The molecular mechanisms of migration of which lead to tumor cell intravasation.

描述（由申请人提供）：本提案描述了一个为期5年的培训计划，用于发展癌症生物学研究事业。主要研究者（Zijlstra博士）概述了一项计划，即利用已建立的基础设施和研究支持，结合导师（Quigley博士）的指导以及与已建立的研究者（Stuhlmann博士和布兰卡福特博士）的合作互动，扩展其科学技能，并调解其向癌症研究独立职业的过渡。虽然转移到重要器官是致命的，但这是一个适合治疗干预的低效生物过程。干预的第一步是确定合适的分子靶点和机制。肿瘤细胞播散的主要要求之一是细胞能够动员自身、内渗并离开原始肿瘤部位。本申请提出表征CD151控制的迁移介导的内渗机制，并鉴定调节体内迁移的新分子靶点。我们已经证明，靶向CD151的功能阻断抗体破坏了体内肿瘤细胞运动的机制，该机制由不同的肿瘤细胞谱系共享。由此产生的体内运动抑制防止了血管内渗并阻止了转移。这些观察结果表明，高度侵袭性的肿瘤可以被固定，我们因此可以防止它们在原发肿瘤部位的内渗能力，从而限制它们的转移能力。本申请提出使用活体成像和我们的定量转移模型在三个特定目标中研究负责内渗的迁移机制：特定目标#1是识别肿瘤细胞内渗的生物学机制和途径。具体目标#2阐明四跨膜蛋白CD151在体内转移性播散过程中调节血管内渗的分子机制。具体目标#3是在体内转移模型中结合阳性选择使用人工转录因子（ATF），以鉴定抑制肿瘤细胞迁移和内渗的分子靶标。项目相关性：转移是癌症相关死亡的主要原因。为了转移，肿瘤细胞已经动员自己并进入循环。拟议的工作重点是识别和理解肿瘤细胞可以被固定的机制。

DESCRIPTION (provided by applicant): This Proposal describes a 5 year training program for the development of a research career in cancer biology. The principal investigator (Dr. Zijlstra) outlines a plan to use an established base of infrastructure and research support in conjunction with guidance from his mentor (Dr. Quigley) and collaborative interactions with established investigators (Dr. Stuhlmann and Dr. Blancafort) to expand his scientific skills and mediate his transition to an independent career in cancer research. Project Summary: While metastasis to vital organs is lethal, it is an inefficient biological process suitable for therapeutic intervention. The first step towards intervention is the identification of suitable molecular targets and mechanisms. One of the primary requirements of tumor cell dissemination is the ability of the cell to mobilize itself, intravasate, and leave the original tumor site. This application proposes to characterize CD151 controlled mechanism of migration-mediated intravasation, and to identify new molecular targets which regulate migration in vivo. We have demonstrated that a function blocking antibody targeted to CD151 disrupts a mechanism of in vivo tumor cell motility shared by divergent tumor cell lineages. The resulting inhibition of in vivo motility prevents intravasation and halts metastasis. These observations suggest that highly aggressive tumors can be immobilized, that we can thereby prevent their ability to intravasate at the site of the primary tumor and, as a consequence, limit their metastatic ability. This application proposes to investigate the mechanism of migration responsible for intravasation with the use of intravital imaging and our quantitative metastasis model in three specific aims: Specific aim #1 is to identify the biological mechanism and route of tumor cell intravasation. Specific aim #2 To elucidate the molecular mechanism by which the tetraspanin CD151 regulates intravasation during metastatic dissemination in vivo. Specific aim #3 is to use Artificial Transcription Factors (ATFs) in conjunction with positive selection in an in vivo metastasis model in order to identify molecular targets that inhibit tumor cell migration and intravasation. Project Relevance: Metastasis is the primary cause of cancer related deaths. In order to metastasize, tumor cells have mobilize themselves and enter the circulation. The proposed work is focused on identifying and understanding the mechanisms by which tumor cells can be immobilized.