Mesenchymal stem cell rescue for bone formation following stereotactic radiotherapy of osteosarcoma
Date
2013
Authors
Schwartz, Anthony L., author
Ehrhart, Nicole, advisor
Ryan, Stewart, committee member
James, Susan, committee member
Goodrich, Laurie, committee member
Custis, Jamie, committee member
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Abstract
Background: Osteosarcoma (OSA) is the most common form of primary bone cancer in dogs and humans. Curative-intent treatment options include amputation, radiation therapy or surgical limb salvage for local tumor control combined with adjuvant chemotherapy for prevention or delay of metastatic disease. Stereotactic radiotherapy (SRT) delivers high dose per fraction radiation to a defined tumor volume with relative sparing of surrounding normal tissues. It has been successfully used as a non-surgical limb salvage procedure to achieve local tumor control of spontaneous OSA in dogs. The most common complication observed with this treatment is pathologic fracture of the irradiated bone. Mesenchymal stem cells (MSCs) are multipotent stem cells that have the capability to differentiate into many cell types including bone. The ability of MSCs to differentiate into bone suggests that they should be investigated as a potential therapy to regenerate bone in SRT treated bone. Methods: In experiments described herein, we developed an orthotopic model of canine osteosarcoma in athymic rats and evaluated the ability of SRT to achieve local tumor control. We then evaluated the ability of MSCs to regenerate bone after SRT treatment of OSA. Results: We demonstrated that the canine OSA cell line reliably engrafted in the rat femur. We characterized progression in order to create a reproducible model in which to replicate a clinical scenario to test MSC behavior following SRT of OSA. Two weeks after OSA cell inoculation was identified as the time period when the same clinical characteristics were observed as in canine OSA cases and was chosen to be an appropriate time for SRT treatment. The optimal SRT protocol to achieve local tumor control while minimizing acute radiation effects was determined to be 3 fractions of 12 Gy delivered on consecutive days. MSCs administered either intravenously or intraosseously 2 weeks after SRT revealed no new bone formation; however, decreased tumor necrosis was observed after MSC treatment. Conclusion: The results herein describe the characterization of an orthotopic rat model of canine OSA. This model was useful for the evaluation of different dose and fractionation SRT protocols along with combination adjuvant therapies that may be clinically relevant for canine or human OSA. The administration of MSCs following SRT did not induce new bone growth. The lack of efficacy is most likely due to the radiation-induced alterations to the bone microenvironment that resulted in conditions poorly suited to MSC survival and/or differentiation.
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Subject
mesenchymal stem cells
stereotactic radiation therapy
osteosarcoma