Caspase 8: Suppressing metastasis
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Caspase 8 suppresses metastasis by promoting apoptosis at the tumor margin in a process initiated by unligated integrins.
The deletion or suppression of the proapoptotic enzyme caspase 8 is a common occurrence in disseminated neuroblastoma tumor. However the consequences of this loss of expression on disease progression has been unclear. Cheresh and colleagues now show that caspase 8 actively suppresses metastasis by promoting apoptosis at the invasive tumor margin in neuroblastoma cells.
The authors analyzed tumor growth and invasiveness of neuroblastoma lines in both chick embryos and mice showing that caspase 8 expression had no effect on primary tumor growth. However, caspase 8 expression in these cell lines did correlate with the suppression of metastasis and an increase in apoptosis at tumor margins. Reconstitution of caspase 8-deficient cells with caspase 8 also suppressed metastasis and led to increased apoptosis in cells at the invasive edge of tumors. Reversely, knock-down of caspase 8 promoted metastasis and decreased levels of apoptosis.
Caspase 8 positive neuroblastoma cells seeded in a collagen matrix died quickly. The authors found that this was due to the presence of high levels of unligated integrins on the tumor cells. This form of apoptosis, termed integrin-mediated death (IMD), occurs when caspase 8 is recruited to the tumor margin by high levels of unligated integrins and consequently activated. Caspase 8 expression does not generally predispose neuroblastoma cells to the induction of apoptosis by other stimuli such as death receptor signaling, but appears to specifically mediate cell death during tissue invasion.
This study presents a new role for IMD in the regulation of cancer cell invasion and proposes that caspase 8 may be a metastasis suppressor gene, the loss of which promotes metastasis by suppressing IMD during tumor cell invasion and dissemination.
Clare Garvey
Signaling Gateway
References
- Dwayne G Stupack, Tal Teitz, Matthew D Potter, David Mikolon, Peter J Houghton, Vincent J Kidd, Jill M Lahti & David A Cheresh. Potentiation of neuroblastoma metastasis by loss of caspase-8. Nature 439, 95 – 99 (2006) | Article | PubMed |
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