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乙酰肝素在调节溶骨性骨转移中的作用，并利用这些知识开发新的治疗方法。硫酸乙酰肝素结合到控制细胞信号传导的效应分子宿主上并调节其功能（例如，生长因子、趋化因子），包括调节转移和骨质溶解的因子。最近的研究表明，乙酰肝素酶介导的硫酸乙酰肝素的裂解通过释放10-20个糖残基长的片段来增强硫酸乙酰肝素的生物活性，所述片段比完整的硫酸乙酰肝素链更好地增强生长因子的活性。乙酰肝素酶活性促进某些肿瘤中的血管生成和转移，并且乙酰肝素酶的表达升高与某些类型的癌症中的不良预后相关。然而，乙酰肝素酶在溶骨性转移中的作用完全未知。我们已经取得了几个惊人的发现，支持的假设，在多发性骨髓瘤和乳腺癌的乙酰肝素酶的表达升高促进溶骨性骨转移。我们的近期目标是通过增强乙酰肝素酶在肿瘤细胞中的表达并在动物模型中测试其生长、转移和溶骨性行为来测试这一假设，所述动物模型包括乙酰肝素酶升高的细胞自发地从皮下部位转移到骨的新模型。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。目标1：自发和实验转移的动物模型将用于确定升高的乙酰肝素酶表达对骨转移的影响。目标二：将肿瘤细胞直接注射到骨中，并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，将在体内和体外检查乙酰肝素酶的作用机制，包括检查乙酰肝素酶活性对破骨细胞刺激因子的影响。目标3：将在动物模型中测试乙酰肝素酶抑制剂，以检查这些化合物的潜在治疗效果，并确认乙酰肝素酶在溶骨性转移中的作用。这项工作将提供一个全面的了解乙酰肝素酶和硫酸乙酰肝素降解如何调节溶骨性骨转移，并保持潜在的发现新的治疗靶点，用于控制骨内肿瘤。

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.