Loss of Caspase-8 in Tumor Cells: Mechanism to Overcome Integrin-Mediated Death?

Abstract

Successful metastasis is determined by the ability of tumor cells to invade surrounding tissue, survive in the circulation, extravasate, arrest, and proliferate within the secondary organ. During this process, mutations in oncogenes and tumor suppressor genes lead to genetic instability, which bestows tumor cells with a selective growth advantage and aids the acquisition of the malignant phenotype. Altered expression and activity of various components of the apoptotic pathway, including receptors, ligands, adaptors, and caspases, can contribute to malfunction of the apoptotic machinery and, ultimately, to a more malignant phenotype. The expression of caspase-8, a key apoptotic factor involved in both the extrinsic and the intrinsic apoptotic pathways, is very frequently lost in high-risk neuroblastomas, the most common group of early childhood tumors. Stupack et al. report a much higher incidence of apoptosis in caspase-8⁺, locally invasive extratumoral cells as compared with that of caspase-8⁻ cells. Conversely, knockdown of cas-pase-8 expression by RNA interference promotes metastasis but has no effect on primary tumor growth. Caspase-8-expressing neuroblastomas undergo apoptosis in a caspase-8-dependent manner that is independent of death receptor activation but rather might be controlled by integrin-mediated death (IMD), a process that occurs in adherent cells and that is distinct from anoikis, a form of programmed cell death resulting from a loss of integrin-mediated cell-matrix contact.