- Email: [email protected]
To eat or not to eat: a question of repulsion
News & Comment
TRENDS in Cell Biology Vol.12 No.11 November 2002
499
To eat or not to eat: a question of repulsion The last, but not least, step of apoptosis consists of the elimination of apoptotic bodies by phagocytes. This guarantees the protection of tissues against the toxic contents of dying cells and prevents inflammatory responses. Thus, it is essential for phagocytes to recognize and engulf only apoptotic bodies and not the neighboring living cells. This is partially achieved by recognition of attractive signals specifically present on apoptotic bodies (e.g. phosphatidylserine). In an interesting study, Brown et al. identify an additional way of ensuring that only the dead are removed – they report that living cells can release a repulsive signal [1]. In an in vitro detachment assay, the authors observed that living, but not dying, neutrophils can detach from a monolayer of macrophages. The authors identified CD31 as the molecule responsible for the
repulsive activity. CD31 is an adhesion molecule belonging to the immunoglobulin superfamily that is involved in diapedesis and can undergo homophilic interactions. In their experiments, the authors used Jurkat cells selected to express low levels of CD31. Although alive, these cells failed to detach from macrophages. Transfection of wild-type CD31 restored the detachment/repulsive function. By contrast, cells transfected with glycosylphosphatidylinositol-linked CD31 or cytoplasmic tail mutants of CD31 could not detach from macrophages. In additional experiments, Brown et al. further demonstrated by immunoblotting that CD31 failed to constitutively interact with the signaling molecules SHP-1 and SHP-2 in dying leukocytes, suggesting that signal transduction is disabled. The authors propose that homophilic CD31 interactions first mediate phagocyte tethering. Then, the
transduction signal delivered by CD31 is selectively switched off or on depending on the viability of the leukocyte. Brown et al. have highlighted an original mechanism of ‘negative sorting’. Nevertheless, identification of mechanisms that disable repulsion in dying cells requires further investigation. Moreover, it remains to be determined whether repulsion through CD31, as a anti-phagocytic signal in living cells, is an unusual feature observed only in leukocytes or is also pertinent for other cell types. 1 Brown. et al. (2002) Apoptosis disables CD31-mediated cell detachment from phagocytes promoting binding and engulfment. Nature 418, 200–203
Jean-Luc Prétet [email protected]
SMAC agonists blaze the TRAIL to tumor cells Of prime concern in cancer therapy is the resistance of many tumors to current treatment regimes, often because of defects in the ability of tumor cells to undergo apoptosis. The aim of cancer biologists is therefore to develop new strategies that exclusively target tumor cells that are resistant to apoptosis. Apoptosis resulting in activation of caspases can be initiated by at least two stimulatory pathways: one requires activation of death receptors by death-inducing ligand members of the tumor necrosis factor (TNF) family and the other, initiated by chemotherapeutic agents, involves the release of pro-apoptotic factors such as cytochrome c and SMAC (second mitochondria-derived activator of caspases) from mitochondria. The cytotoxic ligand TRAIL (TNF-related apoptosis-inducing ligand) is a promising candidate for cancer therapy because it is selectively toxic to tumor cells with little or no toxicity evident in normal cells. The apoptotic signal initiated by TRAIL often results in mitochondrial perturbation and in many cells TRAIL engages a mitochondrial amplification loop for maximal cytotoxicity. Defects in apoptosis and thus an impaired ability of cancer cells to die can be caused by inappropriate expression of anti-apoptotic molecules such as IAPs (inhibitor of http://tcb.trends.com
apoptosis proteins), which are overexpressed in many tumor cells and which inhibit caspases directly. Alternatively, high expression of BCL2 proteins, which act to interfere with the mitochondrial release of pro-apoptotic proteins such as cytochrome c or SMAC, can confer resistance to diverse apoptotic stimuli such as TRAIL or anti-cancer drugs. Significantly, the recent identification of SMAC as a potent IAP antagonist that promotes caspase activation has now raised the possibility that peptides mimicking the key XIAP-targeting residues in SMAC could sensitize previously resistant tumor cells to apoptosis. Fulda et al. [1] have explored this possibility and now report that SMAC peptides can sensitize resistant neuroblastoma and melanoma cells that express high levels of XIAP or BCL2 to TRAIL-induced apoptosis. Importantly, combined treatment with SMAC peptides and TRAIL showed no cytotoxicity to normal human cells. So the sensitization effect of SMAC peptides is specific to tumor cells and notably, under this treatment regime, the tumor selectivity – and potential safety – of TRAIL is retained. Fulda et al. also demonstrate that TRAIL and SMAC peptides can synergise to promote anti-tumor activity in vivo in a malignant glioma xenograft
model. Because TRAIL alone might not be an effective inducer of apoptosis in tumors with defects in the mitochondrial pathway (e.g. high BCL2 expression), SMAC agonists could prove particularly useful to sensitize such cells to TRAIL-induced apoptosis. Consistent with this, SMAC peptides significantly potentiated the anti-tumor activity of TRAIL in vivo but complete eradication of established tumors and survival was only achieved following combined treatment with SMAC peptides and TRAIL. The fact that tumors such as malignant glioma, which are refractory to most current treatment regimes, can be sensitized by the combination of SMAC peptides and TRAIL, has important implications for the future development of novel strategies in cancer therapy. Portions of SMAC can make previously resistant neuroblastoma and melanoma cells sensitive to TRAIL-induced apoptosis, opening doors for new cancer therapies. 1 Fulda, S. et al. (2002) Smac agonists sensitize for Apo2L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo. Nat. Med. 8, 808–815
Marion MacFarlane [email protected]
0962-8924/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved.
