ADAM17 Activity and IL-6 Trans-Signaling in Inflammation and Cancer.
ADAM17
colon cancer
epidermal growth factor receptor (EGF-R)
inflammation associated cancer
interleukin-6
lung cancer
metalloprotease
shedding
trans-signaling
tumor necrosis factor alpha (TNFα)
Journal
Cancers
ISSN: 2072-6694
Titre abrégé: Cancers (Basel)
Pays: Switzerland
ID NLM: 101526829
Informations de publication
Date de publication:
05 Nov 2019
05 Nov 2019
Historique:
received:
30
09
2019
revised:
25
10
2019
accepted:
02
11
2019
entrez:
8
11
2019
pubmed:
7
11
2019
medline:
7
11
2019
Statut:
epublish
Résumé
All ligands of the epidermal growth factor receptor (EGF-R) are transmembrane proteins, which need to be proteolytically cleaved in order to be systemically active. The major protease responsible for this cleavage is the membrane metalloprotease ADAM17, which also has been implicated in cleavage of TNFα and interleukin-6 (IL-6) receptor. It has been recently shown that in the absence of ADAM17, the main protease for EGF-R ligand processing, colon cancer formation is largely abrogated. Intriguingly, colon cancer formation depends on EGF-R activity on myeloid cells rather than on intestinal epithelial cells. A major activity of EGF-R on myeloid cells is the stimulation of IL-6 synthesis. Subsequently, IL-6 together with the ADAM17 shed soluble IL-6 receptor acts on intestinal epithelial cells via IL-6 trans-signaling to induce colon cancer formation, which can be blocked by the inhibitor of IL-6 trans-signaling, sgp130Fc. Blockade of IL-6 trans-signaling therefore offers a new therapeutic window downstream of the EGF-R for the treatment of colon cancer and possibly of other EGF-R related neoplastic diseases.
Identifiants
pubmed: 31694340
pii: cancers11111736
doi: 10.3390/cancers11111736
pmc: PMC6895846
pii:
doi:
Types de publication
Journal Article
Review
Langues
eng
Subventions
Organisme : Deutsche Forschungsgemeinschaft
ID : SFB841, C1; SFB877, A1; Cluster of Excellence "Inflammation at Interfaces"
Déclaration de conflit d'intérêts
S.R.J. has acted as a consultant and speaker for AbbVie, Chugai, Genentech Roche, Pfizer, and Sanofi. He also declares that he is an inventor on patents owned by CONARIS Research Institute, which develops the sgp130Fc protein Olamkicept together with the company IMab. S.R.-J. has stock ownership in CONARIS. N.S. declares no competing interests.
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