BONE SIALOPROTEIN AND BREAST CANCER METASTASIS

描述：(申请人描述) 转移性癌细胞，就像发育中的胎盘的滋养层细胞一样， 具有侵袭性，必须逃脱免疫监视才能生存。补语由来已久 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)和骨涎蛋白(BSP)已被证明是 许多肿瘤强烈上调，后者为阳性 某些肿瘤侵袭潜能的指标。我们最近发现 循环液相BSP和OPN与补体络合 因子H，这种相互作用阻止了它们随后与 整合素。我们还证明了重组OPN和BSP对小鼠的保护作用 红白血病细胞在膜期免受补体的攻击。我们的 假设OPN和BSP在肿瘤细胞中的表达提供了一种 通过(A)与病毒β3的初始结合获得生存的选择性优势 整合素或CD44在细胞表面，(B)将H因子隔离到 细胞表面和H因子对补体介导的细胞的抑制作用 解体。这一假设将通过进一步的表征来检验 BSP/OPN与H因子结合作用的性质和特异性 具体地说，涉及识别和结合的结构区域将 通过受体和配体的定点突变来确定 使用腺病毒表达系统并阻断多肽和抗体。 BSP和OPN特异性保护乳腺癌细胞的能力 补体最初将在体外使用细胞系进行测试。长期的 目标是在小鼠系统(正常和BSP和OPN爆裂)中测试该模型 包括化学诱导的肿瘤和移植的肿瘤细胞)。这是基本的 肿瘤细胞逃避宿主体液监视的模型机制提供 开发新的诊断程序的新见解以及 颠覆肿瘤细胞的新治疗方案的可能性 从免疫/补体系统中隐形。

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.