Abstract
BackgroundOsteosarcoma (OS) is the most common primary bone malignancy. Chemotherapy plays an essential role in OS treatment, potentially doubling 5-year event-free survival if tumour necrosis can be stimulated. The canonical Wnt inhibitor Dickkopf-1 (Dkk-1) enhances OS survival in part through upregulation of aldehyde-dehydrogenase-1A1 which neutralises reactive oxygen species originating from nutritional stress and chemotherapeutic challenge.MethodsA vivo morpholino (DkkMo) was employed to block the expression of Dkk-1 in OS cells. Cell mitosis, gene expression and bone destruction were measured in vitro and in vivo in the presence and absence of doxorubicin (DRB).ResultsDkkMo reduced the expression of Dkk-1 and Aldh1a1, reduced expansion of OS tumours, preserved bone volume and architecture and stimulated tumour necrosis. This was observed in the presence or absence of DRB.ConclusionThese results indicate that administration of DkkMo with or without chemotherapeutics can substantially improve OS outcome with respect to tumour expansion and osteolytic corruption of bone in experimental OS model.
Highlights
Osteosarcoma (OS) is the most common primary bone malignancy
An exon-skipping vivo morpholino was first successfully tested as a treatment for Duchenne Muscular Dystrophy in 2009 [46] and shortly thereafter exon-skipping morpholinos were approved in the USA and Japan
When MOSJ-Dkk-1 cells were exposed to DkkMo, Dkk-1 secretion was dose-dependently inhibited and the rate of accumulation of cells in culture was reduced and when confluent MOSJ-Dkk-1 cells were treated with DkkMo, cell death occurred, phenocopying the parental and control cell lines
Summary
Osteosarcoma (OS) is the most common primary bone malignancy. Chemotherapy plays an essential role in OS treatment, potentially doubling 5-year event-free survival if tumour necrosis can be stimulated. RESULTS: DkkMo reduced the expression of Dkk-1 and Aldh1a1, reduced expansion of OS tumours, preserved bone volume and architecture and stimulated tumour necrosis. This was observed in the presence or absence of DRB. Chemotherapeutic strategies for treating osteosarcoma generally include methotrexate, doxorubicin (DRB) and cisplatin [2] These agents play a positive role in OS treatment, with a reported increase in 5-year event-free survival from 20–40% (surgery alone) to 50–90% with the successful chemotherapeutic intervention [3]. These survival rates can be stratified into responders with greater than 90% tumour necrosis after neoadjuvant therapy versus the remainder, who have 5-year event-free survival rates of 90% and 50–60%, respectively [3]. Reducing the dependence on chemotherapy and the OL burden would significantly improve the impact of OS treatment strategies
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