From: Subject: Potentiation of neuroblastoma metastasis by loss of caspase-8 : Nature Date: Tue, 16 May 2006 19:26:47 +0200 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01C6791E.AC57E8E0" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.2869 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01C6791E.AC57E8E0 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.nature.com/nature/journal/v439/n7072/abs/nature04323.html;jsessionid=19FC63B2C0ED43D379421628C50378C4 Potentiation of = neuroblastoma metastasis by loss of caspase-8 : Nature
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Letter

Nature 439, 95-99 (5 January 2006) | doi:10.1038/nature04323

Potentiation of neuroblastoma metastasis by loss of = caspase-8

Dwayne G. Stupack1,4,=20 Tal Teitz2,4,=20 Matthew D. Potter1,=20 David Mikolon1,=20 Peter J. Houghton3,=20 Vincent J. Kidd2,=20 Jill M. Lahti2=20 and David A. Cheresh1

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Neuroblastoma, the most common paediatric solid tumour, = arises=20 from defective neural crest cells1. Genetic alterations occur = frequently in the most aggressive neuroblastomas1. In = particular,=20 deletion or suppression of the proapoptotic enzyme caspase-8 is common = in=20 malignant, disseminated disease, although the effect of this loss on = disease=20 progression is unclear2, 3, 4. Here we = show=20 that suppression of caspase-8 expression occurs during the establishment = of=20 neuroblastoma metastases in vivo, and that reconstitution of = caspase-8=20 expression in deficient neuroblastoma cells suppressed their metastases. = Caspase-8 status was not a predictor of primary tumour growth; rather, = caspase-8=20 selectively potentiated apoptosis in neuroblastoma cells invading the=20 collagenous stroma at the tumour margin. Apoptosis was initiated by = unligated=20 integrins by means of a process known as integrin-mediated = death5.=20 Loss of caspase-8 or integrin rendered these cells refractory to=20 integrin-mediated death, allowed cellular survival in the stromal=20 microenvironment, and promoted metastases. These findings define = caspase-8 as a=20 metastasis suppressor gene that, together with integrins, regulates the = survival=20 and invasive capacity of neuroblastoma cells.

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  1. Department of Pathology and The John and Rebecca Moores = Cancer=20 Center, The University of California at San Diego, La Jolla, = California=20 92093-0803, USA=20
  2. Department of Genetics and Tumor Cell Biology, and
  3. Department of Molecular Pharmacology, St Jude Children's = Research=20 Hospital, Memphis, Tennessee 38105, USA=20
  4. *These authors contributed equally to this work

Correspondence to: Dwayne G. Stupack1,4Jill=20 M. Lahti2=20 Correspondence and requests for materials should be addressed to D.G.S.=20 (Email: dstupack@ucsd.edu) = or J.M.L.=20 (Email: jill.lahti@stjude.org).

Received 30 August 2005; Accepted 7 October = 2005

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  • Dwayne=20 G. Stupack
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  • Vincent=20 J. Kidd
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ISSN: 0028-0836

EISSN: 1476-4687

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