3促进内皮细胞向间充质转化 通过与CD44的相互作用最终导致细胞外基质的产生和重塑的增加 促进了肺内EMN的生成。我们最重要的假设是 原发肿瘤 肺转移通过TSP1下调激活肺内皮细胞，导致内源性MT增加 内膜结节细胞外基质的产生支持肺定植。我们认为TSP1是一个关键的 EC动态平衡调节因子及其缺失促进EC活化，最终导致细胞外基质 通过MMP3-CD44轴进行生产和重塑。了解内皮细胞在正常肺中的作用 向转移进展将提供对肺最早阶段潜在机制的新见解 并可能为预防转移性疾病提供治疗靶点。

SUMMARY Metastatic disease is a multistep cascade and is the primary cause of cancer-related mortalities. Many studies are investigating how tumor cells acquire the ability to metastasize to distant organs and escape from their primary location. However much less is known about the mechanisms underlying the colonization of normal organs by disseminated and circulating tumor cells, arguably the rate limiting step in metastatic progression. The lung is one of the most common sites of metastases therefore in this proposal, we will investigate the role of endothelial cells (ECs) in the normal lung during extravasation of circulating cancer cells out of the vessel lumen and colonization into the normal lung to establish lung metastases. Disseminated tumor cells undergo significant stress in the circulation such that during extravasation into the normal lung, they require a protective niche composed of extracellular matrix to provide physical anchorage to prevent anoikis and apoptosis. This protective niche allows disseminated tumor cells the opportunity to recover, survive and expand in the lung eventually becoming macrometastatic lesions. We are investigating the processes that activate lung ECs converting normal lung tissue into hospitable “soil” or an early metastatic niche (EMN) to facilitate colonization by circulating tumor cells. Our published studies and preliminary data suggest that lung ECs are activated prior to the arrival of tumor cells in mouse models of lung metastases. Our data also indicate that the matricellular glycoprotein, thrombospondin-1 (TSP1) plays an important role in regulating EC homeostasis during metastatic progression. Tumor cells that specifically metastasize to the lung and tumor conditioned media downregulates TSP1 in lung ECs promoting EC activation. Our pilot studies identified increased expression of matrix metalloproteases (MMPs) 3 in TSP1low ECs. Our preliminary data suggest that MMP3 promotes endothelial-to-mesenchymal through interactions with CD44 ultimately leading to increased extracellular matrix production and remodeling contributing to EMN generation in the lung. Our overarching hypothesis is that primary tumors that metastasize to the lung activate lung ECs by TSP1 downregulation leading to EndoMT and increased extracellular matrix production in the EMN supporting lung colonization. We propose that TSP1 is a critical regulator of EC homeostasis and its loss promotes EC activation and ultimately leads to extracellular matrix production and remodeling via an MMP3-CD44 axis. Understanding the contribution of ECs in the normal lung towards metastatic progression will offer new insight into the mechanisms underlying the earliest stages of lung metastases and may offer therapeutic targets for the prevention of metastatic disease.