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（由申请人提供）：血管内皮细胞瘤是由血管内皮细胞转化引起的肿瘤。它们具有高度侵袭性，存活率低，并迅速发展为终末状态。虽然自发性疾病是罕见的（2%的肉瘤），血管瘤是公认的乳腺创伤和癌症放疗的并发症，随后由于这种继发性疾病的潜在死亡率。血管性肿瘤发生的遗传和环境因素的证据是有限的。与其他肿瘤不同，没有动物模型来研究其生物学或探索潜在的治疗方式。目前血管肿瘤的标准治疗仅涉及手术切除。化疗和放疗不能提高生存率。因此，除非与疾病的基本机制相关的信息得到解决，否则目前的治疗方法不会改变。目前研究的长期目标是确定血管瘤发生的遗传、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，这些基因中的一些也在人类血管瘤中发现突变。这些基因的亚组与细胞骨架动力学、增殖和信号传导有关。其他亚群在调节p53和辐射敏感性中的作用。在正常的内皮细胞转化中复制这些突变，包括软琼脂试验中的锚定非依赖性生长和裸鼠肿瘤生长。这些特征提供了背景和理论基础，以扩大这项研究，并探讨触发内皮细胞转化的机制。在这项资助申请中，我们提出了实验来探索3个基因的一个子集的生物学，这些基因似乎作为血管肉瘤的致病基因一起工作，并阐明导致增殖和侵袭性失调的分子机制。中心假设是RASA 1中的内皮突变易患，但只有当ELMO 1和/或ZMIZ 1也突变时才发生转化。这3个基因共同作用，介导细胞周期控制的丧失和血管瘤典型的高度侵袭性。为了验证这一假设，我们提出：1）描述血管肉瘤中内皮细胞转化所需的关键分子相互作用和遗传相互依赖性; 2）确定RASA 1在内皮细胞增殖失调中的作用。考虑到血管肿瘤患者的生存率很低，并且由于放射治疗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具有重要意义。

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