AKT-Vimentin interaction; a potential role in soft tissue sarcoma progression and

项目摘要/摘要 软组织肉瘤(STS)是一类间充质来源的恶性肿瘤家族。 可能发生在身体的任何地方。由50多个不同的组织亚型组成， ST具有几个明显的特征，包括在以下情况下频繁的局部复发 明确的治疗，显著的化疗耐药，和频繁的转移，特别是对 肺部。这些特征导致了一个令人沮丧的结果，特别是对那些患者来说 具有高度复杂的核型STS组织学，主要包括 平滑肌肉瘤和高度多形性肉瘤(恶性纤维组织细胞瘤 和纤维肉瘤)。为了改善STS的治疗结果，发展STS将是至关重要的 利用分子易损性的潜在STS点的新型试剂； 然而，实现这一紧迫目标的进展受到我们最低限度的了解的阻碍。 STS进展和传播背后的分子决定因素。 包括STS在内的肿瘤细胞对控制生长调节的信号级联反应 过程和恶性过程的其他组成部分，如运动性、侵袭性、 诱导细胞凋亡等。在这些信号机制中，AKT激酶 途径可能在STS的生长和传播中特别重要。 AKT的磷酸化是这一级联反应的关键步骤，HAD与 在STS组织中发现时，STS预后受损。在人类STS细胞系和 人STS移植瘤在免疫功能不全小鼠体内生长，AKT抑制干扰 随着STS的增长，可能通过中断AKT与Vimentin的交互，这是一个关键 也可能具有与肿瘤相关的功能特性的结构蛋白。 我们的小组显然是第一个发现AKT-波形蛋白相互作用存在的人。 我们建议研究这种相互作用的规律，希望了解更多关于 这些相互作用背后的机制，这种相互作用的功能意义 关于它如何影响STS在体内的增殖和转移，最后测试 AKT和Vimentin阻断的临床前治疗方法，希望展示 人STS异种移植小鼠模型与小鼠肉瘤的临床前相关性 模特们。

Project Summary/Abstract Soft tissue sarcomas (STS) constitute a family of mesenchymal -origin malignancies that can occur anywhere in the body. Comprising more than 50 distinct histological subtypes, STS share several distinctive features that include frequent local recurrence after definitive therapy, marked chemoresistance, and frequent metastasis, especially to the lungs. These features translate to a dismal outcome, especially for those patients harboring high grade complex karyotype STS histologies, consisting mainly of leiomyosarcoma and high grade pleomorphic sarcoma ( malignant fibrous histiocytoma and fibrosarcoma). To improve STS therapeutic outcome it will be critical to develop novel agents that capitalize on underlying STS points of molecular vulnerability; however, progress towards this urgent goal are hampered by our minimal understanding of the molecular determinants underlying STS prog ression and dissemination. Tumor cells, including STS, respond to signaling cascades that control growth regulation processes and other components of the malignant process such as motility, invasion, induction of apoptosis, etc. Among theses signaling mechanisms, the AKT kinase pathway may be particularly important in STS growth and dissemination. Phosphorylation of AKT is a critical step in this cascade, had has been associated with impaired STS prognosis when identified in STS tissues. In human STS cell lines and human STS xenografts growing in immuno -incompetent mice, AKT inhibition interferes with STS growth, perhaps by disrupting AKT interaction with vimentin, a critical structural protein that may also have oncologically-relevant functional properties. Our group is apparently the first to identify the existence of AKT -vimentin interactions. We propose to study the regulation of this interaction, hoping to learn more about the mechanisms underlying these interactions, the functional significance of this interaction regarding how it impacts on STS proliferation and metastasis in vivo, and finally to test preclinical therapeutic approaches to AKT and vimentin blockade, hoping to demonstrate preclinical relevance using human STS xenograft mouse models and murine sarcoma models.