title: A critical role for macrophages in promotion of urethane-induced lung carcinogenesis.
abstract: Macrophages have established roles in tumor growth and metastasis, but information about their role in lung tumor promotion is limited. To assess the role of macrophages in lung tumorigenesis, we developed a method of minimally invasive, long-term macrophage depletion by repetitive intratracheal instillation of liposomal clodronate. Compared with controls treated with repetitive doses of PBS-containing liposomes, long-term macrophage depletion resulted in a marked reduction in tumor number and size at 4 mo after a single i.p. injection of the carcinogen urethane. After urethane treatment, lung macrophages developed increased M1 macrophage marker expression during the first 2-3 wk, followed by increased M2 marker expression by week 6. Using a strategy to reduce alveolar macrophages during tumor initiation and early promotion stages (weeks 1-2) or during late promotion and progression stages (weeks 4-16), we found significantly fewer and smaller lung tumors in both groups compared with controls. Late-stage macrophage depletion reduced VEGF expression and impaired vascular growth in tumors. In contrast, early-stage depletion of alveolar macrophages impaired urethane-induced NF-κB activation in the lungs and reduced the development of premalignant atypical adenomatous hyperplasia lesions at 6 wk after urethane injection. Together, these studies elucidate an important role for macrophages in lung tumor promotion and indicate that these cells have distinct roles during different stages of lung carcinogenesis.
authors: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors: Rinat
authors: R
authors: Zaynagetdinov
authors: Taylor P
authors: TP
authors: Sherrill
authors: Vasiliy V
authors: VV
authors: Polosukhin
authors: Wei
authors: W
authors: Han
authors: Jamie A
authors: JA
authors: Ausborn
authors: Allyson G
authors: AG
authors: McLoed
authors: Frank B
authors: FB
authors: McMahon
authors: Linda A
authors: LA
authors: Gleaves
authors: Amber L
authors: AL
authors: Degryse
authors: Georgios T
authors: GT
authors: Stathopoulos
authors: Fiona E
authors: FE
authors: Yull
authors: Timothy S
authors: TS
authors: Blackwell
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002469:Cell Separation; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000139:chemically induced / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014520:Urethane / Q000633:toxicity*
chemical_list: D002273:Carcinogens; D014520:Urethane