Underlying Mechanisms in Angiosarcoma

血管肉瘤的潜在机制

• 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
• 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

 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（由适用提供）：血管肉瘤是由血管内皮细胞转化引起的肿瘤。它们具有高度侵入性，生存率较低，并且迅速发展为终末状态。尽管赞助商很少见（占肉瘤的2％），但血管肉瘤是公认的乳腺外伤和癌症放射疗法的并发症，由于这种继发性疾病而导致随后的潜在死亡率。血管肿瘤出现的遗传和环境因素的证据是有限的。与其他肿瘤不同，没有动物模型可以研究其生物学或探索潜在的治疗方式。当前对血管肿瘤的护理标准仅涉及手术切除。化学疗法和放射线不能提高生存率。因此，除非解决与疾病基本机制有关的信息，否则当前的治疗不会改变。当前研究线的长期目标是确定血管肉瘤发展的遗传，细胞和分子机制。使用小鼠中的转座筛网，我们已经确定了与血管异常，血管肉瘤和海绵状肿瘤的出现有关的81个基因。根据外显子组测序的发现，这些基因中的某些基因也被发现在人体肉瘤中突变。这些基因的子集已在细胞骨架动力学，增殖和信号传导中实现。 p53和辐射敏感性调节中的其他子集。在正常的森植物中的某些突变的复制引起了转化，包括软琼脂分析中锚固无关的生长和裸鼠的肿瘤生长。这些功能为扩展这项研究提供了背景和基本原理，并探索了触发森森转化的机制。在此赠款应用中，我们提出了实验，以探索3个基因的子集的生物学，这些基因似乎是血管肉瘤的休闲基因，并阐明导致失调的增殖和侵入性的分子机制。中心假设是RASA1中的内皮突变易感性，但仅在ELMO1和 /或ZMIZ1也被突变时才会转化。结合结合，这三个基因共同介导细胞周期控制的丧失和典型的血管肉瘤的高度侵入性特性。为了检验这一假设，我们提出：1）表征临界分子相互作用和血管肉瘤内皮转化所需的遗传相互依存关系，以及2）定义RASA1在放松管​​制的内皮增殖中的贡献。考虑到由于放射疗法而导致的血管肿瘤个体的存活率较差以及这种肿瘤类型的增加，我们认为旨在理解触发和维持这种疾病的机制的研究至关重要。

项目成果

Metastasis of Circulating Tumor Cells: Speed Matters.

• DOI: 10.1016/j.devcel.2018.03.005
• 发表时间: 2018-04-09
• 期刊: Developmental cell
• 影响因子: 11.8
• 作者: Freitas VM;Hilfenhaus G;Iruela-Arispe ML
• 通讯作者: Iruela-Arispe ML

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

• 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