Targeting alfa 1beta1 integrin in cancer development

靶向阿尔法 1β1 整合素在癌症发展中的作用

• 批准号: 6862778
• 负责人: CEZARY MARCINKIEWICZ
• 金额: $ 24.22万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6862778
• 关键词: active sites; angiogenesis; apoptosis; athymic mouse; biological signal transduction; cell adhesion; cell adhesion molecules; cell growth regulation; cell line; cell migration; cell motility; cell proliferation; egg /ovum; growth factor; human genetic material tag; inhibitor /antagonist; integrins; laboratory mouse; lung neoplasms; melanoma; metastasis; neoplasm /cancer; neoplastic cell; neoplastic growth; protein sequence; quail; reptile poison; vascular endothelium

DESCRIPTION (provided by applicant): The growing of solid tumors highly depends on angiogenesis. In this new vessel formation process the integrins, expressed on endothelial cells are important mediators. Inhibition of function of these integrins is currently one of the directions in cancer research. Moreover, integrins expressed on cancer cells are involved in migration of these cells during metastasis. In the proposed research plan, we will investigate ct 1131 integrin (VLA-1), which is recognized as a specific collagen IV receptor. We will focus our research on two inhibitors of VLA-1, obtustatin and viperisrastatin. Both of them belong to disintegrin family, and are low molecular mass inhibitors (4.2 kDa) of VLA-1. The activity of these disintegrins has been localized within their integrin-binding loop as an active sequence KTS. Obtustatin showed potent angiostatic activity in the chicken CAM model in vivo, and in tube EC formation assay in vitro. Moreover, obtustatin inhibited Lewis lung cancer development in syngeneic mouse model. The activity of KTS-disintegrins will be further tested on growing tumor induced by mouse melanoma B 16 and M-3 cell lines in the syngeneic mouse, and human melanoma cell lines, MV3, HS.939T, A-375, C32, and A2058 in nude mice. The participation VLA-1 in metastasis of these cell lines to the lung will be investigated in vivo using syngeneic and nude mice. To explain the mechanism of the angiostatic effect of KTS containing disintegrins, series of experiments will be performed to investigate their effect on microvascular EC. The preliminary data showed that obtustatin induced apoptosis in these cells and inhibited their proliferation. Based on the previous reports indicating involvement of VLA-1 in signal transduction pathway dependent on MAPK, the effect of KTS-disintegrins on activation of this pathway will be evaluated. Moreover, radial migration assay in collagen gel will be proposed. That in vitro assay imitates movement of EC during early stage of neovascularization after dissolution of the basement membrane. The effect of both disintegrins in EC motility in this model will be tested. Obtustatin and its naturally occurring analog viperisrastatin may be models for designing of synthetic or recombinant compounds, which may be useful in cancer therapy. In summary, the work with KTS containing disintegrins may lead to the better understanding of the involvement of VLA-1 in cancer progression and metastasis, as well as contribute to an understanding of the role of VLA-1 in angiogenesis.

描述（申请人提供）：实体瘤的生长高度依赖血管生成。在这个新的血管形成过程中，在内皮细胞上表达的整合素是重要的介质。抑制这些整合素的功能是目前癌症研究的方向之一。此外，癌细胞上表达的整合素参与了癌细胞在转移过程中的迁移。在我们的研究计划中，我们将研究ct 1131整合素（VLA-1），这是一种被公认的特异性胶原IV受体。我们将重点研究两种vas -1抑制剂，obtustatin和viperisstatin。它们都属于崩解素家族，是低分子质量（4.2 kDa）的VLA-1抑制剂。这些分解素的活性已经定位在它们的整合素结合环中，作为一个活性序列KTS。在鸡体内CAM模型和体外试管EC形成实验中，奥伐他汀显示出较强的血管抑制活性。此外，在同基因小鼠模型中，他汀抑制Lewis肺癌的发展。我们将进一步测试kts -崩解素在小鼠黑色素瘤B 16和M-3细胞系和裸鼠黑色素瘤细胞系MV3、HS.939T、A-375、C32和A2058诱导的生长肿瘤中的活性。我们将利用同基因小鼠和裸鼠在体内研究VLA-1参与这些细胞系向肺转移的过程。为了解释含有崩解素的KTS的血管抑制作用的机制，我们将进行一系列的实验来研究其对微血管EC的影响。初步结果显示，他汀可诱导这些细胞凋亡，抑制其增殖。基于先前的报道，表明vas -1参与依赖于MAPK的信号转导通路，我们将评估kts -解体素对该通路激活的影响。此外，还将提出在胶原凝胶中进行径向迁移试验。体外实验模拟了基底膜溶解后EC在新生血管形成早期的运动。在这个模型中，我们将测试两种崩解素对EC运动的影响。奥司他汀及其天然类似物维培司他汀可能是设计合成或重组化合物的模型，这可能在癌症治疗中有用。综上所述，对含有崩解素的KTS的研究可能有助于更好地理解VLA-1在癌症进展和转移中的作用，并有助于理解VLA-1在血管生成中的作用。