Macrophages promote urethane-induced lung adenocarcinoma

Background: Macrophages play a key role in neoplastic progression. We recently reported a profound tumor-protective effect of clodronate-mediated macrophage ablation against urethane (a smoke carcinogen)-induced lung oncogenesis (Zaynagetdinov, R. et al. J Immunol 2011;187:5703-11). Aims: To investigate the impact of genetic macrophage ablation on chemical-induced lung tumor development. Methods: Homozygote Dta f/f mice that express cell-suicidal Diphtheria toxin upon CRE recombinase-mediated recombination were crossed with Lyz2.Cre +/+ mice that express CRE specifically in macrophages. The above controls, as well as double heterozygote offspring Lyz2.Cre +/- ;Dta f/wt mice, all on the C57BL/6 background, received ten weekly doses of intraperitoneal urethane (1 g/Kg) to overcome the resistance of these mice to tumor induction, and lungs were retrieved six months after the first urethane dose for lung tumor examination. Results: Macrophage-deficient mice ( Lyz.Cre +/- ;Dta f/wt ) were markedly protected from urethane-induced lung tumor development compared with both Dta f/f and Lyz2.Cre +/+ controls. To this end, the number and diameter of urethane-triggered lung tumors in Lyz2.Cre +/+ (n = 13), Dta f/f (n = 8), and Lyz.Cre +/- ;Dta f/wt (n = 6) mice (mean±SEM) were 3.5±1.0, 2.3±0.6, and 0.3±0.2 (P Conclusions: These results corroborate that macrophages play a key role in tumor initiation and progression during chemical carcinogenesis in the respiratory tract. Funding: European Research Council Starting Independent Investigator Grant #260524.