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 Dtaf/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+/-;Dtaf/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 +/-;Dtaf/wt ) were markedly protected from urethane-induced lung tumor development compared with both Dtaf/f and Lyz2.Cre+/+ controls. To this end, the number and diameter of urethane-triggered lung tumors in Lyz2.Cre+/+(n = 13), Dtaf/f (n = 8), and Lyz.Cre +/-;Dtaf/wt(n = 6) mice (meanSEM) were 3.51.0, 2.30.6, and 0.30.2 (P < 0.05) and 0.410.07, 0.420.08, and 0.120.07 mm (P < 0.05), respectively.
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.