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

描述（由申请人提供）：此提案描述了一个为期5年的癌症生物学研究职业发展培训计划。首席研究员（Zijlstra博士）概述了一项计划，利用已建立的基础设施和研究支持，结合他的导师（Quigley博士）的指导，以及与已建立的研究人员（Stuhlmann博士和Blancafort博士）的合作互动，扩大他的科学技能，并调解他向癌症研究独立职业的过渡。项目总结：肿瘤转移到重要器官是致命的，但它是一个低效的生物过程，适合进行治疗干预。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具有自我动员、内渗和离开原肿瘤部位的能力。本应用旨在表征CD151调控的迁移介导内渗机制，并发现体内调控迁移的新分子靶点。我们已经证明，靶向CD151的功能阻断抗体破坏了不同肿瘤细胞系共享的体内肿瘤细胞运动机制。由此产生的体内运动抑制可防止体内渗透并阻止转移。这些观察结果表明，高侵袭性肿瘤可以被固定化，因此我们可以阻止它们在原发肿瘤部位内渗的能力，从而限制它们的转移能力。本申请旨在通过活体成像和我们的定量转移模型来研究肿瘤细胞内渗的迁移机制，具体目的有三个：具体目的1是确定肿瘤细胞内渗的生物学机制和途径。特异性目的2：阐明四联蛋白CD151在体内转移传播过程中调控体内循环的分子机制。具体目标#3是在体内转移模型中使用人工转录因子（ATFs）与阳性选择相结合，以确定抑制肿瘤细胞迁移和体内浸润的分子靶点。项目相关性：转移是癌症相关死亡的主要原因。为了转移，肿瘤细胞必须自我动员并进入循环系统。提出的工作重点是识别和理解肿瘤细胞可以固定的机制。

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.