【正文】 t select for leukaemia cells that have elevated MCL1 levels. ? Human melanomas and a murine Bcell lymphoma cell line were shown to express high levels of FLIP, which interferes with apoptosis induction at the level of the death receptors. Moreover, in EBVpositive Burkitt39。s lymphoma cell lines, an increased FLIP:caspase8 ratio was correlated with resistance to CD95mediated apoptosis93. Viral analogues of FLIP, called viral FLIPs (vFLIPs), are encoded by some tumorigenic viruses, including HHV8. In cells that are latently infected with HHV8, vFLIP is expressed at low levels, but its expression is increased in advanced Kaposi39。s saras or on serum withdrawal from lymphoma cells in culture. Therefore, vFLIPs might contribute to the persistence and oncogenicity of vFLIPencoding viruses. Although FLIP expression prevents apoptosis induction through death receptors, it does not inhibit cell death induced by perforin/granzyme, chemotherapeutic drugs or girradiation. Nevertheless, it mediates the immune escape of tumours in mouse models. Tumours with high expression levels of FLIP were shown to escape from Tcellmediated immunity in vivo, despite the presence of the perforin/granzyme pathway, so tumour cells with elevated FLIP levels seem to have a selective advantage. FLIP overexpression also prevents rejection of tumours by perforindeficient NK cells. Expression of antiapoptotic proteins ? Another mechanism by which tumours interfere with deathreceptormediated apoptosis might be the expression of soluble receptors that act as decoys for death ligands. To date, two distinct soluble receptors — soluble CD95 (sCD95) and decoy receptor 3 (DcR3) — have been shown to petitively inhibit CD95 signalling. sCD95 is expressed in various malignancies, and elevated levels can be found in the sera of cancer patients. High sCD95 serum levels were associated with poor prognosis in melanoma patients. ? DcR3 binds to CD95L and the TNF family member LIGHT (a cytokine that is homologous to lymphotoxins, exhibits inducible expression and petes with herpes simplex virus (HSV) glycoprotein D for herpesvirus entry mediator (HVEM), a receptor expressed by T cells) and inhibits CD95Linduced apoptosis. It is geically amplified in several lung and colon carcinomas and is overexpressed in several adenocarcinomas, glioma cell lines and glioblastomas. Ectopic expression of DcR3 in a rat glioma model resulted in decreased immunecell infiltration, which indicates that DcR3 is involved in immune evasion of malignant glioma. Expression of antiapoptotic proteins ? Expression of the IAPfamily protein survivin is highly tumour specific. It is found in most human tumours but not in normal adult tissues. In neuroblastoma, expression correlates with a more aggressive and unfavourable disease. But although survivin has a BIR domain, it is not clear whether it directly acts as an apoptosis inhibitor, for example by binding to caspase9 or interacting with SMAC/DIABLO. Survivin might also be necessary for pletion of the cell cycle. Nevertheless, overexpression of survivin counteracts apoptosis in some settings: in transgenic mice that express survivin in the skin, its antiapoptotic function was more prominent than its role in cell division. Survivin inhibited UVBinduced apoptosis in vitro and in vivo, whereas it did not affect CD95induced cell death. Expression of a nonphosphorylatable mutant of survivin induces cytochrome c release and cell death. In xenograft tumour models, this mutant suppressed tumour growth and reduced intraperitoneal tumour dissemination. Expression of antiapoptotic proteins ? Another IAP family member, cIAP2, is affected by the translocation t(11。18)(q21。q21) that is found in about 50% of marginal cell lymphomas of the mucosaassociated lymphoid tissue (MALT). This indicates a role for cIAP2 in the development of MALT lymphoma. MLIAP is expressed at high levels in melanoma cell lines, but not in primary melanocytes. Melanoma cell lines that express MLIAP are significantly more resistant to druginduced apoptosis than those that do not express MLIAP. ? Finally, tumour cells resist killing by cytotoxic lymphocytes not only by blocking the deathreceptor pathway, but also by interfering with the perforin/granzyme pathway. Expression of the serine protease inhibitor PI9/SPI6, which inhibits granzyme B, results in the resistance of tumour cells to cytotoxic lymphocytes, leading to immune escape. Inactivation of proapoptotic genes. ? Besides overexpression of antiapoptotic genes, tumours can acquire apoptosis resistance by downregulating or mutating proapoptotic molecules. In certain types of cancer, the proapoptotic BCL2 family member BAX is mutated. Frameshift mutations that lead to loss of expression, and mutations in the BH domains that result in loss of functions, are mon. Tumour cell lines with frameshift mutations are more resistant to apoptosis. Reduced BAX expression is associated with a poor response rate to chemotherapy and shorter survival in some situations. Several studies in mice have confirmed the function of Bax as a tumour suppressor. In a transgenic mouse tumour, Bax expression is induced by p53, resulting in slow tumour growth and a high percentage of apoptotic cells. In Baxdeficient mice, however, tumour growth is accelerated and apoptosis decreases, indicating that Bax is required for a full p53mediated response. In a different study, induction of Bax expression in an inducible cell line restored sensitivity to apoptosis and significantly reduced tumour growth in severe bined immunodeficient (SCID) mice. ? Moreover, others showed that inactivation of wildtype Bax confers a strong advantage during clonal evolution of the tumour.