Mechanism of angiogenesis and chondrosarcoma
Mentor: Jack Wands, MD
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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 involving comprise d of histone deacetylase 4 (HDAC4), runt-related transcription factor 2 (Runx2), and vascular endothelial growth factor (VEGF), that regulates chondrocyte maturation and endochondral ossification in the growth plate is reactivated in chondrosarcoma and is a basis for the causes angiogenesis. Our hypothesis is based on preliminary data showing that loss of HDAC4 in chondrosarcoma cell s lines 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.
In addition to VEGF, a new target of the transcription factor Runx2 has been identified: the tumor suppressor gene p16. The p16 protein is both a cell cycle regulator and inhibi tor ts of VEGF expression, whereas Runx2 upregulates VEGF. Thus, increased Runx2 expression increases upregulates VEGF directly and indirectly through p16. Downregulation of decreased p16 is also a cause of additional malignant phenotypes. The proposed experiments utilize an integrative molecular approach to study more fully understand the mechanisms by which HDAC4, Runx2, p16, and HIF -1 interact to ultimately drive angiogenesis in chondrosarcoma.
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.