Complement System in Cutaneous Squamous Cell Carcinoma

Abstract

Epidermal keratinocyte-derived cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer with high mortality rates in the advanced stage. Chronic inflammation is a recognized risk factor for cSCC progression and the complement system, as a part of innate immunity, belongs to the microenvironment of tumors. The complement system is a double-edged sword in cancer, since complement activation is involved in anti-tumor cytotoxicity and immune responses, but it also promotes cancer progression directly and indirectly. Recently, the role of several complement components and inhibitors in the regulation of progression of cSCC has been shown. In this review, we will discuss the role of complement system components and inhibitors as biomarkers and potential new targets for therapeutic intervention in cSCC.

Keywords: complement; skin cancer; squamous cell carcinoma.

Figure 1

Complement cascade. The complement system can be activated via three major pathways. (1) The classical pathway is typically activated by antigen-antibody complexes on the cell surface. The C1 complex consists of C1q, C1r, and C1s molecules, and cleaves serum proteins C4 and C2. C4b binds to the target cell surface and C2a binds C4b and forms the complex C4b2a, which is a classical pathway C3 convertase. (2) The lectin pathway is activated by binding pattern-recognizing mannose-binding lectins (MBLs) to carbohydrate ligands on the surface of pathogens. Activated MBL-associated serine proteinase (MASP)-2 in the MBL-MASP-2 complex cleaves C4 and C2. The MASP-1/3 can activate complement factor D (CFD). (3) The alternative pathway is activated by any permissive surface. Constant spontaneous breakdown of C3 takes place at a low level in plasma and by the surfaces of microbes and generates C3b. Complement factor B (CFB) binds to C3b and forms a complex C3bB. Complement factor D (CFD) cleaves CFB to Ba and Bb. The fragment Bb stays attached to C3b and C3 convertase (C3bBb) is formed. Properdin stabilizes C3 convertase. All these three pathways lead to activation of the lytic pathway. C3b associates with C3 convertase to form C5 convertase and cleaves C5. C5b engages C6, C7, C8, and C9 to form the terminal membrane attack complex (MAC), which induces cell lysis. The activation of complement is strictly regulated to prevent damage to host cells. Complement factor I (CFI) and complement factor H (CFH) are the main inhibitors of complement pathways. CFH competes with CFB for binding to active C3b and inhibits C3 convertase by displacing Bb from this complex. CFI cleaves C3b to an inactive form and also inhibits the classical pathway by cleaving C4b. CFH also acts as a cofactor CFI.

Figure 2

The role of tumor cell-derived complement components and inhibitors in cutaneous squamous cell carcinoma (cSCC). During progression of the cSCC complement factor H (CFH) and serine proteinases C1r, C1s, C3, CFB, and CFI exert effects on cSCC cells other than those related to complement activation. C1r, C1s, C3, CFB, and CFI promote cSCC tumor growth in vivo. C1r and C1s promote angiogenesis in cSCC tumors in vivo. C1r, C1s, C3, CFB, CFI, and CFH increase proliferation and viability of cSCC cells. C1r and C1s inhibit apoptosis of cSCC cells. The migration of cSCC cells is stimulated by C3, CFB, CFI, CFH, C1r, and C1s. ↑ indicates stimulation, ↓ indicates inhibition.