Is complement good or bad for cancer patients? A new perspective on an old dilemma

Abstract

Several studies of human cancers have established that chronic and insidious inflammation promotes the process of carcinogenesis and exacerbates the growth of existing tumors. Conversely, acute inflammation seems to have the opposite effect. Recent discoveries indicate that this dualism in the role of inflammation in cancer is mirrored by the effects of the complement system on this disease process. Previous studies have suggested that complement proteins can contribute to the immune surveillance of malignant tumors. However, a very recent study has indicated that complement proteins can also promote tumor growth. Here, we describe our current understanding of the role of complement in tumor development and progression.

Figure 1

Complement effectors generated during activation contribute to various mechanisms that limit tumor growth. The complement system can be activated through several distinctive pathways. The classical pathway is initiated when C1q binds to its various targets. The lectin pathway begins with the binding of mannose-binding lectin (MBL) or ficolins to pathogen associated molecular patterns (PAMPs) or apoptotic host cells. This binding activates MBL-associated serine proteases (MASPs). Finally, the alternative pathway is initiated by low-grade cleavage of C3 in plasma and the generation of small amounts of C3b. The C3b cleavage product iC3b binds to tumor cells and through the interaction with complement receptor 3 (CD11b/CD18) on mononuclear phagocytes and natural killer (NK) cells enhances antibody-dependent cellular cytotoxicity (ADCC). C5a inhibits growth of tumors in a mammary sarcoma model in mice. The terminal complement complex (TCC) is thought to contribute to complement-dependent cytotoxicity (CDC), which is one of the mechanisms for eliminating tumor cells by therapeutic antibodies. C3a, which contributes to the mobilization of hematopoietic progenitor cells, probably contributes to tumor immune surveillance. Unbroken lines connect complement proteins to functions which inhibit tumor growth, whereas broken lines connect complement proteins to functions that can currently only be hypothetically linked to inhibition of tumor growth.

Figure 2

Some complement proteins can accelerate tumor growth. C5a, probably generated through the classical pathway, activates myeloid-derived suppressor cells (MDSCs). Activated MDSCs migrate to tumors and produce highly immunosuppressive reactive oxygen species (ROS) and reactive nitrogen species (RNS) that inhibit the anti-tumor T-cell response. In addition, tumor cells are protected from co attack by membrane complement regulatory proteins (mCRPs) and soluble complement inhibitors, secreted in the tumor microenvironment, such as factor H (fH) and factor I (fI). Factor H is a cofactor for fI-mediated cleavage of C3b to iC3b and accelerates the decay of the alternative pathway C3 convertase. The terminal complement complex (TCC) can be incorporated into cell membranes at sublytic doses and activate target cells. Unbroken lines connect complement proteins to their functions in tumor growth. Broken lines connect complement proteins to functions that currently can only be hypothetically linked to tumor growth.