TRENDS in Cell Biology Vol.12 No.11 November 2002
499
To eat or not to eat: a question of repulsion The last, but not least, step of apoptosis consists of the elimination of apoptotic bodies by phagocytes. This guarantees the protection of tissues against the toxic contents of dying cells and prevents inflammatory responses. Thus, it is essential for phagocytes to recognize and engulf only apoptotic bodies and not the neighboring living cells. This is partially achieved by recognition of attractive signals specifically present on apoptotic bodies (e.g. phosphatidylserine). In an interesting study, Brown et al. identify an additional way of ensuring that only the dead are removed – they report that living cells can release a repulsive signal [1]. In an in vitro detachment assay, the authors observed that living, but not dying, neutrophils can detach from a monolayer of macrophages. The authors identified CD31 as the molecule responsible for the
repulsive activity. CD31 is an adhesion molecule belonging to the immunoglobulin superfamily that is involved in diapedesis and can undergo homophilic interactions. In their experiments, the authors used Jurkat cells selected to express low levels of CD31. Although alive, these cells failed to detach from macrophages. Transfection of wild-type CD31 restored the detachment/repulsive function. By contrast, cells transfected with glycosylphosphatidylinositol-linked CD31 or cytoplasmic tail mutants of CD31 could not detach from macrophages. In additional experiments, Brown et al. further demonstrated by immunoblotting that CD31 failed to constitutively interact with the signaling molecules SHP-1 and SHP-2 in dying leukocytes, suggesting that signal transduction is disabled. The authors propose that homophilic CD31 interactions first mediate phagocyte tethering. Then, the
transduction signal delivered by CD31 is selectively switched off or on depending on the viability of the leukocyte. Brown et al. have highlighted an original mechanism of ‘negative sorting’. Nevertheless, identification of mechanisms that disable repulsion in dying cells requires further investigation. Moreover, it remains to be determined whether repulsion through CD31, as a anti-phagocytic signal in living cells, is an unusual feature observed only in leukocytes or is also pertinent for other cell types. 1 Brown. et al. (2002) Apoptosis disables CD31-mediated cell detachment from phagocytes promoting binding and engulfment. Nature 418, 200–203
Jean-Luc Prétet [email protected]
SMAC agonists blaze the TRAIL to tumor cells Of prime concern in cancer therapy is the resistance of many tumors to current treatment regimes, often because of defects in the ability of tumor cells to undergo apoptosis. The aim of cancer biologists is therefore to develop new strategies that exclusively target tumor cells that are resistant to apoptosis. Apoptosis resulting in activation of caspases can be initiated by at least two stimulatory pathways: one requires activation of death receptors by death-inducing ligand members of the tumor necrosis factor (TNF) family and the other, initiated by chemotherapeutic agents, involves the release of pro-apoptotic factors such as cytochrome c and SMAC (second mitochondria-derived activator of caspases) from mitochondria. The cytotoxic ligand TRAIL (TNF-related apoptosis-inducing ligand) is a promising candidate for cancer therapy because it is selectively toxic to tumor cells with little or no toxicity evident in normal cells. The apoptotic signal initiated by TRAIL often results in mitochondrial perturbation and in many cells TRAIL engages a mitochondrial amplification loop for maximal cytotoxicity. Defects in apoptosis and thus an impaired ability of cancer cells to die can be caused by inappropriate expression of anti-apoptotic molecules such as IAPs (inhibitor of http://tcb.trends.com
apoptosis proteins), which are overexpressed in many tumor cells and which inhibit caspases directly. Alternatively, high expression of BCL2 proteins, which act to interfere with the mitochondrial release of pro-apoptotic proteins such as cytochrome c or SMAC, can confer resistance to diverse apoptotic stimuli such as TRAIL or anti-cancer drugs. Significantly, the recent identification of SMAC as a potent IAP antagonist that promotes caspase activation has now raised the possibility that peptides mimicking the key XIAP-targeting residues in SMAC could sensitize previously resistant tumor cells to apoptosis. Fulda et al. [1] have explored this possibility and now report that SMAC peptides can sensitize resistant neuroblastoma and melanoma cells that express high levels of XIAP or BCL2 to TRAIL-induced apoptosis. Importantly, combined treatment with SMAC peptides and TRAIL showed no cytotoxicity to normal human cells. So the sensitization effect of SMAC peptides is specific to tumor cells and notably, under this treatment regime, the tumor selectivity – and potential safety – of TRAIL is retained. Fulda et al. also demonstrate that TRAIL and SMAC peptides can synergise to promote anti-tumor activity in vivo in a malignant glioma xenograft
model. Because TRAIL alone might not be an effective inducer of apoptosis in tumors with defects in the mitochondrial pathway (e.g. high BCL2 expression), SMAC agonists could prove particularly useful to sensitize such cells to TRAIL-induced apoptosis. Consistent with this, SMAC peptides significantly potentiated the anti-tumor activity of TRAIL in vivo but complete eradication of established tumors and survival was only achieved following combined treatment with SMAC peptides and TRAIL. The fact that tumors such as malignant glioma, which are refractory to most current treatment regimes, can be sensitized by the combination of SMAC peptides and TRAIL, has important implications for the future development of novel strategies in cancer therapy. Portions of SMAC can make previously resistant neuroblastoma and melanoma cells sensitive to TRAIL-induced apoptosis, opening doors for new cancer therapies. 1 Fulda, S. et al. (2002) Smac agonists sensitize for Apo2L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo. Nat. Med. 8, 808–815
Marion MacFarlane [email protected]
0962-8924/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved.