An anti-tumor necrosis factor-alpha antibody inhibits the development of experimental skin tumors.
The proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) was originally considered to have activity against malignant disease. However, recent studies suggest TNF-alpha may also act as an endogenous tumor promoter. In the present work, mice deficient in TNF-alpha either genetically (TNF-alpha(-/-)) or after blockade with a neutralizing antibody (cV1q) were used to investigate the role of TNF-alpha in skin tumor development. Papillomas were induced in wild-type (wt) mice after treatment of skin with the initiating agent 9,10-dimethyl-1,2-benzanthracene followed by promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA) for 15 weeks. TNF-alpha(-/-) mice were resistant to papilloma development when compared with wt mice on C57Bl/6J, 129/SvEv, and BALB/c genetic backgrounds. Primary murine keratinocytes (newborn keratinocytes) and skin homogenates were used to characterize TPA-stimulated TNF-alpha expression. TPA induced TNF-alpha protein in newborn keratinocytes in vitro and epidermis in vivo. Neutralization of TNF-alpha protein with cV1q in vivo for 0-15 weeks of promotion significantly decreased skin tumor development after 9,10-dimethyl-1,2-benzanthracene/TPA treatment. cV1q treatment during the early stages of tumor promotion (0-6 weeks) was equally effective. These data suggest that early induction of TNF-alpha is critical for skin tumor promotion. cV1q also reduced TPA-stimulated expression of matrix metalloproteinase 9 and granulocyte macrophage colony-stimulating factor, proteins that are differentially regulated in wt and TNF-alpha(-/-) epidermis. Treatment of the 410.4 transplantable breast carcinoma with cV1q reduced tumor growth in vivo, illustrating that inhibition of tumor growth through neutralization of TNF-alpha is not limited to skin carcinogenesis. These results provide further evidence for procancer actions of TNF-alpha and give some rationale for use of TNF-alpha antagonists in cancer prevention and treatment.
Scott
Kate A
KA
Cancer Research UK Translational Oncology Laboratory, John Vane Science Centre, Barts & The London, Queen Mary's School of Medicine and Dentistry, London EC1M 6BQ, United Kingdom. kate.scott@cancer.org.uk
Moore
Robert J
RJ
Arnott
Caroline H
CH
East
Nick
N
Thompson
Richard G
RG
Scallon
Bernard J
BJ
Shealy
David J
DJ
Balkwill
Frances R
FR
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D002273:Carcinogens / Q000633:toxicity; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D007113:Immunity, Innate; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009367:Neoplasm Staging; D010212:Papilloma / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D012878:Skin Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D016211:Transforming Growth Factor alpha / Q000276:immunology*
D000911:Antibodies, Monoclonal; D002273:Carcinogens; D016211:Transforming Growth Factor alpha; D015127:9,10-Dimethyl-1,2-benzanthracene; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D020780:Matrix Metalloproteinase 9; D013755:Tetradecanoylphorbol Acetate