Elsevier

Molecular Immunology

Volume 36, Issues 13–14, September–October 1999, Pages 929-939
Molecular Immunology

Complement resistance of tumor cells: basal and induced mechanisms

https://doi.org/10.1016/S0161-5890(99)00115-7Get rights and content

Abstract

Clinical and experimental studies have suggested that complement may play a role in tumor cytotoxicity. However, the efficiency of complement-mediated tumor cell lysis is hampered by various protective mechanisms, which may be divided into two categories: basal and induced mechanisms. The basal mechanisms are spontaneously expressed in cells without a need for prior activation, whereas the induced mechanisms develop in cells subjected to stimulation with cytokines, hormones, drugs or with sublytic doses of complement and other pore-formers. Membrane-associated complement regulatory proteins, such as CD55 (DAF, Decay-Accelerating Factor), CD46 (MCP, Membrane Cofactor Protein), CD35 (CR1, Complement Receptor type 1) and CD59, which serve as an important mechanism of self protection and render autologous cells insensitive to the action of complement, appear to be over-expressed on certain tumors. Furthermore, tumor cells secrete several soluble complement inhibitors. Tumor cells may also express proteases that degrade complement proteins, such as C3, or ecto-protein kinases which can phosphorylate complement components, such as C9. Besides this basal resistance, nucleated cells resist, to some extent, complement damage by removing the membrane attack complexes (MAC) from their surface. Several biochemical pathways, including protein phosphorylation, activation of G-proteins and turnover of phosphoinositides have been implicated in resistance to complement. Calcium ion influx and activation of protein kinase C (PKC) and of mitogen-activated protein kinase (MAPK) have also been demonstrated to be associated with the complement-induced enhanced resistance to lysis. The complete elucidation of the molecular mechanisms involved in basal and induced tumor cell resistance will enable the development of strategies for interfering with these evasion mechanisms and the use of the cytotoxic complement system against tumor cells.

Introduction

The complement system (for review see: Rother et al., 1998) provides a rapid and efficient means to protect the host from invasive microorganisms. Complement is considered an important mediator of inflammation and contributes to the regulation of immune response. Under physiological conditions, an uncontrolled activation of complement is prevented by a vast array of regulatory proteins, either circulating in the plasma, or expressed on the cell surface (Morgan and Harris, 1999).

The potential role of complement in the control of malignant cells has been emphasized by various studies. In cancer patients, complement activation with subsequent deposition of complement components on tumor tissue has been demonstrated (Lucas et al., 1996, Niculescu et al., 1992, Yamakawa et al., 1994, Bernet-Camard et al., 1996, Niehans et al., 1996). Treatment of cancer patients with microbial vaccines, dating back to the last century, attempted to stimulate the immune system in the hope to reverse the malignant process. The effect of Corynebacterium parvum and Staphylococcus aureus protein A has been correlated with the activation of the alternative pathway and macrophage infiltration (reviewed in Cooper, 1985). However, complement as the fundamental principle behind positive anti-cancer effects could never be clearly shown. Anti-tumor effects of mouse monoclonal antibodies (mAb) against human tumors growing in nude mice have been shown to be mediated through complement activation (Capone et al., 1983, Chapman et al., 1990). Furthermore, recently a new pathway of complement action against tumors has been described. It was shown that mannan binding protein (MBP) recognizes and binds specifically to oligosaccharide residues expressed on the surfaces of a human colorectal carcinoma (Ma et al., 1999). Recombinant vaccinia virus carrying the human MBP gene was demonstrated to possess a potent growth-inhibiting activity against human colorectal carcinoma cells transplanted in nude mice when injected into the tumor or subcutaneously. However, in general, complement resistance of tumor cells is limiting the potential of anti-tumor antibodies.

It is well established that nucleated cells vary in their sensitivities to complement-mediated killing. This variation in susceptibility to complement has been ascribed to the nature of targeting antibodies, the protection of the cell by surface complement regulators and various other properties of the target cell, such as repair mechanisms, involving protein and lipid synthesis (the latter extensively reviewed in Ohanian and Schlager, 1981). Several of these protective mechanisms which are considered to be employed by all nucleated cells may also support tumor progression and confer additional resistance on neoplastic cells against therapy with complement-activating anti-tumor antibodies.

As described below, complement resistance mechanisms can be divided into two categories: basal and induced mechanisms. Basal resistance is provided by constitutively expressed membrane-associated and/or soluble complement regulators (Fig. 1, Fig. 2). In addition, upon stimulation of cells with cytokines, hormones, drugs or with sublytic doses of complement and other pore-formers, additional resistance mechanisms are induced (Fig. 3).

Section snippets

Membrane-bound complement regulatory proteins (mCRP)

Normal and neoplastic cells are protected from autologous complement attack by different cell-surface complement inhibitors (Fig. 1), such as CD35 (complement receptor type 1, CR1), CD55 (decay accelerating factor, DAF), CD46 (membrane cofactor protein, MCP) and CD59 (Protectin). These molecules regulate either the activation sequence of the complement cascade by affecting the generation of the C3 convertase (CD35, CD46, CD55) or interfere with the formation of the membrane attack complex

Induced mechanisms of complement resistance

In addition to basal complement resistance mechanisms, which can be modulated by various mediators as described above, complement resistance can be upregulated by various agents. Interestingly, one of the most potent agents to increase resistance to complement attack is the membrane attack complex (MAC) itself (Reiter et al., 1992). To lyse nucleated cells multiple MAC channels are required (Koski et al., 1983), whereas one functional channel is sufficient to lyse an erythrocyte (Ohanian and

Conclusion

All investigators of the interaction of tumor cells with complement share a common goal which is to search for the most potent strategy to sensitize tumor cells to the lytic action of the patient’s own complement system. As shown here, this is not going to be an easy task. Tumor cells are equipped with an array of protective mechanisms which act concomitantly to assure a complement resistant phenotype. Each tumor has a different ‘cocktail’ of evasion mechanisms that will have to be dealt with

Acknowledgements

This work was supported in part by the Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum (DKFZ) and Israeli’s Ministry of Science (MOS).

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