This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Scott, K. A. Articles by Balkwill, F. R. Search for Related Content PubMed PubMed Citation Articles by Scott, K. A. Articles by Balkwill, F. R.

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 [K. A. S., R. J. M., C. H. A., N. E., R. G. T., F. R. B.], and Centocor, Malvern, Pennsylvania 19355 [B. J. S., D. J. S.]

² To whom requests for reprints should be addressed, at Cancer Research UK Translational Oncology Laboratory, Barts & The London, Queen Mary’s School of Medicine and Dentistry, 3^rd Floor, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, United Kingdom. Phone: 44-207-882-5797; Fax: 44-207-882-6110; E-mail: kate.scott{at}cancer.org.uk

The proinflammatory cytokine tumor necrosis factor- (TNF-) was originally considered to have activity against malignant disease. However, recent studies suggest TNF- may also act as an endogenous tumor promoter. In the present work, mice deficient in TNF- either genetically (TNF-^-/-) or after blockade with a neutralizing antibody (cV1q) were used to investigate the role of TNF- 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-^-/- 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- expression. TPA induced TNF- protein in newborn keratinocytes in vitro and epidermis in vivo. Neutralization of TNF- 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- 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-^-/- 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- is not limited to skin carcinogenesis. These results provide further evidence for procancer actions of TNF- and give some rationale for use of TNF- antagonists in cancer prevention and treatment.

This article has been cited by other articles:

				Y.-S. Lee, K.-H. Lim, X. Guo, Y. Kawaguchi, Y. Gao, T. Barrientos, P. Ordentlich, X.-F. Wang, C. M. Counter, and T.-P. Yao The Cytoplasmic Deacetylase HDAC6 Is Required for Efficient Oncogenic Tumorigenesis Cancer Res., September 15, 2008; 68(18): 7561 - 7569. [Abstract] [Full Text] [PDF]

				L. Tonnetti, S. Netzel-Arnett, G. A. Darnell, T. Hayes, M. S. Buzza, I. E. Anglin, A. Suhrbier, and T. M. Antalis SerpinB2 Protection of Retinoblastoma Protein from Calpain Enhances Tumor Cell Survival Cancer Res., July 15, 2008; 68(14): 5648 - 5657. [Abstract] [Full Text] [PDF]

				W. Ouyang, Y. Hu, J. Li, M. Ding, Y. Lu, D. Zhang, Y. Yan, L. Song, Q. Qu, D. Desai, et al. Direct evidence for the critical role of NFAT3 in benzo[a]pyrene diol-epoxide-induced cell transformation through mediation of inflammatory cytokine TNF induction in mouse epidermal Cl41 cells Carcinogenesis, October 1, 2007; 28(10): 2218 - 2226. [Abstract] [Full Text] [PDF]

				J. Ding, X. Zhang, J. Li, L. Song, W. Ouyang, D. Zhang, C. Xue, M. Costa, J. A. Melendez, and C. Huang Nickel Compounds Render Anti-apoptotic Effect to Human Bronchial Epithelial Beas-2B Cells by Induction of Cyclooxygenase-2 through an IKKbeta/p65-dependent and IKK{alpha}- and p50-independent Pathway J. Biol. Chem., December 22, 2006; 281(51): 39022 - 39032. [Abstract] [Full Text] [PDF]

				B. Yan, H. Wang, Z. N. Rabbani, Y. Zhao, W. Li, Y. Yuan, F. Li, M. W. Dewhirst, and C.-Y. Li Tumor Necrosis Factor-{alpha} Is a Potent Endogenous Mutagen that Promotes Cellular Transformation Cancer Res., December 15, 2006; 66(24): 11565 - 11570. [Abstract] [Full Text] [PDF]

				J. Chen, X. Cheng, M. Merched-Sauvage, C. Caulin, D. R. Roop, and P. J. Koch An unexpected role for keratin 10 end domains in susceptibility to skin cancer J. Cell Sci., December 15, 2006; 119(24): 5067 - 5076. [Abstract] [Full Text] [PDF]

