Potentiation of neuroblastoma metastasis by loss of caspase-8

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, alth...

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Bibliographic Details
Published in:Nature 2006-01, Vol.439 (7072), p.95-99
Main Authors: Stupack, Dwayne G, Lahti, Jill M, Teitz, Tal, Potter, Matthew D, Mikolon, David, Houghton, Peter J, Kidd, Vincent J, Cheresh, David A
Format: Article
Language:English
Subjects:
Ageing, cell death
Animals
Apoptosis
Biological and medical sciences
Brain cancer
Caspase 8
Caspases - deficiency
Caspases - genetics
Caspases - metabolism
Cell Line, Tumor
Cell physiology
Cell Survival
Chick Embryo
Enzymes
Female
Fundamental and applied biological sciences. Psychology
Gene Expression Regulation, Neoplastic
Humans
Integrins - metabolism
Kidney - pathology
Medical sciences
Mice
Mice, Nude
Molecular and cellular biology
Neoplasm Metastasis - genetics
Neoplasm Metastasis - pathology
Neoplasm Transplantation
Neuroblastoma - enzymology
Neuroblastoma - genetics
Neuroblastoma - pathology
Neurology
Oncology
Ovary - pathology
RNA, Messenger - genetics
RNA, Messenger - metabolism
Tumors
Tumors of the nervous system. Phacomatoses
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Summary: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.
ISSN:0028-0836
1476-4687
1476-4679
DOI:10.1038/nature04323