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

描述(由申请者提供)：本建议书描述了一项为期5年的癌症生物学研究发展培训计划。首席研究人员(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基础，以及他的导师(Quigley博士)的指导，以及与现有研究人员(Stuhlmann博士和Blancafort博士)的合作互动，以扩展他的科学技能，并调解他向癌症研究的独立职业生涯的过渡。项目摘要：虽然转移到重要器官是致命的，但它是一种低效的生物学过程，适合于治疗干预。进行干预的第一步是确定合适的分子靶点和机制。肿瘤细胞扩散的主要要求之一是细胞能够动员自己，进入血管内，并离开原始肿瘤部位。这项应用提出了表征CD151控制的迁移介导的血管内凝血的机制，并寻找新的分子靶点来调控体内的迁移。我们已经证明，针对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可防止血管内凝血并阻止肿瘤转移。这些观察表明，高度侵袭性的肿瘤可以被固定，因此我们可以防止它们在原发肿瘤部位的血管内扩散，从而限制它们的转移能力。这项应用建议利用活体成像和我们的定量转移模型在三个特定目标上研究肿瘤细胞内转移的机制：特定目标1是确定肿瘤细胞内转移的生物学机制和途径。具体目的#2阐明Tetraspanin CD151在体内转移转移过程中调节血管内转移的分子机制。具体目的#3是在体内转移模型中联合使用人工转录因子(ATF)和阳性选择，以确定抑制肿瘤细胞迁移和血管内皮细胞生长的分子靶点。项目相关性：转移是癌症相关死亡的主要原因。为了转移，肿瘤细胞已经动员起来，进入循环。这项拟议的工作侧重于识别和了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.