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Potentiation of neuroblastoma metastasis by loss of caspase-8

Abstract

Neuroblastoma, the most common paediatric solid tumour, arises from defective neural crest cells1. Genetic alterations occur frequently in the most aggressive neuroblastomas1. 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 unclear2,3,4. 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 death5. 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.

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Figure 1: Increased survival among caspase-8-deficient neuroblastoma invading stroma.
Figure 2: Assessment of neuroblastoma tumour formation and spontaneous metastasis in the chick embryo.
Figure 3: Loss of capase-8 occurs in metastatic neuroblastoma in mice.
Figure 4: The induction of apoptosis is dependent on caspase-8 and integrins.

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Acknowledgements

In memory of V.J.K. who died 7 May 2004. We thank K. Zhu, J. Creech, J. Grenet, T. Lai and K. Boyd for help. This work was supported by National Cancer Institute grants to D.A.C., D.G.S., P.J.H., V.J.K. and J.M.L., and an NCI CCSG grant and ALSAC support to St Jude Children's Research Hospital. The mU6pro vector was generously provided by D. L. Turner. Caspase-8 shRNA vectors were provided by G. Singh.

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Correspondence to Dwayne G. Stupack or Jill M. Lahti.

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Stupack, D., Teitz, T., Potter, M. et al. Potentiation of neuroblastoma metastasis by loss of caspase-8. Nature 439, 95–99 (2006). https://doi.org/10.1038/nature04323

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