title: Potentiation of neuroblastoma metastasis by loss of caspase-8.
abstract: Neuroblastoma, the most common paediatric solid tumour, arises from defective neural crest cells. Genetic alterations occur frequently in the most aggressive neuroblastomas. In particular, deletion or suppression of the proapoptotic enzyme caspase-8 is common in malignant, disseminated disease, although the effect of this loss on disease progression is unclear. Here we show that suppression of caspase-8 expression occurs during the establishment of neuroblastoma metastases in vivo, and that reconstitution of caspase-8 expression in deficient neuroblastoma cells suppressed their metastases. Caspase-8 status was not a predictor of primary tumour growth; rather, caspase-8 selectively potentiated apoptosis in neuroblastoma cells invading the collagenous stroma at the tumour margin. Apoptosis was initiated by unligated integrins by means of a process known as integrin-mediated death. Loss of caspase-8 or integrin rendered these cells refractory to integrin-mediated death, allowed cellular survival in the stromal microenvironment, and promoted metastases. These findings define caspase-8 as a metastasis suppressor gene that, together with integrins, regulates the survival and invasive capacity of neuroblastoma cells.
authors.affiliation: Department of Pathology and The John and Rebecca Moores Cancer Center, The University of California at San Diego, La Jolla, California 92093-0803, USA. dstupack@ucsd.edu
authors.forename: Dwayne G
authors.initials: DG
authors.lastname: Stupack
authors.forename: Tal
authors.initials: T
authors.lastname: Teitz
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Potter
authors.forename: David
authors.initials: D
authors.lastname: Mikolon
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Kidd
authors.forename: Jill M
authors.initials: JM
authors.lastname: Lahti
authors.forename: David A
authors.initials: DA
authors.lastname: Cheresh
mesh_terms: D000818:Animals; D017209:Apoptosis; D053181:Caspase 8; D020169:Caspases / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D002642:Chick Embryo; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016023:Integrins / Q000378:metabolism; D007668:Kidney / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology*; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D010053:Ovary / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D016023:Integrins; D012333:RNA, Messenger; C505530:CASP8 protein, human; C505526:Casp8 protein, mouse; D053181:Caspase 8; D020169:Caspases