The main objective of the project is the assessment of TRAIL biological activity on a panel of human cells from colon and bladder tissues, either normal or neoplastic, and of the molecular mechanisms governing the response to TRAIL. The results of these studies could lead to the development of an alternative or complementary approach to the conventional treatment of bladder and colon carcinomas, by using TRAIL in combination with traditional or new pharmacological compounds, which can increase the average TRAIL-mediated cytotoxicity and thus overcome the resistance to conventional chemotherapy. In particular, the research is focused on the following aspects: characterizing the TRAIL effects on the above-mentioned types of cells; studying TRAIL role in the mutual interaction of NK and LAK cells with their tumor targets and understanding whether and how TRAIL can be upregulated on the surface of normal NK cells; defining the molecular bases of TRAIL biological activity on the cells considered; exploring/developing pharmacological combinations, in order to increase TRAIL cytotoxicity against bladder and colon carcinomas. The tests carried out lead us to believe that recombinant TRAIL and/or anti-TRAIL-R1 and anti-TRAIL-R2 antibodies are very promising biological molecules from the oncological point of view, with regard to their applicability to solid and haematological neoplasias. Together with a direct antineoplastic effect due to TRAIL capacity to induce cellular apoptotic death in several types of cancer cells deriving from solid or haematological neoplasia, the intense research activity carried out by the project groups made it possible to establish that TRAIL could play a significant role even in the osteoclastogenesis modulation, a major process which characterizes bone destruction in several types of solid and haematological neoplasias. The availability of oncologically relevant animal patterns (SCID-human mice) to directly test the potential therapeutic effect of TRAIL or anti-TRAIL-R1/-R2 antibodies is the natural continuation of the studies carried out in this field and represents a major challenge for the near future.