C3 Drives Inflammatory Skin Carcinogenesis Independently of C5.
9,10-Dimethyl-1,2-benzanthracene
/ administration & dosage
Animals
Carcinogens
/ administration & dosage
Carcinoma, Squamous Cell
/ chemically induced
Complement Activation
/ genetics
Complement C3
/ genetics
Complement C5
/ metabolism
Complement Membrane Attack Complex
/ metabolism
Disease Models, Animal
Disease Progression
Humans
Mice
Mice, Knockout
Mice, Transgenic
Neoplasms, Experimental
/ blood
Receptor, Anaphylatoxin C5a
/ genetics
Receptors, Complement
/ genetics
Signal Transduction
/ genetics
Skin
/ drug effects
Skin Neoplasms
/ chemically induced
Tumor Escape
Journal
The Journal of investigative dermatology
ISSN: 1523-1747
Titre abrégé: J Invest Dermatol
Pays: United States
ID NLM: 0426720
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
13
03
2020
revised:
30
05
2020
accepted:
10
06
2020
pubmed:
20
7
2020
medline:
18
9
2021
entrez:
20
7
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32682912
pii: S0022-202X(20)31839-X
doi: 10.1016/j.jid.2020.06.025
pmc: PMC8150327
pii:
doi:
Substances chimiques
C3 protein, human
0
C3 protein, mouse
0
C5ar1 protein, mouse
0
C5ar2 protein, mouse
0
Carcinogens
0
Complement C3
0
Complement C5
0
Complement Membrane Attack Complex
0
Receptor, Anaphylatoxin C5a
0
Receptors, Complement
0
complement C3a receptor
0
9,10-Dimethyl-1,2-benzanthracene
57-97-6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
404-414.e6Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 108008/Z/15/Z
Pays : United Kingdom
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
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