Underlying Mechanisms in Angiosarcoma

 描述(申请人提供)：血管肉瘤是血管内皮细胞转化而产生的肿瘤。它们具有高度侵袭性，存活率低，进展迅速，处于晚期状态。虽然自发性疾病很少见(肉瘤的2%)，但血管肉瘤是乳房创伤和癌症放射治疗的公认并发症，随后可能会因这种继发性疾病而死亡。关于血管肿瘤发生的遗传和环境因素的证据有限。与其他肿瘤不同的是，没有动物模型来研究其生物学或探索潜在的治疗方式。目前对血管肿瘤的治疗标准只包括手术切除。化疗和放疗并不能提高存活率。因此，除非与疾病的基本机制有关的信息得到解决，否则目前的治疗方法不会改变。目前这一系列研究的长期目标是确定血管肉瘤发生的遗传、细胞和分子机制。在小鼠中使用转座子筛选，我们已经确定了81个与血管异常、血管肉瘤和海绵状肿瘤的出现相关的基因。根据外显子组测序的结果，在人类血管肉瘤中也发现了其中一些基因的突变。这些基因的亚群与细胞骨架动力学、增殖和信号转导有关。P53和辐射敏感性的调节中的其他亚群。在正常内皮细胞中复制这些突变中的一些会引起转化，包括软琼脂试验中的锚定非依赖性生长和裸鼠体内的肿瘤生长。这些特征为扩大这项研究和探索触发内皮转化的机制提供了背景和理论基础。在这项拨款申请中，我们建议进行实验，以探索似乎共同作用的3个基因的子集作为血管肉瘤的致病基因的生物学，并阐明导致放松调控的增殖和侵袭性的分子机制。中心假设是RASA1中的内皮细胞突变易于发生，但只有当ELMO1和/或ZMIZ1也发生突变时才会转化。这三个基因结合在一起，共同调节细胞周期控制的丧失和血管肉瘤典型的高侵袭性。为了验证这一假设，我们建议：1)表征血管肉瘤中内皮转化所需的关键分子相互作用和遗传相关性；2)确定RASA1在非调控的内皮细胞增殖中的作用。考虑到患有血管肿瘤的患者存活率很低，以及放射治疗导致这种肿瘤类型的发病率上升，我们认为，旨在了解引发和维持这种疾病的机制的研究具有至关重要的意义。

 DESCRIPTION (provided by applicant): Angiosarcomas are tumors arising from transformation of vascular endothelial cells. They are highly invasive, have low survival rates and progress rapidly to a terminal state. While spontaneous disease is rare (2% of sarcomas), angiosarcomas are a recognized complication of breast trauma and cancer radiotherapy, with subsequent potential mortality due to this secondary disease. Evidence for genetic and environmental factors underlying the emergence of vascular tumors is limited. Unlike other tumors, there are no animal models in which to study its biology or explore potential treatment modalities. The current standard of care for vascular tumors involves surgical resection alone. Chemotherapy and radiation do not improve survival. Therefore, current treatment will not change unless information related to the basic mechanisms of disease are addressed. The long term goal of the current line of investigation is to identify genetic, cellular and molecular mechanisms underlying the development of angiosarcomas. Using a transposon screen in mice, we have identified 81 genes that are associated with the emergence of vascular anomalies, angiosarcomas, and cavernous tumors. Some of these genes were also found mutated in human angiosarcomas, as per findings from exome sequencing. Subsets of these genes have been implicated in cytoskeletal dynamics, proliferation and signaling. Other subsets in the regulation of p53 and radiation sensitivity. Replication of some of these mutations in normal endothelium elicits transformation, including anchorage-independent growth in soft agar assays and tumor growth in nude mice. These features provide the background and rationale to expand this research and explore the mechanisms that trigger endothelial transformation. In this grant application, we propose experiments to explore the biology of a subset of 3 genes that appear to work together as causative genes for angiosarcoma and to clarify the molecular mechanisms that lead to deregulated proliferation and invasiveness. The central hypothesis is that endothelial mutations in RASA1 predispose, but are only transforming if either ELMO1 and / or ZMIZ1 are also mutated. In combination these 3 genes work together to mediate loss of cell-cycle control and highly invasive properties typical of angiosarcomas. To test this hypothesis we propose: 1) To characterize critical molecular interactions and genetic interdependencies required for endothelial transformation in angiosarcoma and 2) To define the contribution of RASA1 in deregulated endothelial proliferation. Considering the poor survival rate of individuals with vascular tumors and the rising incidence of this tumor type as a consequence of radiation therapy, we believe that research aimed at understanding the mechanisms that trigger and sustain this disease are of paramount relevance.