Tumor Cell Resistance to Complement-Mediated Lysis

Abstract

Complement-mediated tumor cell lysis is hampered by several protective mechanisms. Basal mechanisms of resistance are constitutively expressed in cells without a need for prior activation. These include the (over)expression of membrane-associated complement regulatory proteins, such as CD55 (DAF, Decay-Accelerating Factor), CD46 (MCP, Membrane Cofactor Protein) and CD59, on tumor cells. To generate a protective microenvironment, tumor cells secrete several soluble complement inhibitors and express on their surface ecto-proteases that degrade complement proteins or ecto-protein kinases which impair by phosphorylation the functional activity of certain complement components. Increased sialic acid expression also confers complement resistance to cancer cells and has been correlated with increased metastatic activity in certain tumors. Tumor cell protection can be also induced or augmented upon stimulation with cytokines, hormones, drugs or even with sublytic doses of complement and other pore-forming molecules. Intracellular protective pathways facilitate in cancer cells the removal of the membrane attack complexes and repair processes. Increase in cytosolic calcium ion concentration, activation of protein kinase C (PKC) and of the mitogen-activated protein kinase ERK, heat shock proteins, lipid metabolism and protein synthesis, have all been implicated in cancer cell protection from complement attack. First attempts are now being made to counteract these resistance mechanisms, including a targeted neutralisation of mCRP on tumor cells. Understanding the complex molecular mechanisms involved in basal and induced tumor cell resistance to complement is essential for development of strategies of interference with these evasion mechanisms and for effectively targeting the cytotoxic activity of the complement system to cancer cells.