Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Potentiation of neuroblastoma metastasis by loss of caspase-8


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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it


Prices may be subject to local taxes which are calculated during checkout

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.


  1. Brodeur, G. M. Neuroblastoma: biological insights into a clinical enigma. Nature Rev. Cancer 3, 203–216 (2003)

    Article  CAS  Google Scholar 

  2. Takita, J. et al. Allelic imbalance on chromosome 2q and alterations of the caspase 8 gene in neuroblastoma. Oncogene 20, 4424–4432 (2001)

    Article  CAS  Google Scholar 

  3. Teitz, T., Lahti, J. M. & Kidd, V. J. Aggressive childhood neuroblastomas do not express caspase-8: an important component of programmed cell death. J. Mol. Med. 79, 428–436 (2001)

    Article  CAS  Google Scholar 

  4. Teitz, T. et al. Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN. Nature Med. 6, 529–535 (2000)

    Article  CAS  Google Scholar 

  5. Stupack, D. G., Puente, X. S., Boutsaboualoy, S., Storgard, C. M. & Cheresh, D. A. Apoptosis of adherent cells by recruitment of caspase-8 to unligated integrins. J. Cell Biol. 155, 459–470 (2001)

    Article  CAS  Google Scholar 

  6. Kim, J., Yu, W., Kovalski, K. & Ossowski, L. Requirement for specific proteases in cancer cell intravasation as revealed by a novel semiquantitative PCR-based assay. Cell 94, 353–362 (1998)

    Article  CAS  Google Scholar 

  7. Zijlstra, A. et al. A quantitative analysis of rate-limiting steps in the metastatic cascade using human-specific real-time polymerase chain reaction. Cancer Res. 62, 7083–7092 (2002)

    CAS  PubMed  Google Scholar 

  8. Beltinger, C. & Debatin, K. M. Murine models for experimental therapy of pediatric solid tumors with poor prognosis. Int. J. Cancer 92, 313–318 (2001)

    Article  CAS  Google Scholar 

  9. DuBois, S. G. et al. Metastatic sites in stage IV and IVS neuroblastoma correlate with age, tumour biology, and survival. J. Pediatr. Hematol. Oncol. 21, 181–189 (1999)

    Article  CAS  Google Scholar 

  10. Ziegler, M. M., Ishizu, H., Nagabuchi, E., Takada, N. & Arya, G. A comparative review of the immunobiology of murine neuroblastoma and human neuroblastoma. Cancer 79, 1757–1766 (1997)

    Article  CAS  Google Scholar 

  11. Lode, H. N. et al. Targeted interleukin-2 therapy for spontaneous neuroblastoma metastases to bone marrow. J. Natl Cancer Inst. 89, 1586–1594 (1997)

    Article  CAS  Google Scholar 

  12. Barnhart, B. C., Alappat, E. C. & Peter, M. E. The CD95 type I/type II model. Semin. Immunol. 15, 185–193 (2003)

    Article  CAS  Google Scholar 

  13. Wang, S. & El-Deiry, W. S. TRAIL and apoptosis induction by TNF-family death receptors. Oncogene 22, 8628–8633 (2003)

    Article  CAS  Google Scholar 

  14. Teitz, T. et al. Caspase-9 and Apaf-1 are expressed and functionally active in human neuroblastoma tumor cell lines with 1p36 LOH and amplified MYCN. Oncogene 21, 1848–1858 (2002)

    Article  CAS  Google Scholar 

  15. Zhao, H., Ross, F. P. & Teitelbaum, S. L. Unoccupied αvβ3 integrin regulates osteoclast apoptosis by transmitting a positive death signal. Mol. Endocrinol. 19, 771–780 (2005)

    Article  CAS  Google Scholar 

  16. Patan, S., Haenni, B. & Burri, P. H. Implementation of intussusceptive microvascular growth in the chicken chorioallantoic membrane (CAM). Microvasc. Res. 53, 33–52 (1997)

    Article  CAS  Google Scholar 

  17. Zijlstra, A. et al. Collagenolysis-dependent angiogenesis mediated by matrix metalloproteinase-13 (collagenase-3). J. Biol. Chem. 279, 27633–27645 (2004)

    Article  CAS  Google Scholar 

  18. Bredesen, D. E., Mehlen, P. & Rabizadeh, S. Apoptosis and dependence receptors: a molecular basis for cellular addiction. Physiol. Rev. 84, 411–430 (2004)

    Article  CAS  Google Scholar 

  19. Bogenrieder, T. & Herlyn, M. Axis of evil: molecular mechanisms of cancer metastasis. Oncogene 22, 6524–6536 (2003)

    Article  CAS  Google Scholar 

  20. Bates, R. C., Edwards, N. S. & Yates, J. D. Spheroids and cell survival. Crit. Rev. Oncol. Hematol. 36, 61–74 (2000)

    Article  CAS  Google Scholar 

  21. Zahir, N. & Weaver, V. M. Death in the third dimension: apoptosis regulation and tissue architecture. Curr. Opin. Genet. Dev. 14, 71–80 (2004)

    Article  CAS  Google Scholar 

  22. Eggert, A. et al. Expression of the neurotrophin receptor TrkB is associated with unfavorable outcome in Wilms' tumor. J. Clin. Oncol. 19, 689–696 (2001)

    Article  CAS  Google Scholar 

  23. Frisch, S. M. & Ruoslahti, E. Integrins and anoikis. Curr. Opin. Cell Biol. 9, 701–706 (1997)

    Article  CAS  Google Scholar 

  24. Jan, Y. et al. A mitochondrial protein, Bit1, mediates apoptosis regulated by integrins and Groucho/TLE corepressors. Cell 116, 751–762 (2004)

    Article  CAS  Google Scholar 

  25. Stupack, D. G. & Cheresh, D. A. Get a ligand, get a life: integrins, signalling and cell survival. J. Cell Sci. 115, 3729–3738 (2002)

    Article  CAS  Google Scholar 

  26. Shivapurkar, N. et al. Differential inactivation of caspase-8 in lung cancers. Cancer Biol. Ther. 1, 65–69 (2002)

    Article  CAS  Google Scholar 

  27. Pingoud-Meier, C. et al. Loss of caspase-8 protein expression correlates with unfavorable survival outcome in childhood medulloblastoma. Clin. Cancer Res. 9, 6401–6409 (2003)

    CAS  PubMed  Google Scholar 

  28. Kim, H. S. et al. Inactivating mutations of caspase-8 gene in colorectal carcinomas. Gastroenterology 125, 708–715 (2003)

    Article  CAS  Google Scholar 

  29. Tweddle, D. A. et al. The p53 pathway and its inactivation in neuroblastoma. Cancer Lett. 197, 93–98 (2003)

    Article  CAS  Google Scholar 

  30. Berger, J. C., Vander Griend, D. J., Robinson, V. L., Hickson, J. A. & Rinker-Schaeffer, C. W. Metastasis suppressor genes: From gene identification to protein function and regulation. Cancer Biol. Ther. 4, 805–812 (2005)

    Article  CAS  Google Scholar 

Download references


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.

Author information

Authors and Affiliations


Corresponding authors

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

Ethics declarations

Competing interests

Reprints and permissions information is available at The authors declare no competing financial interests.

Supplementary information

Supplementary Notes

This file contains Supplementary Figures 1–8 and Supplementary Tables 1 and 2. (DOC 3214 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Stupack, D., Teitz, T., Potter, M. et al. Potentiation of neuroblastoma metastasis by loss of caspase-8. Nature 439, 95–99 (2006).

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing