Abstract
Nonmelanoma skin cancer such as cutaneous squamous cell carcinoma (cSCC) is the most common form of cancer and can occur as a consequence of DNA damage to the epithelium by UVR or chemical carcinogens. There is growing evidence that the complement system is involved in cancer immune surveillance; however, its role in cSCC remains unclear. Here, we show that complement genes are expressed in tissue from patients with cSCC, and C3 activation fragments are present in cSCC biopsies, indicating complement activation. Using a range of complement-deficient mice in a two-stage mouse model of chemically-induced cSCC, where a subclinical dose of 7,12-dimethylbenz[a]anthracene causes oncogenic mutations in epithelial cells and 12-O-tetradecanoylphorbol-13-acetate promotes the outgrowth of these cells, we found that C3-deficient mice displayed a significantly reduced tumor burden, whereas an opposite phenotype was observed in mice lacking C5aR1, C5aR2, and C3a receptor. In addition, in mice unable to form the membrane attack complex, the tumor progression was unaltered. C3 deficiency did not affect the cancer response to 7,12-dimethylbenz[a]anthracene treatment alone but reduced the epidermal hyperplasia during 12-O-tetradecanoylphorbol-13-acetate–induced inflammation. Collectively, these data indicate that C3 drives tumorigenesis during chronic skin inflammation, independently of the downstream generation of C5a or membrane attack complex.
Highlights
Epithelial cells (ECs) line the surface of the skin and are exposed to a variety of potential carcinogens, including chemicals and UV irradiation
Because C3 activation leads to the generation of C5a, which is a potent proinflammatory mediator, and to the formation of the membrane attack complex (MAC), we explored the role of these pathways using mice lacking the receptors for C5a (C5aR1 or C5aR2) and mice lacking C6
Given the strong expression of complement receptors (CR) such as CR3 and CR4 on mononuclear phagocytes, we performed double immunostaining for macrophages and C3d, a complement activation product that remains bound on the cell surface, to determine colocalization. In both mouse (Figure 5c) and human (Figure 5d) specimens, we found that C3d-positive cells were in very close proximity to macrophages (F4/80þ in mouse and CD163þ in human samples), indicating that complement activation may orchestrate the interactions between the phagocytic cells and the tumor cells with important implications for tumor progression
Summary
Epithelial cells (ECs) line the surface of the skin and are exposed to a variety of potential carcinogens, including chemicals and UV irradiation. UV irradiation is a wellknown DNA-damaging agent of the skin, but chemical carcinogens are prevalent in the environment, including polyaromatic hydrocarbons such as 7,12-dimethylbenz[a] anthracene (DMBA). The contribution of these carcinogens to the prevalence of nonmelanoma skin cancers is unclear. The complement system is an important arm of innate immunity and plays key roles in the activation and regulation of adaptive immunity (Merle et al, 2015a, 2015b). Complement can be activated through three pathways: the classical, the alternative, or the lectin pathway, with these pathways converging at the level of C3. Its role in cellular metabolism (Kolev et al, 2015) and survival (Liszewski et al, 2013), tissue homeostasis, and immune surveillance is becoming recognized (Reis et al, 2019)
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