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: 6726626
• 负责人: CEZARY MARCINKIEWICZ
• 金额: $ 22.57万
• 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/6726626
• 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（由申请人提供）：实体瘤的生长高度取决于血管生成。在这个新容器形成过程中，在内皮细胞上表达的整联蛋白是重要的介体。这些整合素功能的抑制是目前是癌症研究的方向之一。此外，在癌细胞上表达的整联蛋白参与转移过程中这些细胞的迁移。在拟议的研究计划中，我们将研究CT 1131整联蛋白（VLA-1），该整合素（VLA-1）被认为是特定的胶原蛋白IV受体。我们将研究将研究重点放在VLA-1，obst毒素和毒蛇毒素的两个抑制剂上。它们俩都属于崩解蛋白家族，并且是VLA-1的低分子质量抑制剂（4.2 kDa）。这些崩解蛋白的活性已定位在其整联蛋白结合环中，作为活性序列KTS。在体内的鸡肉凸轮模型和在体外的管EC形成测定中，c. cast亵的血管抑制剂在体内表现出有效的血管静脉活性。此外，casd肽抑制了同步小鼠模型中的刘易斯肺癌的发展。 KTS-杂型蛋白的活性将进一步测试是在裸小鼠中由小鼠MV3，HS.939T，A-939T，A-375，C32和A2058中的小鼠黑色素瘤B 16和M-​​3细胞系诱导的生长肿瘤。这些细胞线向肺的转移中的参与VLA-1将在体内使用Syngeneic和Nude小鼠在体内进行研究。为了解释含有KTS拆解蛋白的血管抑制作用的机制，将进行一系列实验以研究其对微血管EC的影响。初步数据表明，cas灭素在这些细胞中诱导凋亡并抑制它们的增殖。基于先前的报告，表明VLA-1参与信号转导途径取决于MAPK的信号转导途径，将评估KTS-二脑蛋白对该途径激活的影响。此外，将提出胶原蛋白凝胶中的径向迁移测定。该体外测定模仿了基底膜溶解后新血管形成早期EC的运动。两种崩解蛋白在该模型中的EC运动中的影响将进行测试。 s亵及其天然发生的模拟毒素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。总而言之，与含有分解蛋白的KTS的工作可能会更好地理解VLA-1在癌症进展和转移中的参与，并有助于理解VLA-1在血管生成中的作用。