Tumor dormancy has important implications for early detection and treatment of cancer. Nevertheless, the biological mechanisms and genetic characteristics of the tumor dormancy phenomenon remain mostly unknown. miRNAs, small non-coding RNA molecules which regulate gene expression at the post-transcriptional level, are emerging as key regulators in physiological and pathological processes, including tumorigenesis. We hypothesized that specific miRs may also play a key role in the regulation of tumor dormancy and the “angiogenic switch”. To elucidate the molecular mechanisms of tumor dormancy and to imitate the clinical setting, in which tumor progression depends on sequential events, including a switch to the angiogenic phenotype, we established a pair of cells that generate dormant avascular or fast-growing angiogenic osteosarcomas in SCID mice (Saos-2-D and Saos-2-E respectively). Although these cells share similar growth rate in vitro, when inoculated into mice, Saos-2-E cells generate vascularized and palpable tumors within one month, while Saos-2-D cells remain avascular and non-palpable for a year. In order to explore the mechanisms which led to these phenotypic differences, Saos-2 cells were analyzed for their microRNA (miR) profile.Several miRs that were differentially-expressed in the dormant versus fast-growing-tumor-generating cells were selected for further evaluation. Out of those miRs, miR-200c and miR-93 reverted cells forming fast-growing tumors to a dormant non-angiogenic phenotype, both in vitro and in vivo, suggesting that miR-200c and miR-93 play a role in the switch from dormancy to progressive disease.Therefore, our work presented here uncovers new molecular targets involved in the tumor dormancy phenomenon and can provide important tools for novel dormancy-directed tumor therapy strategies.
