This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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 clinicalpractice 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. Our hypothesis is based on preliminary data showing that loss of HDAC4 in Chondrosarcoma cells results in increased Runx2 and VEGF expression. Furthermore, a new target of the transcription factor Runx2 has been identified: p16, which is downregulated by Runx2. The p16 protein inhibits VEGF expression, whereas Runx2 upregulates VEGF. Thus, increased Runx2 expression increases VEGF directly and indirectly through decreased p16. The proposed experiments utilize an integrative molecular approach to study the mechanisms by which HDAC4, Runx2, p16, and HIF-1 interact to ultimately drive angiogenesis in Chondrosarcoma.
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 mediated regulation of VEGF and Runx2 regulation of VEGF.(3) Analyze the mechanism of Runx2 downregulation of p16 expression and the effect on angiogenesis. 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 ofpatients with Chondrosarcoma.
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