Neutralization of Tumor Necrosis Factor Bioactivity Ameliorates Urethane-Induced Pulmonary Oncogenesis in Mice

• Published in: Neoplasia (New York, N.Y.) Vol. 13; no. 12; pp. 1143 - 1151
• Main Authors: Karabela, Sophia P, Kairi, Chrysoula A, Magkouta, Sophia, Psallidas, Ioannis, Moschos, Charalampos, Stathopoulos, Ioannis, Zakynthinos, Spyros G, Roussos, Charis, Kalomenidis, Ioannis, Stathopoulos, Georgios T
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2011; Elsevier
• Subjects: Animals; Carcinogens - administration & dosage; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Transformation, Neoplastic - drug effects; Etanercept; Immunoglobulin G - administration & dosage; Immunoglobulin G - pharmacology; Immunologic Factors - administration & dosage; Immunologic Factors - pharmacology; Interferon-gamma - biosynthesis; Interleukin-10 - biosynthesis; Lung - drug effects; Lung - metabolism; Lung - pathology; Lung Neoplasms - chemically induced; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Macrophages - drug effects; Macrophages - metabolism; Mice; Mice, Inbred BALB C; Neovascularization, Pathologic - drug therapy; Oncology; Pneumonia - chemically induced; Pneumonia - drug therapy; Receptors, Tumor Necrosis Factor - administration & dosage; Receptors, Tumor Necrosis Factor - metabolism; Signal Transduction - drug effects; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - metabolism; Urethane - administration & dosage; terminal deoxynucleotidyl nick-end labeling; Lewis lung carcinoma; LLC; CBA; IL; PCNA; cytometric bead array; interferon; BAL; MTS; TNF; F8A; nuclear factor; IFN; proliferating cell nuclear antigen; 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2 H-tetrazolium, inner salt; TUNEL; tumor necrosis factor; NF; factor VIII–associated protein; interleukin; bronchoalveolar lavage; COPD; chronic obstructive pulmonary disease
• ISSN: 1476-5586; 1522-8002; 1476-5586; 1522-8002
• DOI: 10.1593/neo.111224

Abstract Tumor necrosis factor (TNF) has been implicated in inflammation-associated tumor progression. Although multiple reports identified a role for TNF signaling in established cancers, few studies have assessed the impact of TNF blockade on early tumor formation promotion. We aimed at exploring the effects of TNF neutralization in a preclinical mouse model of lung carcinogenesis. For this, Balb/c mice ( n = 42) received four weekly intraperitoneal urethane injections (1 g/kg) and twice-weekly intraperitoneal soluble TNF receptor (etanercept; 10 mg/kg) administered during tumor initiation/promotion, tumor progression, or continuously (months 1, 6, and 1-8 after urethane start, respectively). Lung oncogenesis was assessed after 8 months. In separate short-term studies, Balb/c mice ( n = 21) received a single control or urethane injection followed by twice-weekly intraperitoneal control or sTNFR:Fc injections. Lung inflammation was assessed after 1 week. We found that sTNFR:Fc treatment during tumor initiation/promotion resulted in a significant reduction of tumor number but not dimensions. However, sTNFR:Fc administered during tumor progression did not impact tumor multiplicity but significantly decreased tumor diameter. Continued sTNFR:Fc administration was effective in halting both respiratory tumor formation and progression in response to urethane. This favorable impact was associated with impaired cellular proliferation and new vessel formation in lung tumors. In addition, TNF neutralization altered the lung inflammatory response to urethane, evidenced by reductions in TNF and macrophage and increases in interferon γ and interleukin 10 content of the air spaces. sTNFR:Fc treatment of RAW264.7 macrophages downregulated TNF and enhanced interferon γ and interleukin 10 expression. In conclusion, TNF neutralization is effective against urethane-induced lung oncogenesis in mice and could present a lung chemoprevention strategy worth testing clinically.