Center of Biomedical Research Excellence (COBRE) for Skeletal Health and Repair

Mechanisms of Angiogenesis in Chondrosarcoma

Principal Investigator: Richard Terek, MD

Abstract

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. The 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 anti- angiogenic factors.

The 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. The 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 Aim 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.
  • Specific Aim 2:
    • Investigate the cross-talk between HIF-1 mediated regulation of VEGF and Runx2 regulation of VEGF.
    • 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 of patients with chondrosarcoma.

Funding Awarded: NIH/NCI R01CA166089

Publications:

  1. Bluman EM, Sun X, Lin C, Coulie PG, Meitner PA., Terek RM: Lysis of human chondrosarcoma cells by cytolic T Lymphocytes recognizing a MAGE-A3 antigen presented by HLA-A1 molecules .J Orthop Res. 2007 May;25(5):678-84
  2. Tashjian RZ, Lin C, Aswad B, Terek, RM: 11β-Hydroxysteroid Dehydrogenase Type 1 Expression in Periprosthetic Osteolysis. Orthopedics, 2008; 31:545.
  3. Terek RM, Sun X, Allen S: Molecular Mechanisms of Angiogenesis in Chondrosarcoma. US Musculoskeletal Review 2008; 3(1):48.
  4. Guise TA, O’Keefe R, Randall RL, Terek RM: Molecular Biology and Therapeutics in Musculoskeletal Oncology, J Bone and Joint Surgery (Am) 2009;91-A(3):724-732.
  5. Sun X, Wei L, Chen Q, Terek RM. HDAC4 represses vascular endothelial growth factor expression in chondrosarcoma by modulating RUNX2 activity. J Biol Chem. 2009 Aug 14;284(33):21881-90.
  6. Sun X, Wei L, Chen Q, Terek RM. CXCR4/SDF1 mediate hypoxia induced chondrosarcoma cell invasion through ERK signaling and increased MMP1 expression. Mol Cancer. 2010 Jan 26;9:17.
  7. Wei L, Kanbe K, Lee M, Wei X, Pei M, Sun X, Terek R, Chen Q. Stimulation of Chondrocyte hypertrophy by chemokine stromal cell-derived factor 1 in the chondro-osseous junction during endochondral bone formation. Dev Biol. 2010 May 1;341(1):236-45.
  8. Schraeder TL, Terek RM, Smith CC. Clinical evaluation of the knee. N Engl J Med. 2010 Jul 22;363(4):e5.Guan Y, Chen Q, Yang X, Haines P, Pei M, Terek R, Wei X, Zhao T, and Wei L: 9.Subcellular Relocation of Histone Deacetylase 4 Regulates Growth Plate Chondrocyte Differentiation through Ca2+/Calmodulin-Dependent Kinase IV. American J Physiology - Cell Physiology, 2012 Jul;303(1):C33-40.
  9. Wei F, Zhou J, Wei X, Zhang J, Fleming BC, Terek R, Pei M, Chen Q, Liu T, Wei L: Activation of Indian Hedgehog Promotes Chondrocyte Hypertrophy and Upregulation of MMP-13 in Human Osteoarthritic Cartilage. Osteoarthritis and Cartilage, 2012 Jul;20(7):755-63.
  10. Jayasuriya CT, Goldring MB, Terek R, Chen Q. Matrilin-3 induction of IL-1 receptor antagonist is required for up-regulating collagen II and aggrecan as well as down-regulating ADAMTS-5 gene expression. Arthritis Res Ther. 2012 Sep 11;14(5):R197. PubMed PMID: 22967398; PubMed Central PMCID: PMC3580507.
  11. Xiaojuan Sun, Cherie Charbonneau, Wei Lei, Wentian Yang, Qian Chen, and Richard Terek: CXCR4-targeted Therapy Inhibits VEGF Expression and Chondrosarcoma Angiogenesis and Metastasis. Mol Cancer Ther. 2013 Jul;12(7):1163-70. PubMed PMID: 23686836; PubMed Central PMCID: PMC3707941.
  12. Yang W, Wang J, Moore DC, Liang H, Dooner M, Wu Q, Terek R, Chen Q, Ehrlich MG, Quesenberry PJ, Neel BG. Ptpn11 deletion in a novel progenitor causes metachondromatosis by inducing hedgehog signaling. Nature. 2013 Jul 25;499(7459):491-5. PubMed PMID: 23863940.
Center of Biomedical Research Excellence (COBRE) for Skeletal Health and Repair