MicroRNA Expression Analysis in a Model of Osteosarcoma Dormancy Reveals Novel Regulators of Osteosarcoma Progression and Tumor-Host Interactions

The presence of dormant, microscopic cancerous lesions possesses a major obstacle for the treatment of metastatic and recurrent cancers. While it is well-established that microRNAs play a major role in tumorigenesis, their involvement in tumor dormancy has yet to be fully elucidated. We developed a human osteosarcoma dormancy model of a pair of cells originating from the same parental tissue; one that remains avascular and non-palpable a year following inoculation into mice and another that generates vascularized palpable tumors one month following inoculation. Using this model of cell lines generating dormant or fast-growing osteosarcomas, we identified three novel regulators of osteosarcoma dormancy: miR-34a, miR-93 and miR-200c. This is the first time to show that loss of these three microRNAs occurs during the switch from dormant avascular into fast-growing angiogenic phenotype. Furthermore, we validated their downregulation in patients` tumor samples compared to normal bone. Reconstitution of these microRNAs into Soas-2 and MG-63 cells, which generate fast-growing osteosarcomas, reduced the levels of their targets, MET proto-oncogene, hypoxia-inducible factor 1α, and moesin, critical to cancer angiogenesis and cancer cells` migration. We further demonstrate that these miRNAs attenuate the angiogenic capabilities of fast-growing osteosarcoma in vitro and in vivo. Moreover, treatment with each of these microRNAs using our novel polyglycerol dendritic nanocarrier significantly prolonged their dormancy period. Taken together, these findings suggest that miR-34a, miR-93 and miR-200c have a key role in osteosarcoma progression, and provide the rationale for the development of novel diagnostic and therapeutic tools for osteosarcoma and other malignancies.