Caspases are crucial components of the pro-apoptotic pathway, and although loss of expression of caspase 8 occurs in various cancer types, the functional significance of this has not been determined. Now, the Stupack, Lahti and Cheresh laboratories show that loss of caspase 8 in neuroblastoma facilitates the formation of metastases.

The authors used developing chick embryos to analyse the growth, invasion and spontaneous metastasis of implanted, patient-derived neuroblastoma cell lines. They noted that the more invasive neuroblastoma lines did not express caspase 8 and that those that did express the enzyme showed a much higher level of apoptosis when invading the surrounding tissues. Caspase-8 expression did not affect the size of the primary tumour, but it did limit the establishment of metastases in the lung and bone marrow. Moreover, the use of RNA interference to reduce the expression of the caspase-8 protein increased the ability of the caspase-8-expressing cells to establish metastases.

Caspase-8 activation can occur when cells are grown in an inappropriate extracellular matrix. This activation is triggered by unligated or antagonized integrins and is known as integrin-mediated cell death (IMD). Type 1 collagen is the principal matrix component in many stromal tissues, and the authors found that caspase-8-expressing neuroblastoma cells underwent apoptosis when plated in a three-dimensional type-1-collagen matrix. However, inhibition of the death-receptor pathway, which also recruits and activates caspase 8, did not prevent the death of these cells. This finding questions whether the death-receptor pathway has a function in limiting neuroblastoma metastases. The authors also showed that decreased expression of the α3β1 integrin occurred in metastases isolated from patients and increased the survival of caspase-8-expressing cells in the type-1-collagen matrix. This indicates that unligated integrins might function similarly to dependence receptors and induce apoptosis when their ligand is absent.

So, it seems likely that caspase 8 is a metastasis suppressor and that overcoming IMD by suppressing caspase 8 expression, or through changes in integrin expression, facilitates tumour invasion by increasing cell survival.