Loss of miR-198 and -206 during primary tumor progression enables metastatic dissemination in human osteosarcoma.

The metastatic dissemination is a complex multistep process by which tumor cells from a primary site enter into the systemic circulation to finally spread at distant sites. Even if this mechanism is rare at the tumor level, it remains the major cause of Osteosarcoma-patients' relapse and mortality. MicroRNAs (miRNAs) have recently been described as novel epigenetics' genes' expression regulators actively implicated in cancer progression and dissemination. The understanding of their implication in the metastatic spreading could help clinicians to improve the outcome of osteosarcoma. We established the miRNA's expression-profile between primary bone-tumors (PTs), circulating tumor cells (CTCs) and lung metastatic (META) samples from in vivo mice xenograft models. Our results show that the expression level of the miR-198 and -206 was decreased in META samples, in which the expression of the metastasis-related receptor C-Met was up-regulated. Those expression variations were validated in osteosarcoma patient biopsies from matching primary tumors and lung metastasis. We validated in vitro the endogenous miRNAs inhibitory effects on both migration and invasion, as well as we confirmed by luciferase assays that the C-Met receptor is one of their bona-fide targets. The anti-metastatic effect of these miRNAs was also validated in vivo, as their direct injections into the tumors reduce the number of lung-metastases and prolongs the overall survival of the treated animals. All together, our results suggest the absence of the miR-198 and -206 as powerful predictive biomarkers of the tumor cell dissemination and the rationale of their potential therapeutic use in the treatment of Osteosarcoma.

miRNA-193a-5p repression of p73 controls Cisplatin chemoresistance in primary bone tumors.

Osteosarcoma and Ewing Sarcoma are the two most common types of Bone Sarcomas, principally localized at the long bones of the extremities and mainly affecting adolescents and young adults. Cisplatin is one of the current options in the therapeutic arsenal of drugs available to cure these aggressive cancers. Unfortunately, chemoresistance against this agent is still a major cause of patient relapse. Thus, a better understanding of the molecular pathways by which these drugs induce cancer cell death, together with a better delineation of the origins of chemoresistance are required to improve the success rate of current treatments. Furthermore, as p53 is frequently mutated in Bone Sarcomas, other pathways in these cancers must mediate drug-induced cell death. Here, we demonstrate for the first time that TAp73ß, a p53-family protein, is implicated in Cisplatin-induced apoptosis of Bone Sarcomas'. Furthermore, while acquired resistance developed by cancer cells against such drugs can have multiple origins, it is now well accepted that epigenetic mechanisms involving microRNAs (miRNAs) are one of them. We show that miRNA-193a-5p modulates the viability, the clonogenic capacity and the Cisplatin-induced apoptosis of the Bone Sarcoma cells through inhibition of TAp73ß. Collectively, these results shed light on the involvement of miR-193a-5p in Cisplatin chemoresistance of Bone Sarcomas', and they open the road to new therapeutic opportunities provided by targeting the miR-193a-5p/TAp73ß axis in the context of these malignancies.

Circulating Tumor Cells: A Review of Non-EpCAM-Based Approaches for Cell Enrichment and Isolation.

BACKGROUND: Circulating tumor cells (CTCs) are biomarkers for noninvasively measuring the evolution of tumor genotypes during treatment and disease progression. Recent technical progress has made it possible to detect and characterize CTCs at the single-cell level in blood. CONTENT: Most current methods are based on epithelial cell adhesion molecule (EpCAM) detection, but numerous studies have demonstrated that EpCAM is not a universal marker for CTC detection because it fails to detect both carcinoma cells that undergo epithelial-mesenchymal transition (EMT) and CTCs of mesenchymal origin. Moreover, EpCAM expression has been found in patients with benign diseases. A large proportion of the current studies and reviews about CTCs describe EpCAM-based methods, but there is evidence that not all tumor cells can be detected using this marker. Here we describe the most recent EpCAM-independent methods for enriching, isolating, and characterizing CTCs on the basis of physical and biological characteristics and point out the main advantages and disadvantages of these methods. SUMMARY: CTCs offer an opportunity to obtain key biological information required for the development of personalized medicine. However, there is no universal marker of these cells. To strengthen the clinical utility of CTCs, it is important to improve existing technologies and develop new, non-EpCAM-based systems to enrich and isolate CTCs.