RI COBRE: MECHANISMS OF ANGIOGENESIS IN CHONDROSARCOMA

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 软骨肉瘤是一种原发的骨肿瘤，预后很差，因为这种疾病的患者会发生致命的肺转移。由于这些肿瘤对细胞毒性化疗具有耐药性，因此存活率并未提高。抗血管生成治疗是一种相对较新的治疗策略，但尚未尝试用于软骨肉瘤。我们的长期目标是通过确定适当的分子靶点，为将这种治疗方法应用于临床奠定基础。诱导血管生长的信号来源于对缺氧的正常生理反应，主要受缺氧诱导因子-1(HIF-1)的调节，以及肿瘤细胞中的遗传异常导致促血管生成因子和抗血管生成因子之间的平衡失调。我们的总体假设是，在软骨肉瘤中，由组蛋白脱乙酰酶4(HDAC4)、矮小相关转录因子2(Runx2)和血管内皮生长因子(VEGF)组成的调控生长板中软骨细胞成熟和软骨内成骨的途径被重新激活，并导致血管生成。 具体目的：(1)明确HDAC4和Runx2在软骨肉瘤血管内皮生长因子表达调控中的作用，评价HDAC4/Runx2正常表达对血管生成的生物学影响。 (2)探讨HIF-1/CXCR4/SDF1对基质金属蛋白酶-1和血管内皮生长因子的调节作用。 (3)分析Runx2下调p16表达的机制及其对血管生成的影响。 意义：了解血管生成的机制是制定合理的抗血管生成治疗策略的必要的第一步。此外，更好地了解软骨肉瘤中的血管生成途径可能有助于全面了解软骨生物学、软骨组织工程以及其他肿瘤中血管生成的机制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Chondrosarcoma is a primary bone tumor with a poor prognosis as patients with this disease develop fatal pulmonary metastases. Survival has not improved since these tumors are resistant to cytotoxic chemotherapy. Antiangiogenesis therapy is a relatively new treatment strategy yet to be tried for chondrosarcoma. Our long-term goal is to provide the groundwork for bringing this treatment into clinical practice by identifying the appropriate molecular targets. The signals that induce growth of blood vessels arise from the normal physiologic response to hypoxia, primarily regulated by hypoxia inducing factor-1 (HIF-1), and genetic aberrations in tumor cells resulting in dysregulation of the balance between pro- and antiangiogenic factors. Our overall HYPOTHESIS is that the pathway regulating chondrocyte maturation and endochondral ossification in the growth plate comprised of histone deacetylase 4 (HDAC4), runt-related transcription factor 2 (Runx2), and vascular endothelial growth factor (VEGF), is reactivated in chondrosarcoma and causes angiogenesis. Specific Aims: (1) Define the role of HDAC4 and Runx2 in the regulation of VEGF expression in chondrosarcoma and assess the biologic impact of normalizing HDAC4/Runx2 expression on angiogenesis. (2) Investigate the role of HIF-1/CXCR4/SDF1 mediated regulation of MMP-1 and VEGF. (3) Analyze the mechanism of Runx2 downregulation of p16 expression and the effect on angiogenesis. Significance: An understanding of the mechanisms of angiogenesis is a necessary first step in developing rationally based antiangiogenic treatment strategies. In addition, a better understanding of angiogenic pathways in chondrosarcoma may contribute to the overall understanding of cartilage biology, tissue engineering of cartilage, and mechanisms of angiogenesis in other tumors.