RI COBRE: MECHANISMS OF ANGIOGENESIS IN CHONDROSARCOMA

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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 dismal prognosis; most 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 cross-talk between HIF-1 and CXCR4 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; this could ultimately have a substantial impact on the fate of patients with chondrosarcoma. 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.