Nuovi approcci basati su TRAIL ed MSC per la terapia delle malattie oncoematologiche

TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily of cytokines, including 18 genes which code 19 transmembrane proteins, strictly correlated, and playing important roles in: cell death regulation, immune response and inflammation. In humans at least 5 different TRAIL receptors have been described belonging to the TNF-R family, each one expressed in different cellular lines. TRAIL-R1 (DR4) and TRAIL-R2 (DR5) transduce apoptotic signals, while TRAIL-R3 (DcR1), TRAIL-R4 (DcR2) and osteoprotegerina (OPG) are decoy receptors unable to induce cellular death. Significant levels of TRAIL have been detected in many human tissues, including spleen, prostate, lungs, thymus, kidney, intestine, ovary and, at lower levels, heart, skeletal muscle cells, pancreas, liver, brain and testicle. One of the primary functions of TRAIL is to induce apoptosis in numerous transformed cell lines and cancer cells in vivo, without significant cytotoxicity on normal cells or tissues. With the aim to identify antitumor agents, we have focused our attention on the therapeutic potential of TRAIL. During the last three years, we tested new strategies based on TRAIL in order to induce death selectively in neoplastic cells which have developed resistance to conventional treatment. For this purpose we conducted a set of studies in vitro and in vivo employing recombinant TRAIL. Furthermore our research has concentrated on the therapeutic efficacy of human bone marrow (BM) mesenchymal stem cells (MSC), which are considered the stromal progenitor stem cells within the bone marrow. Our objective was to explore the antitumor activity of these cells and to describe the mechanisms causing this effect. The development of an animal model in SCID (Severe Combined Immunodeficiency) mice of Non-Hodgkin lymphoma (NHL) was necessary in order to investigate the in vivo dissemination of cancer cells and to assess the therapeutic efficacy of recombinant TRAIL and BM-MSC. These models were established by intraperitoneal (i.p.) injection of EBV- Burkitt-type BJAB and EBV+ B lymphoblastoid SKW6.4 cell lines. Xenografts mice were then i.p. injected on the opposite site with either human recombinant TRAIL or BM-MSC at a lymphoma:MSC assessing mice survival after the treatment. The results reported in this paper demonstrate that both treatments reduce the growth of the tumoral masses, with a consequent significantly higher rate of mice survival. Furthermore, similar results were obtained when mesenchimal stem cells, previously embedded in hyaluronan scaffolds to avoid the integration of mesenchymal cells in the fibrovascular cancer network, were implanted in mice. Interestingly, this hyaluronan-embedded MSC exert anti-lymphoma activity by ameliorating hepatic functionality, as demonstrated by measurement of serum ALT/AST levels. In conclusion, our research suggests that both strategies, i.e. rTRAIL and mesenchymal stem cells can exert antitumoral activity and are good candidate for development of new therapies.