For more than a decade, I have focused my laboratory research on one of the most difficult cancers to cure—chondrosarcoma. This bone cancer, composed of malignant cartilage cells, has presented a formidable scientific challenge. By pursing a variety of approaches, however, my research has resulted in the identification and cloning of a novel gene (CSAGE) expressed in chondrosarcoma, the further elucidation of mutations in classic tumor suppressor genes and mechanisms of chemotherapy resistance, and in vitro testing of immunotherapy for this uncommon and difficult to treat disease.

At the AAOS research symposium Developmental Biology in Orthopaedics (DBO) this past October, I had the opportunity to present my research and observations on angiogenesis in chondrosarcoma. Currently, my laboratory colleagues and I are focused on the mechanisms by which these tumors induce formation of blood vessels, which is necessary for tumor growth and development of metastases.

If we can understand how the process of angiogenesis—the formation of new blood vessels—is regulated in chondrosarcoma, we may be able to identify appropriate molecular targets for anti-angiogenic treatment strategies. We have made the following four observations regarding angiogenesis in chondrosarcoma:

1. Chondrosarcoma grades II and III show increased microvascularity.
2. They also exhibit increased expression of vascular endothelial growth factor (VEGF).
3. The increased expression of VEGF during hypoxia is mediated by the hypoxia inducing factor-1 alpha (HIF-1a).
4. A new mechanism of VEGF expression in chondrosarcoma involves the transcription factor runt-related transcription factor 2 (Runx2).

The problem with chondrosarcoma

Chondrosarcomas are resistant to treatment primarily because they are relatively unresponsive to chemotherapy and radiation therapy, the standard adjuvant treatments used in conjunction with surgery. My initial interest in angiogenesis was stimulated by a new treatment paradigm based on understanding how tumors induce angiogenesis from surrounding normal tissue. My ultimate goal, of course, is to block that crucial interaction.

Angiogenesis is a tightly regulated process that occurs during normal growth and development and healing, but becomes unregulated during growth of neoplasms. Similar to all neoplasms, the two most important traits of cancer are unrestrained growth and development of metastases. The ability to induce sustained angiogenesis in all tumors, including chondrosarcoma, is a necessary condition for both of these traits.

Specifically, our work has demonstrated that grade II and III chondrosarcomas have more microvascularity than benign or grade I tumors. This is interesting because cartilage is an avascular tissue and microvascularity correlates with clinical behavior, as it is primarily grade II and III chondrosarcomas that metastasize. Thus, chondrosarcoma development is linked to angiogenesis at higher grades.

The impact of VEGF

VEGF is one of the most important proangiogenic molecules. VEGF is frequently overexpressed in higher grade tumors and our published work has demonstrated upregulation of VEGF in chondrosarcoma. Of note, VEGF expression is determined by normal physiologic pathways relating to hypoxia and genetic abnormalities that accumulate as tumors develop.

By utilizing molecular biology techniques to analyze gene expression in chondrosarcoma cell lines cultured in the laboratory under normal oxygen levels as compared to hypoxic conditions, we have shown that the normal physiologic response to hypoxia mediated by HIF-1a is intact in chondrosarcoma and increases expression of VEGF.

Through my collaborations with Qian Chen, PhD, Lei Wei, MD, PhD, and Xiaojuan Sun, MD, PhD at Brown University, we have analyzed chondrosarcoma for molecular pathways that regulate angiogenesis during endochondral ossification in the growth plate. In the growth plate, avascular cartilage becomes vascularized as it transforms into bone during endochondral ossification. The paradigm is that embryologic pathways from phenotypically related tissue that facilitate growth and metastatic behavior are re-expressed by the tumor cells.

At the DBO symposium, I had the opportunity to discuss a new mechanism of VEGF expression in chondrosarcoma involving the transcription factor Runx2 that regulates endochondral ossification and angiogenesis in the growth plate. This implies that an antiangiogenic treatment would need to take into account both the genetic abnormalities and the hypoxia-related factors that are driving expression of proangiogenic cytokines in the tumor.

The DBO was an extraordinary forum to brainstorm and develop collaborations with developmental biologists from around the world who are also working on musculoskeletal tissues to advance our understanding of orthopaedic diseases. As someone who is working at the interface between clinical medicine and basic science, I look forward to continuing these collaborative efforts to improve our understanding of this bone tumor and the outlook for chondrosarcoma patients.

Richard M. Terek, MD, is an associate professor of orthopaedic surgery at Brown University and director of orthopaedic oncology at Rhode Island Hospital. His research has been supported by grants from the Orthopaedic Research and Education Foundation. He serves on the AAOS Research Development Committee and helps direct the annual research symposia. He can be reached at (401) 457-1555 or Richard_Terek@Brown.edu