C3 Drives Inflammatory Skin Carcinogenesis Independently of C5.

Abstract Non-melanoma 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 UV radiation 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 (DMBA) causes oncogenic mutations in epithelial cells and 12-O-tetradecanoylphorbol-13-acetate (TPA) promotes the outgrowth of these cells, we found that C3 deficient mice displayed a significantly reduced tumor burden, whilst an opposite phenotype was observed in animals lacking C5aR1, C5aR2 and C3aR. In addition, in mice unable to form the membrane-attack complex (MAC) the tumor progression was unaltered. C3 deficiency did not affect the cancer response to DMBA treatment alone, but reduced the epidermal hyperplasia during TPA-induced inflammation. Collectively these data indicate that C3 drives tumorigenesis during chronic skin inflammation, independently of the downstream generation of C5a or MAC.