Chronic
inflammation is a risk factor for
lung cancer, and low-dose
aspirin intake reduces
lung cancer risk. However, the roles that specific inflammatory cells and their products play in lung
carcinogenesis have yet to be fully elucidated. In mice, alveolar macrophage numbers increase as lung
tumors progress, and pulmonary macrophage programing changes within 2 weeks of
carcinogen exposure. To examine how macrophages specifically affect lung
tumor progression, they were depleted in mice bearing
urethane-induced lung
tumors using
clodronate-encapsulated
liposomes. Alveolar macrophage populations decreased to ≤50% of control levels after 4-6 weeks of liposomal
clodronate treatment.
Tumor burden decreased by 50% compared to vehicle treated mice, and
tumor cell proliferation, as measured by Ki67 staining, was also attenuated. Pulmonary fluid levels of
insulin-like growth factor-I, CXCL1,
IL-6, and CCL2 diminished with
clodronate liposome treatment. Tumor-associated macrophages expressed markers of both M1 and M2 programing in vehicle and
clodronate liposome-treated mice. Mice lacking CCR2 (the receptor for
macrophage chemotactic factor CCL2) had comparable numbers of alveolar macrophages and showed no difference in
tumor growth rates when compared to similarly treated wild-type mice suggesting that while CCL2 may recruit macrophages to lung tumor microenvironments, redundant pathways can compensate when CCL2/CCR2 signaling is inactivated. Depletion of pulmonary macrophages rather than inhibition of their recruitment may be an advantageous strategy for attenuating
lung cancer progression.