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- Title
Expression of both TNF-a receptor subtypes is essential for optimal skin tumour development.
- Authors
Moore, Robert J.; Robinson, Stephen C.; Thompson, Richard G.; Balkwill, Frances R.; Scott, Kate A.; Arnott, Caroline H.
- Abstract
Keratinocyte-derived TNF-a acts as an endogenous tumour promoter and can also regulate AP-1 activity in mouse epidermis. To gain further insight into TNF-a 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-a-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-a receptors act independently via different AP-1 complexes to transduce TNF-a signals during tumour promotion. In addition, TNFR2 cooperated with TNFR1 to optimise TNFR1-mediated TNF-a bioactivity on keratinocytes in vitro. Our data provide further insight into TNF-a signalling in malignancy and provide some rationale for the use of TNF-a antagonists in the treatment of cancer.Oncogene (2004) 23, 1902-1910. doi:10.1038/sj.onc.1207317 Published online 8 December 2003
- Publication
Oncogene, 2004, Vol 23, Issue 10, p1902
- ISSN
0950-9232
- Publication type
Academic Journal
- DOI
10.1038/sj.onc.1207317