Role of alpha4-paxillin signaling in lymphangiogenesis

描述（由申请人提供）：淋巴结是许多实体瘤（包括乳腺癌和黑色素瘤）的初始临床检测转移部位。临床记录提示从淋巴结转移进展为远处转移。事实上，切除肿瘤，引流淋巴结可以改善许多肿瘤类型的临床结果。令人惊讶的是，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，原发性肿瘤在转移前诱导肿瘤中以及引流和远端淋巴结中的整合素α 4介导的淋巴管生成。整合素a4拮抗剂可预防淋巴结淋巴管生成和淋巴结转移。α 4整联蛋白直接与粘着斑蛋白桩蛋白结合，桩蛋白是细胞迁移的重要调节因子。桩蛋白作为一种支架蛋白，通过将在促进细胞迁移中至关重要的信号分子紧密靠近来发挥作用。由于桩蛋白可以直接与整合素α 4结合，因此，它可能在促进淋巴管生成的信号事件中起关键作用。实际上，初步研究表明，携带阻止α 4-桩蛋白相互作用的敲入突变（C57 B1/6 α 4 Y 991 A）的小鼠表现出淋巴管生成和肿瘤转移的缺陷。因此，我建议进一步表征α 4-桩蛋白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。该提议的目的是1）确定整联蛋白α 4-桩蛋白相互作用和桩蛋白磷酸化是否对淋巴内皮细胞（LEC）迁移至关重要，2）确定Rac途径是否是LEC迁移期间α 4-桩蛋白相互作用的下游效应物，和3）检查体内淋巴管生成和转移期间整联蛋白α 4介导的桩蛋白信号传导的作用。通过表征调节整合素a4介导的淋巴管生成的信号转导途径，所提出的研究可能导致预防肿瘤转移的新疗法的发展。公共卫生相关性：肿瘤转移至远处器官是一个值得关注的问题，因为这决定了患者的临床结局。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这种肿瘤转移，将使新的治疗方法被开发用于治疗和/或预防转移。

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.