title: Neutralization of tumor necrosis factor bioactivity ameliorates urethane-induced pulmonary oncogenesis in mice.
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.
authors.affiliation: Applied Biomedical Research & Training Center Marianthi Simou, Department of Critical Care & Pulmonary Services, General Hospital Evangelismos, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Sophia P
authors.initials: SP
authors.lastname: Karabela
authors.forename: Chrysoula A
authors.initials: CA
authors.lastname: Kairi
authors.forename: Sophia
authors.initials: S
authors.lastname: Magkouta
authors.forename: Ioannis
authors.initials: I
authors.lastname: Psallidas
authors.forename: Charalampos
authors.initials: C
authors.lastname: Moschos
authors.forename: Ioannis
authors.initials: I
authors.lastname: Stathopoulos
authors.forename: Spyros G
authors.initials: SG
authors.lastname: Zakynthinos
authors.forename: Charis
authors.initials: C
authors.lastname: Roussos
authors.forename: Ioannis
authors.initials: I
authors.lastname: Kalomenidis
authors.forename: Georgios T
authors.initials: GT
authors.lastname: Stathopoulos
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000008:administration & dosage; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D000068800:Etanercept; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000494:pharmacology; D007155:Immunologic Factors / Q000008:administration & dosage / Q000494:pharmacology; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014520:Urethane / Q000008:administration & dosage
chemical_list: D002273:Carcinogens; D007074:Immunoglobulin G; D007155:Immunologic Factors; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D014520:Urethane; D007371:Interferon-gamma; D000068800:Etanercept