Potentiation of neuroblastoma metastasis by loss of caspase-8

Abstract

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.

Morphological and molecular assessment of apoptotic mechanisms in peripheral neuroblastic tumours

“…In the present study, among the genes involved in the extrinsic route, TRAIL-R1 (DR4) and TRAIL-R2 (DR5) were expressed at high level in both favourable and unfavourable NTs, and no associations with MYCN amplification or other prognostic features were shown. In agreement with previous studies reporting a loss of caspase 8 expression in aggressive NBs (HopkinsDonaldson et al, 2000;Teitz et al, 2000;Stupack et al, 2006), in our series a low expression of caspase 8 mRNA was found in all tumours, with a tendency for high risk tumours to express even lower levels.…”

Dependence receptors: a new paradigm in cell signaling and cancer therapy

“…Low or no transcript levels were observed in lymphoblastic leukemia, promyelocytic leukemia and Burkitt's lymphoma cells (Johannessen et al, 2006;Desmond et al, 2007). Finally, caspase 8 expression is selectively lost during establishment of neuroblastoma metastases, rendering these cells refractory to unligated integrin-mediated cell death (Stupack et al, 2006).…”

MYCN/c-MYC-induced microRNAs repress coding gene networks associated with poor outcome in MYCN/c-MYC-activated tumors

“…Other pathways known to be involved in neuroblastoma, such as CREB signaling (Jiang et al, 2008), CNTF signaling (Peterson and Bogenmann, 2004) and integrin signaling were also identified. Integrin signaling is of particular interest as decreased expression of integrins selectively enhances neuroblastoma survival and metastasis (Stupack et al, 2006). Both integrin receptors and downstream signaling molecules were among the predicted 7mer and 8mer targets of the MYCN/c-MYCactivated miRNAs.…”