Halting neuroblastoma metastasis by controlling integrin-mediated death.
Neuroblastoma, a common tumor of nervous system origin in young children, is usually detected only after the primary tumor has metastasized and the chances of its complete removal are low. Metastatic neuroblastoma cells commonly suppress expression of the gene encoding caspase-8. In a neuroblastoma murine model, expression of caspase-8 and integrin alpha3beta1 was dramatically reduced during tumor development. Analysis of clinical biopsies supported the observation that expression of both genes is low in human patients with metastatic disease. These data suggest that loss of expression of both caspase-8 and unligated integrins contribute to the survival of tumor cells migrating from the primary tumor. Integrin receptors that are unable to find appropriate ligands can form a large molecular complex containing caspase-8, explaining why cells that have diminished expression of either of these two genes have a significant survival advantage in foreign microenvironments. Thus, upregulating expression of caspase-8 and integrins, or alternatively, antagonizing integrins within the primary tumor may be important therapeutically in halting neuroblastoma metastasis.
Teitz
Tal
T
Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. tal.teitz@stjude.org
Stupack
Dwayne G
DG
Lahti
Jill M
JM
D000818:Animals; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D039201:Integrin alpha3beta1 / Q000378:metabolism*; D051379:Mice; D009362:Neoplasm Metastasis / Q000473:pathology*; D009447:Neuroblastoma / Q000473:pathology*
D039201:Integrin alpha3beta1; D049452:Green Fluorescent Proteins; C505530:CASP8 protein, human; C505526:Casp8 protein, mouse; D053181:Caspase 8; D020169:Caspases