Role of alpha4-paxillin signaling in lymphangiogenesis

描述(申请人提供)：对于许多实体肿瘤，包括乳腺癌和黑色素瘤，淋巴结是最初临床检测到的转移部位。临床记录显示从淋巴转移到远处转移有进展。事实上，切除带瘤、引流的淋巴结可以改善许多肿瘤类型的临床结果。令人惊讶的是，人们对淋巴结微环境中可能导致肿瘤转移的因素知之甚少。Varner实验室的研究表明，原发肿瘤在转移前在肿瘤以及引流和远端淋巴结中诱导整合素A4介导的淋巴管生成。整合素A4拮抗剂既可预防淋巴管生成，又可预防淋巴结转移。Alpha4整合素直接与粘着斑蛋白Paxlin结合，后者是细胞迁移的重要调节因子。帕克西林作为一种支架蛋白，使在促进细胞迁移中至关重要的信号分子接近。由于巴西林可以直接与整合素A4结合，因此，它可能在促进淋巴管生成的信号事件中发挥关键作用。事实上，初步研究表明，携带阻止A4-帕克西林相互作用的敲门突变(C57BI/6 A4 Y991A)的小鼠在淋巴管生成和肿瘤转移方面存在缺陷。因此，我建议进一步研究A4-帕西林相互作用在促进淋巴管内皮细胞迁移和淋巴管生成中的作用。本研究的目的是：1)确定整合素A4-帕西林相互作用和帕西林磷酸化是否对淋巴管内皮细胞(LEC)迁移起关键作用；2)确定RAC通路是否是淋巴管内皮细胞迁移过程中A4-帕西林相互作用的下游效应因子；3)研究整合素A4介导的帕西林信号在淋巴管生成和体内转移中的作用。通过表征调控整合素A4介导的淋巴管生成的信号转导通路，拟议的研究可能会导致开发新的治疗方法来防止肿瘤转移。公共卫生相关性：肿瘤转移到远处器官是一个重要的问题，因为这决定了患者的临床结果。实体瘤(即乳腺癌)，在扩散到其他器官之前转移到淋巴结。了解淋巴结如何准备和允许肿瘤转移，将使治疗和/或预防转移的新疗法得以开发。

DESCRIPTION (provided by applicant): Lymph nodes are the initial, clinically detected sites of metastasis for many solid tumors, including breast carcinoma and melanoma. The clinical record suggests a progression from lymph node metastases to distant metastases. Indeed, excision of tumor-bearing, draining lymph nodes can improve the clinical outcome for many tumor types. Surprisingly, little is known about factors in the lymph node microenvironment that may contribute to tumor metastasis. Studies from the Varner lab indicate that primary tumors induce integrin a4-mediated lymphangiogenesis in tumors and in draining and distal lymph nodes prior to metastasis. Antagonists of integrin a4 prevent both lymph node lymphangiogenesis and lymph node metastasis. The alpha4 integrin binds directly to the focal adhesion protein paxillin, an important regulator of cell migration. Paxillin acts as a scaffolding protein by bringing into close proximity signaling molecules that are crucial in promoting cell migration. As paxillin can directly associate with integrin a4, it may, therefore, play a critical role in the signaling events promoting lymphangiogenesis. Indeed, preliminary studies indicate that mice bearing a knockin mutation that prevent a4-paxillin interactions (C57BI/6 a4 Y991A) exhibit defects in lymphangiogenesis and tumor metastasis. Therefore, I propose to characterize further the role of a4-paxillin interactions in promoting lymphatic endothelial cell migration and lymphangiogenesis. The aims of this proposal are 1) To determine whether integrin a4-paxillin interactions and paxillin phosphorylation are critical for lymphatic endothelial cell (LEC) migration, 2) To determine whether the Rac pathway is a downstream effector of a4-paxillin interactions during LEC migration, and 3) To examine the role of integrin a4 mediated paxillin signaling during lymphangiogenesis and metastasis in vivo. By characterizing the signal transduction pathways that regulate integrin a4 mediated lymphangiogenesis, the proposed studies could lead to the development of new therapies for preventing tumor metastasis. PUBLIC HEALTH RELEVANCE: Tumor metastases to distant organs is of significant concern as this determines the clinical outcome of the patient. Solid tumors (i.e. breast carcinomas), metastasize to the lymph nodes prior to spreading to other organs. Understanding how the lymph nodes prepare and permit for this tumor metastasis, will enable new therapies to be developed for treating and/or preventing metastases.