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RESEARCH PRODUCT
C3 Drives Inflammatory Skin Carcinogenesis Independently of C5
Jessica StridKunyuan TianKatie BestBeatrice BelmonteLiliane Fossati-jimackAlessandro GulinoWilliam D. JacksonJörg KöhlJörg KöhlRocio Castro SeoaneMarina Bottosubject
0301 basic medicineWT wild typeSkin NeoplasmsComplement receptorComplement Membrane Attack Complexmedicine.disease_causeBiochemistrychemistry.chemical_compoundMice0302 clinical medicineCR complement receptorComplement ActivationSkinMice KnockoutcSCC cutaneous squamous cell carcinomaComplement C5Complement C3Receptors Complement030220 oncology & carcinogenesisCarcinoma Squamous CellDisease ProgressionTumor BiologyOriginal ArticleMAC membrane attack complexSignal TransductionHPV16 human papillomavirus type 16910-Dimethyl-12-benzanthraceneTPA 12-O-tetradecanoylphorbol-13-acetateMice TransgenicDermatologySettore MED/08 - Anatomia Patologica03 medical and health sciencesmedicineAnimalsHumansC3Molecular BiologyReceptor Anaphylatoxin C5aDMBA 712-dimethylbenz[a]anthracenebusiness.industry712-Dimethylbenz[a]anthraceneCancerCell BiologyNeoplasms Experimentalmedicine.diseaseComplement systemDisease Models Animal030104 developmental biologychemistryTumor progressionCancer researchCarcinogensTumor EscapeSkin cancerbusinessCarcinogenesisComplement membrane attack complexSkin carcinogenesis.EC epithelial celldescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2021-02-01 |