Survivin is a member of the inhibitor of apoptosis protein (IAP) family, that has been implicated in both control of cell division and inhibition of apoptosis. Specifically, its anti-apoptotic function seems to be related to the ability to directly or indirectly inhibit caspases. Survivin is selectively expressed in the most common human neoplasms and appears to be involved in tumor cell resistance to some anticancer agents and ionizing radiation. On the basis of these findings survivin has been proposed as an attractive target for new anticancer interventions. Several preclinical studies have demonstrated that down-regulation of survivin expression/function, accomplished through the use of antisense oligonucleotides, dominant negative mutants, ribozymes, small interfering RNAs and cyclin-dependent kinase inhibitors, increased the apoptotic rate, reduced tumor-growth potential and sensitized tumor cells to chemotherapeutic drugs with different action mechanisms and γ-irradiation in in vitro and in vivo models of different human tumor types.

Mesenchymal sem cells (MSCs) are multipotent progenitors with the ability to differentiate along multiple cell lineages and are today considered a useful tool for cell therapy and tissue engineering approaches. Concerns that adult human MSCs may undergo malignant transformation have been recently raised. In fact, human adipose tissue-derived MSCs have been shown to spontaneously transform after long-term in vitro culture. Aim of this study was to investigate the susceptibility to transformation of human bone marrow (BM)-derived MSCs at different time points of in vitro culture. MSCs were isolated from BM of 10 healthy donors and propagated continuously in vitro until reaching a senescence phase or passage (P) 25. MSCs in the senescence phase were closely monitored for 8–12 weeks, to look for the appearance of a crisis phase. MSCs were characterized by morphology, differentiation capacity and immunophenotype at different time-points in culture. The genetic characterization of MSCs was investigated through array comparative genomic hybridization (array-CGH), classical cytogenetics and subtelomeric FISH analysis both before and after prolonged in vitro culture. MSCs were tested for the expression of telomerase activity (TA), hTERT transcripts and alternative mechanisms of telomere lengthening (ALT) at different time-points in culture. MSCs from 5 donors were also analyzed for telomere length at P3 and P15. p53 gene status was also analyzed in MSCs from donors #1 and #2 that rapidly reached senescence in culture. A huge variability between donors was noted in terms of proliferative capacity and in vitro life-span of MSCs. All MSCs maintained the typical spindle-shaped morphology, phenotype and ability to differentiate into osteoblasts and adipocytes throughout the culture period. All MSCs displayed a progressive decrease in the proliferative capacity until reaching senescence, not followed by any further growth. Array-CGH, karyotype and subtelomeric FISH analyses demonstrated that MSCs expanded in vitro did not show chromosomal rearrangements, also after long term culture. TA was not evidenced in the samples tested, including a post-senescence culture. hTERT transcripts (full-length and the additional splice variants a−, b−, a−b−) were found not to be expressed in any of the examined cultures. Telomeres shortened during the culture period. ALT were not evidenced in the MSCs tested, as indicated by the lack of ALT-associated promyelocytic leukemia bodies. Direct DNA sequencing of exons 2–11 in pre-senescence cultures from donors #1 and #2 did not evidence the presence of mutation in the p53 gene. Human BM-derived MSCs do not display an aptitude for spontaneous transformation and can be safely expanded in vitro without any sign of immortalization or development of chromosomal abnormalities. Our results provide support to the concept that the biological properties of human BM-derived MSCs after ex vivo expansion remain suitable for use in cell-therapy approaches; however, it is strongly recommended that phenotype, functional and genetic characteristics of MSCs after in vitro culture and before in vivo infusion are tested, to further guarantee safety for the patient.

Epithelioid hemangioendothelioma (EHE) is an ultra-rare, translocated, vascular sarcoma. EHE clinical behavior is variable, ranging from that of a low-grade malignancy to that of a high-grade sarcoma and it is marked by a high propensity for systemic involvement. No active systemic agents are currently approved specifically for EHE, which is typically refractory to the antitumor drugs used in sarcomas. The degree of uncertainty in selecting the most appropriate therapy for EHE patients and the lack of guidelines on the clinical management of the disease make the adoption of new treatments inconsistent across the world, resulting in suboptimal outcomes for many EHE patients. To address the shortcoming, a global consensus meeting was organized in December 2020 under the umbrella of the European Society for Medical Oncology (ESMO) involving >80 experts from several disciplines from Europe, North America and Asia, together with a patient representative from the EHE Group, a global, disease-specific patient advocacy group, and Sarcoma Patient EuroNet (SPAEN). The meeting was aimed at defining, by consensus, evidence-based best practices for the optimal approach to primary and metastatic EHE. The consensus achieved during that meeting is the subject of the present publication.

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