TELOMERE MAINTENANCE MECHANISMS IN TUMOR OF MESENCHYMAL ORIGIN: EVALUATION OF PROGNOSTIC SIGNIFICANCE AND CHARACTERIZATION OF RELEVANT MOLECULAR PATHWAYS

A limitless proliferative potential is one of the hallmarks of tumour cells and can be achieved through the activation of telomere maintenance mechanisms (TMM), which rely on telomerase reactivation (TA) or, alternatively, on recombination-based processes known as alternative lengthening of telomeres (ALT). Since a substantial fraction of tumours of mesenchymal origin utilizes ALT mechanisms, they represent an interesting model to study the molecular pathways involved in the activation of TMM. With the present work, we extended our knowledge about the prevalence and the prognostic significance of the two known TMMs in different soft-tissue sarcoma histotypes (Malignant peripheral nerve sheath tumors –MPNST-, leiomyosarcoma, liposarcoma) and mixed origin tumours (Wilms’ tumour), showing the relatively low frequency of telomerase activity in soft tissue sarcomas if compared to tumors of epithelial origin, and the important role of ALT in these malignancies. Controversial results have been obtained about the clinical relevance of TMMs, whose prognostic role seems to be dependent on tumor histotypes. Specifically, ALT is a strong determinant of an unfavorable outcome in liposarcoma and leiomyosarcoma patients, whereas it failed to significantly affect the outcome of patients with MPNST (for whom TA proved to be an important predictor of poor survival). This scenario could be due, at least in part, to the lack of standardized methods to properly classify tumours with respect to their TMM status; in this context, we comparatively analysed the prognostic relevance of ALT in a series of liposarcoma as a function of the characteristic used to classify the tumour, with the final aim to identify the most suitable ALT marker. Moreover, we also proposed to identify microRNAs expressed as a function of the different TMM operating in the tumour, which could be either involved in the regulation of such mechanisms or represent surrogate markers of TA-positive or ALT-positive phenotypes. The knowledge of the specific factors/pathways by which the two known TMMs are differentially regulated in distinct tumour histotypes of mesenchymal origin might be important for a better understanding of the pathogenesis of these malignancies and for the identification of new therapeutic targets.