Expression of both TNF-alpha receptor subtypes is essential for optimal skin tumour development.
Keratinocyte-derived TNF-alpha acts as an endogenous tumour promoter and can also regulate AP-1 activity in mouse epidermis. To gain further insight into TNF-alpha signalling during skin tumour formation, mice deficient in TNFR1 (TNFR1-/- mice) or TNFR2 (TNFR2-/- mice) were subjected to chemical carcinogenesis. Tumour multiplicity was significantly reduced in TNFR1-/- and TNFR2-/- mice compared to wild-type (wt) mice, suggesting that both receptors have protumour activity. However, TNFR1-/- mice were markedly more resistant to tumour development than TNFR2-/- mice indicating that TNFR1 is the major mediator of TNF-alpha-induced tumour formation. TNFR1 and TNFR2 were both expressed in wt epidermis during tumour promotion and by primary keratinocytes in vitro. TPA-induced c-Jun expression was transient in TNFR1-/- and TNFR2-/- compared to wt epidermis and this was reflected by reduced induction of the AP-1-responsive genes granulocyte/macrophage-colony stimulating factor, matrix metalloproteinase-9 and matrix metalloproteinase-3. These genes were differentially regulated in TNFR1-/- compared to TNFR2-/- epidermis, suggesting that the TNF-alpha receptors act independently via different AP-1 complexes to transduce TNF-alpha signals during tumour promotion. In addition, TNFR2 cooperated with TNFR1 to optimise TNFR1-mediated TNF-alpha bioactivity on keratinocytes in vitro. Our data provide further insight into TNF-alpha signalling in malignancy and provide some rationale for the use of TNF-alpha antagonists in the treatment of cancer.
Arnott
Caroline H
CH
Cancer Research UK Translational Oncology Laboratory, Barts & The London, Queen Mary's School of Medicine and Dentistry, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
Scott
Kate A
KA
Moore
Robert J
RJ
Robinson
Stephen C
SC
Thompson
Richard G
RG
Balkwill
Frances R
FR
D000818:Animals; D000831:Animals, Newborn; D015703:Antigens, CD / Q000235:genetics* / Q000502:physiology; D002478:Cells, Cultured; D004817:Epidermis / Q000187:drug effects / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000187:drug effects / Q000473:pathology; D012878:Skin Neoplasms / Q000235:genetics*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D015703:Antigens, CD; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D013755:Tetradecanoylphorbol Acetate