Novel protease mediated mechanisms promote the spread of cancer cells via the blood circulation

Abstract

Although the dysfunctional activities of proteases in cancer metastasis have been recognised for some time, the particular mechanisms mediating the roles of these enzymes in the spread of cancer remain poorly defined. Recently we have demonstrated that signals initiated by proteolytic cleavage of cell surface receptors can initiate metastasis promoting responses. One of these receptors is the cell surface glycoprotein CUB domain containing protein 1 (CDCP1). Our data indicate that CDCP1 is cleaved at the cell surface in vitro and in vivo by serine proteases thereby initiating intracellular signalling cascades involving activation and docking to CDCP1 of the kinases Src and PKCδ and downstream activation of Akt. Interestingly, we have shown that this cascade protects cancer cells as they disseminate via blood vessels in vivo and we have identified proteases initiating this protection in model systems. Our findings further demonstrate roles for CDCP1 in cell migration in vitro including its competition as a Src substrate with a critical mediator of cell adhesion, FAK, and its role in migration induced by EGFR signalling. Targeting CDCP1 and its signalling effectors may be a rational approach to treat cancer patients at risk of recurrent disease.Support: Wesley Research Institute, Australian Research Council, Cancer Council Queensland, National Health and Medical Research Council of Australia