Role of heparanase in osteolytic bone metastasis

描述(由申请人提供)： 这项工作的长期目标是确定硫酸肝素在调节溶骨性骨转移中的作用，并利用这一知识开发新的治疗方法。硫酸肝素与一系列控制细胞信号的效应分子(如生长因子、趋化因子)结合并调节其功能，包括调节转移和骨溶解的因子。最近的研究表明，乙酰肝素酶介导的硫酸肝素裂解通过释放10-20个糖基残基的片段来增强硫酸肝素的生物活性，这些片段比完整的硫酸肝素链更能增强生长因子的活性。在某些肿瘤中，肝素酶活性促进血管生成和转移，在某些类型的癌症中，肝素酶表达升高与预后不良有关。然而，肝素酶在溶骨性转移中的作用是完全未知的。我们已经有了几个惊人的发现，支持了乙酰肝素酶在多发性骨髓瘤和乳腺癌中的高表达促进溶骨性骨转移的假设。我们的直接目标是通过增强肿瘤细胞中乙酰肝素酶的表达，并在动物模型中测试其生长、转移和溶骨行为来验证这一假设，其中包括一种新的模型，在该模型中，乙酰肝素酶升高的细胞自发从皮下部位转移到骨。这一目标将通过使用骨髓瘤和乳腺癌细胞执行三个特定目标来实现。目的：采用自发转移和实验性转移的动物模型，研究乙酰肝素酶表达升高对骨转移的影响。目的：将肿瘤细胞直接注射入骨中，分析乙酰肝素酶表达升高对骨内肿瘤生长和骨转换的影响。此外，将在体内和体外研究肝素酶的作用机制，包括检测肝素酶活性对破骨细胞刺激因子的影响。目的：在动物模型中测试乙酰肝素酶的抑制剂，以检验这些化合物的潜在治疗作用，并确认肝素酶在溶骨转移中的作用。这项工作将全面了解肝素酶和肝素硫酸盐的降解如何调节溶骨性骨转移，并有可能发现新的治疗靶点来控制骨内肿瘤。

DESCRIPTION (provided by applicant): The long-term objective of this work is to determine the role of heparan sulfate in regulating osteolytic bone metastasis and to use this knowledge to develop novel therapies. Heparan sulfates bind to, and regulate the function of, a host of effector molecules that control cell signaling (e.g., growth factors, chemokines), including factors that regulate metastasis and osteolysis. Recent studies demonstrate that heparanase mediated cleavage of heparan sulfate enhances the biological activity of heparan sulfate by releasing fragments 10-20 sugar residues long that potentiate the activity of growth factors better than do intact heparan sulfate chains. Heparanase activity promotes angiogenesis and metastasis in some tumors and elevated expression of heparanase is associated with a poor prognosis in some types of cancer. However, the role of heparanase in osteolytic metastasis is wholly unknown. We have made several striking discoveries supporting the hypothesis that elevated expression of heparanase in multiple myeloma and breast cancer promotes osteolytic bone metastasis. Our immediate goal is to test this hypothesis by enhancing heparanase expression in tumor cells and testing their growth, metastatic and osteolytic behavior in animal models including a new model in which cells with elevated heparanase spontaneously metastasize from subcutaneous sites to bone. This goal will be accomplished by execution of three specific aims using both myeloma and breast cancer cells. Aim 1: Animal models of both spontaneous and experimental metastasis will be used to determine the effect of elevated heparanase expression on metastasis to bone. Aim 2: Tumor cells will be directly injected into bone and the effect of elevated heparanase expression on the growth of tumor within the bone and on bone turnover will be analyzed. In addition, the mechanism of heparanase action will be examined both in vivo and in vitro, including examining the effect of heparanase activity on osteoclast-stimulating factors. Aim 3: Inhibitors of heparanase will be tested in the animal models to examine the potential therapeutic effects of these compounds and to confirm the role of heparanase in osteolytic metastasis. This work will provide a comprehensive understanding of how heparanase and degradation of heparan sulfate regulates osteolytic bone metastasis and holds potential for discovery of new therapeutic targets for controlling tumors within bone.