RT Journal Article
SR Electronic
T1 An Anti-Tumor Necrosis Factor-α Antibody Inhibits the Development of Experimental Skin Tumors
JF Molecular Cancer Therapeutics
JO Mol Cancer Ther
FD American Association for Cancer Research
SP 445
OP 451
VO 2
IS 5
A1 Scott, Kate A.
A1 Moore, Robert J.
A1 Arnott, Caroline H.
A1 East, Nick
A1 Thompson, Richard G.
A1 Scallon, Bernard J.
A1 Shealy, David J.
A1 Balkwill, Frances R.
YR 2003
UL http://mct.aacrjournals.org/content/2/5/445.abstract
AB The proinflammatory cytokine tumor necrosis factor-α (TNF-α) was originally considered to have activity against malignant disease. However, recent studies suggest TNF-α may also act as an endogenous tumor promoter. In the present work, mice deficient in TNF-α either genetically (TNF-α−/−) or after blockade with a neutralizing antibody (cV1q) were used to investigate the role of TNF-α 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-α−/− 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-α expression. TPA induced TNF-α protein in newborn keratinocytes in vitro and epidermis in vivo. Neutralization of TNF-α 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-α 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-α−/− 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-α is not limited to skin carcinogenesis. These results provide further evidence for procancer actions of TNF-α and give some rationale for use of TNF-α antagonists in cancer prevention and treatment.