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Potentiation of neuroblastoma
metastasis by loss of caspase-8
Dwayne G. Stupack1,4,
Tal Teitz2,4, Matthew D.
Potter1, David Mikolon1,
Peter J. Houghton3, Vincent
J. Kidd2, Jill M. Lahti2
and David A. Cheresh1
1Department
of Pathology and The John and Rebecca Moores Cancer Center, The
University of California at San Diego, La Jolla, California
92093-0803, USA. 2Department of
Genetics and Tumor Cell Biology, and 3Department
of Molecular Pharmacology, St Jude Children's Research Hospital,
Memphis, Tennessee 38105, USA. 4These
authors contributed equally to this work.
Correspondence to: Dwayne G. Stupack1,4
Jill M. Lahti2 Correspondence and
requests for materials should be addressed to D.G.S. (Email: dstupack@ucsd.edu)
or J.M.L. (Email: jill.lahti@stjude.org). Received 30 August
2005; Accepted 7 October 2005.
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.
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