Underlying Mechanisms in Angiosarcoma

血管肉瘤的潜在机制

基本信息

批准号：
10058167
负责人：
M. LUISA IRUELA-ARISPE
金额：
$ 28.22万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10058167
关键词：
Underlying Mechanisms Angiosarcoma

项目摘要

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.

描述（由申请人提供）：血管肉瘤是由血管内皮细胞转化产生的肿瘤，它们具有高度侵袭性，存活率低并且迅速进展至终末状态，虽然自发性疾病很少见（占肉瘤的 2%），但血管肉瘤是一种常见的肿瘤。公认的乳腺创伤和癌症放射治疗的并发症，以及由于这种继发性疾病而导致的潜在死亡。与其他肿瘤不同，这种继发性疾病的遗传和环境因素的证据有限。研究其生物学或探索潜在治疗方式的模型目前的血管肿瘤治疗标准仅涉及手术切除和放疗并不能提高生存率，因此，除非获得与疾病基本机制相关的信息，否则当前的治疗不会改变。目前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，通过对小鼠进行转座子筛选，我们已经确定了 81 个与血管异常出现相关的基因。根据外显子组测序的结果，其中一些基因在人类血管肉瘤中也发现了突变，这些基因的子集与细胞骨架动力学、增殖和信号传导有关，其他子集与 p53 和辐射敏感性的调节有关。这些突变中的一些在正常内皮细胞中的复制引起转化，包括软琼脂测定中的贴壁依赖性生长和裸鼠中的肿瘤生长，这些特征提供了背景和原理。为了扩展这项研究并探索触发内皮转化的机制，在这项资助申请中，我们提出了实验来探索 3 个基因子集的生物学，这些基因似乎作为血管肉瘤的致病基因一起发挥作用，并阐明导致血管肉瘤的分子机制。核心假设是，RASA1 中的内皮突变容易发生，但只有当 ELMO1 和/或 ZMIZ1 也发生突变时，才会发生转化。介导血管肉瘤典型的细胞周期控制丧失和高度侵袭性特性为了检验这一假设，我们提出：1) 表征血管肉瘤内皮转化所需的关键分子相互作用和遗传相互依赖性，2) 定义 RASA1 在失调的内皮细胞中的作用。考虑到血管瘤患者的生存率很低，而且放射治疗导致这种肿瘤类型的发病率不断上升，我们认为旨在了解触发和维持这种疾病的机制的研究是重要的。最重要的相关性。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

State-of-the-Art Methods for Evaluation of Angiogenesis and Tissue Vascularization: A Scientific Statement From the American Heart Association.

评估血管生成和组织血管化的最先进方法：美国心脏协会的科学声明。

DOI：
10.1161/res.0000000000000054
发表时间：
2015-05-22
期刊：
Circulation Research
影响因子：
20.1
作者：
Simons M;Alitalo K;Annex BH;Augustin HG;Beam C;Berk BC;Byzova T;Carmeliet P;Chilian W;Cooke JP;Davis GE;Eichmann A;Iruela-Arispe ML;Keshet E;Sinusas AJ;Ruhrberg C;Woo YJ;Dimmeler S;American Heart Association Council on Basic Cardiovascular Sciences and Council on Cardiovascular Surgery and Anesthesia
通讯作者：
American Heart Association Council on Basic Cardiovascular Sciences and Council on Cardiovascular Surgery and Anesthesia

Metastasis of Circulating Tumor Cells: Speed Matters.

循环肿瘤细胞的转移：速度很重要。