				N. Devoogdt, H. Revets, A. Kindt, Y. Q. Liu, P. De Baetselier, and G. H. Ghassabeh The Tumor-Promoting Effect of TNF-{alpha} Involves the Induction of Secretory Leukocyte Protease Inhibitor J. Immunol., December 1, 2006; 177(11): 8046 - 8052. [Abstract] [Full Text] [PDF]

				J. Ding, J. Li, C. Xue, K. Wu, W. Ouyang, D. Zhang, Y. Yan, and C. Huang Cyclooxygenase-2 Induction by Arsenite Is through a Nuclear Factor of Activated T-cell-dependent Pathway and Plays an Antiapoptotic Role in Beas-2B Cells J. Biol. Chem., August 25, 2006; 281(34): 24405 - 24413. [Abstract] [Full Text] [PDF]

				Y. Yan, J. Li, W. Ouyang, Q. Ma, Y. Hu, D. Zhang, J. Ding, Q. Qu, K. Subbaramaiah, and C. Huang NFAT3 is specifically required for TNF-{alpha}-induced cyclooxygenase-2 (COX-2) expression and transformation of Cl41 cells J. Cell Sci., July 15, 2006; 119(14): 2985 - 2994. [Abstract] [Full Text] [PDF]

				T. Hagemann, J. Wilson, F. Burke, H. Kulbe, N. F. Li, A. Pluddemann, K. Charles, S. Gordon, and F. R. Balkwill Ovarian cancer cells polarize macrophages toward a tumor-associated phenotype. J. Immunol., April 15, 2006; 176(8): 5023 - 5032. [Abstract] [Full Text] [PDF]

				P. W. Szlosarek, M. J. Grimshaw, H. Kulbe, J. L. Wilson, G. D. Wilbanks, F. Burke, and F. R. Balkwill Expression and regulation of tumor necrosis factor {alpha} in normal and malignant ovarian epithelium. Mol. Cancer Ther., February 1, 2006; 5(2): 382 - 390. [Abstract] [Full Text] [PDF]

				S. D. Tachado, J. Zhang, J. Zhu, N. Patel, and H. Koziel HIV Impairs TNF-{alpha} Release in Response to Toll-Like Receptor 4 Stimulation in Human Macrophages In Vitro Am. J. Respir. Cell Mol. Biol., December 1, 2005; 33(6): 610 - 621. [Abstract] [Full Text] [PDF]

				R. Montesano, P. Soulie, J. A. Eble, and F. Carrozzino Tumour necrosis factor {alpha} confers an invasive, transformed phenotype on mammary epithelial cells J. Cell Sci., August 1, 2005; 118(15): 3487 - 3500. [Abstract] [Full Text] [PDF]

				B. Shan, Y. Zhuo, D. Chin, C. A. Morris, G. F. Morris, and J. A. Lasky Cyclin-dependent Kinase 9 Is Required for Tumor Necrosis Factor-{alpha}-stimulated Matrix Metalloproteinase-9 Expression in Human Lung Adenocarcinoma Cells J. Biol. Chem., January 14, 2005; 280(2): 1103 - 1111. [Abstract] [Full Text] [PDF]

				K. E. Peterson, S. Hughes, D. E. Dimcheff, K. Wehrly, and B. Chesebro Separate Sequences in a Murine Retroviral Envelope Protein Mediate Neuropathogenesis by Complementary Mechanisms with Differing Requirements for Tumor Necrosis Factor Alpha J. Virol., December 1, 2004; 78(23): 13104 - 13112. [Abstract] [Full Text] [PDF]

				C. J. Nicol, M. Yoon, J. M. Ward, M. Yamashita, K. Fukamachi, J. M. Peters, and F. J. Gonzalez PPAR{gamma} influences susceptibility to DMBA-induced mammary, ovarian and skin carcinogenesis Carcinogenesis, September 1, 2004; 25(9): 1747 - 1755. [Abstract] [Full Text] [PDF]