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.