BONE SIALOPROTEIN AND BREAST CANCER METASTASIS

骨唾液酸蛋白与乳腺癌转移

• 批准号: 6167539
• 负责人: NEAL S FEDARKO
• 金额: $ 12.28万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2003-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6167539
• 关键词: Adenoviridae; CD44 molecule; bone sialoprotein; breast neoplasms; complement; enzyme activity; erythroleukemia; hyaluronate; integrins; metalloendopeptidases; metastasis; osteopontin; recombinant proteins; site directed mutagenesis; tissue /cell culture

DESCRIPTION: (Applicant's Description) Metastatic cancer cells, like trophoblasts of the developing placenta, are invasive and must escape immune surveillance to survive. Complement has long been thought to playa significant role in the tumor surveillance mechanism. Two small integrin-binding glycoproteins expressed by trophoblasts, osteopontin (OPN, ETA-1) and bone sialoprotein (BSP), have been shown to be strongly up-regulated by many tumors with the latter being a positive indicator of the invasive potential of some tumors. We have recently found that circulating solution phase BSP and OPN are complexed with complement factor H and that this interaction blocks their subsequent binding to integrins. We have also shown that recombinant OPN and BSP can protect murine erythroleukemia cells from attack by complement at the membrane phase. Our hypothesis is that the expression of OPN and BSP in tumor cells provides a selective advantage for survival via (a) initial binding to aV beta 3 integrins or CD44 on the cell surface, (b) sequestration of factor H to the cell surface and factor H-mediated dampening of complement mediated cell lysis. This hypothesis will be tested through further characterization of the nature and specificity of the BSP/OPN binding interaction with factor H. Specifically, the structural regions involved in recognition and binding will be determined through site directed mutagenesis of both receptor and ligand using an adenovirus expression system and blocking peptides and antibodies. The ability of BSP and OPN to specifically protect breast cancer cells from complement will initially be tested in vitro using cell lines. A long term goal is to test the model in murine systems (both normal and BSP and OPN knock outs, with chemically induced tumors and implanted tumor cells). This basic model mechanism for tumor cell evasion of host humoral surveillance provides novel insight into developing new diagnostic procedures as well as the potential for new therapeutic regimens involving subversion of tumor cell cloaking from the immune/complement system.

描述：（申请人的描述） 转移性癌细胞，如发育中胎盘的滋养层细胞， 侵入性，必须逃避免疫监视才能生存。补充长期 被认为在肿瘤监测机制中起着重要作用。 滋养层细胞表达的两种小的整合素结合糖蛋白， 骨桥蛋白（OPN，ETA-1）和骨唾液蛋白（BSP），已被证明是 许多肿瘤强烈上调，后者是一个阳性 一些肿瘤的侵袭潜力的指标。我们最近发现 循环溶液相BSP和OPN与补体复合， 这种相互作用阻断了它们随后与H因子的结合， 整合素我们还表明，重组OPN和BSP可以保护小鼠 红白血病细胞在膜期受到补体的攻击。我们 一种假说认为，骨桥蛋白和BSP在肿瘤细胞中的表达提供了 通过（a）初始结合aV β 3 （B）将因子H螯合到细胞表面上的整合素或CD 44， 细胞表面和 H因子介导的补体介导细胞的抑制 溶解这一假设将通过进一步表征 BSP/OPN与因子H结合相互作用的性质和特异性。 具体来说，参与识别和结合的结构区域将 通过受体和配体的定点诱变来确定 使用腺病毒表达系统和阻断肽和抗体。 BSP和OPN特异性保护乳腺癌细胞免受 最初将使用细胞系在体外测试补体。 长期 目的是在小鼠系统中测试该模型（正常和BSP和OPN敲除 用化学诱导的肿瘤和植入的肿瘤细胞）。这一基本 肿瘤细胞逃避宿主体液监视的模型机制提供了 开发新的诊断程序以及 涉及肿瘤细胞颠覆的新治疗方案的潜力 从免疫/补体系统中隐藏起来