Abstract
Osteosarcoma (OSA) represents the most common primary bone tumor in humans and pet dogs. Little progress has been made with regard to viable treatment options in the past three decades and patients presenting with metastatic disease continue to have a poor prognosis. Recent mouse studies have suggested that microRNA-34a (miR-34a) may have anti-tumor activities in human OSA models. Due to the conservation of microRNA across species, we hypothesized that a bioengineered miR-34a prodrug (tRNA/miR-34a) would have similar effects in canine OSA, providing a valuable preclinical model for development of this therapeutic modality. Using a panel of canine OSA cell lines, we found that tRNA/miR-34a reduced viability, clonogenic growth, and migration and invasion while increasing tumor cell apoptosis. Furthermore, canine OSA cells successfully process the tRNA/miR-34a into mature miR-34a which reduces expression of target proteins such as platelet derived growth factor receptor alpha (PDGFRα), Notch1 and vascular endothelial growth factor (VEGF). Additionally, our subcutaneous OSA xenograft model demonstrated in vivo tumor growth delay, increased necrosis and apoptosis by tRNA/miR-34a, and decreased cellular proliferation ability. Taken together, these data support that this novel microRNA-based therapy may possess clinical utility in a spontaneously-occurring large animal model of OSA, which can then serve to inform the clinical development of this therapy for human OSA patients.
Highlights
Osteosarcoma (OSA) is an aggressive, high-grade bone neoplasm derived from mesenchymal stem cells with the capacity to produce osteoid and represents the most common primary malignant tumor of bone in humans and dogs [1, 2]
Taking into account that miR-34 is highly conserved across species and canine OSA is a well-known, naturally occurring model of human OSA, we aimed to evaluate the effectiveness of this human bioengineered miR-34a prodrug in canine OSA cells in order to validate canine OSA as a useful model for informing future clinical development of this novel therapeutic agent
TUNEL staining and caspase-3/-7 activity assay suggest a trend towards apoptosis, we evaluated the apoptosis profiles in canine OSA cells at 48 hours post-treatment (5 nM) employing a bivariate Propidium Iodide (PI)/Annexin-V analysis, which was performed by flow cytometry (Fig 3)
Summary
Osteosarcoma (OSA) is an aggressive, high-grade bone neoplasm derived from mesenchymal stem cells with the capacity to produce osteoid and represents the most common primary malignant tumor of bone in humans and dogs [1, 2]. Human and canine OSA share notable clinical, histological and molecular similarities, such as predilection for metaphysis of weightbearing bones, metastatic pattern (lungs, bones, lymph nodes), undetectable pulmonary. Novel miR-34a prodrug inhibits canine model of osteosarcoma
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