Abstract
Osteosarcoma has a high mortality rate and remains in need of more effective therapeutic approaches. Survivin is an inhibitor of apoptosis family member protein that blocks apoptosis and drives proliferation in human cancer cells where it is commonly elevated. In this study, we illustrate the superiority of a canine osteosarcoma model as a translational tool for evaluating survivin-directed therapies, owing to the striking similarities in gross and microscopic appearance, biologic behavior, gene expression, and signaling pathway alterations. Elevated survivin expression in primary canine osteosarcoma tissue correlated with increased histologic grade and mitotic index and a decreased disease-free interval (DFI). Survivin attenuation in canine osteosarcoma cells inhibited cell-cycle progression, increased apoptosis, mitotic arrest, and chemosensitivity, and cooperated with chemotherapy to significantly improve in vivo tumor control. Our findings illustrate the utility of a canine system to more accurately model human osteosarcoma and strongly suggest that survivin-directed therapies might be highly effective in its treatment.
Highlights
Osteosarcoma is the most common primary bone tumor in dogs and humans [1,2,3] and is characterized by both aggressive local tissue infiltration and a very high metastatic rate
Cell lines and conditions The Abrams canine osteosarcoma cell line was provided by Dr William Dernell, and the D17 canine osteosarcoma cell line was purchased from American Type Culture Collection
After preliminary validation of survivin as a viable target by confirming elevated survivin expression in 4 of 4 canine osteosarcoma cell lines by Western blot analysis, we proceeded with survivin knockdown experiments
Summary
Osteosarcoma is the most common primary bone tumor in dogs and humans [1,2,3] and is characterized by both aggressive local tissue infiltration and a very high metastatic rate. The dog is a well-established model for spontaneous osteosarcoma in humans, owing to striking similarity in biology and gene expression [3, 4]. The large size of dogs, relative outbreeding, and immunocompetence increase their model potential. Dogs with spontaneous tumors naturally develop therapy resistance and metastasis. Tumor burdens in spontaneously arising cancers of dogs are more similar to humans than the experimentally induced tumors found in murine models, which may be important with regard to biologic factors such as hypoxia and clonal variation. The size of canine tumors allows for serial imaging and tissue collection over time [3, 4]
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