Foxm1 transcription factor is required for macrophage migration during lung inflammation and tumor formation

• Published in: Oncogene Vol. 31; no. 34; pp. 3875 - 3888
• Main Authors: Balli, D, Ren, X, Chou, F-S, Cross, E, Zhang, Y, Kalinichenko, V V, Kalin, T V
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.08.2012; Nature Publishing Group
• Subjects: 3-Methylcholanthrene; 631/45/612/822; 692/420/755; 692/698/690/292; 692/699/67/1612; Adoptive Transfer; Animals; Apoptosis; Butylated hydroxytoluene; Butylated Hydroxytoluene - analogs & derivatives; Cancer; Care and treatment; Cell Biology; Cell Movement - genetics; Cell proliferation; Chemokine CCL3 - genetics; Chemokine CCL3 - metabolism; Chemokine CXCL2 - genetics; Chemokine CXCL2 - metabolism; Chemokine receptors; CX3C Chemokine Receptor 1; CX3CR1 protein; CXCR4 protein; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; Cyclooxygenase-2; Development and progression; Flow Cytometry; Forkhead Box Protein M1; Forkhead protein; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Gene expression; Health aspects; Human Genetics; IL-1β; Inflammation; Interleukin 1; Interleukin 6; Interleukin-1beta - genetics; Interleukin-1beta - metabolism; Interleukin-6 - genetics; Interleukin-6 - metabolism; Internal Medicine; Leukocyte migration; Lung cancer; Lung Neoplasms - chemically induced; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Macrophage inflammatory protein; Macrophage inflammatory protein 1; Macrophages; Macrophages - metabolism; Macrophages - pathology; Matrix Metalloproteinase 12 - genetics; Matrix Metalloproteinase 12 - metabolism; Medicine; Medicine & Public Health; Mice; Mice, Knockout; Monocytes; Monocytes - metabolism; Monocytes - transplantation; Nitric Oxide Synthase Type II - genetics; Nitric Oxide Synthase Type II - metabolism; Nitric-oxide synthase; Oncology; original-article; Pathogenesis; Physiological aspects; Pneumonia - chemically induced; Pneumonia - genetics; Pneumonia - metabolism; Prognosis; Promoter Regions, Genetic - genetics; Properties; Protein Binding; Proteins; Receptors, CXCR4 - genetics; Receptors, CXCR4 - metabolism; Receptors, Cytokine - genetics; Receptors, Cytokine - metabolism; Receptors, HIV - genetics; Receptors, HIV - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Transcription factors; Transfection; Transgenic animals; Tumor cells; Tumorigenesis; United States; lung cancer; macrophages; tumor microenvironment; transgenic mice; Forkhead transcription factor FoxM1; monocyte migration
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2011.549

Macrophages have a key role in tumor-associated pulmonary inflammation that supports the proliferation of tumor cells and promotes lung tumor growth. Although increased numbers of tumor-associated macrophages are linked to poor prognosis in lung cancer patients, little is known regarding the transcriptional mechanisms controlling recruitment of macrophages during lung tumorigenesis. Forkhead Box m1 (Foxm1) transcription factor is induced in multiple cell types within tumor lesions and its increased expression is associated with poor prognosis in patients with lung adenocarcinomas. To determine the role of Foxm1 in recruitment of tumor-associated macrophages, a mouse line with macrophage-specific Foxm1 deletion was generated ( macFoxm1 −/− ). Lung tumorigenesis was induced using a 3-methylcholanthrene/butylated hydroxytoluene (BHT; 3,5-di-t-butyl-4-hydroxytoluene) tumor initiation/promotion protocol. Ablation of Foxm1 in macrophages reduced the number and size of lung tumors in macFoxm1 −/− mice. Decreased tumorigenesis was associated with diminished proliferation of tumor cells and decreased recruitment of macrophages during the early stages of tumor formation. The expression levels of the pro-inflammatory genes iNOS , Cox-2 , interleukin-1b ( IL-1b ) and IL-6 , as well as the migration-related genes macrophage inflammatory protein-1 ( MIP-1 α), MIP-2 and MMP-12 , were decreased in macrophages isolated from macFoxm1 −/− mice. Migration of Foxm1-deficient macrophages was reduced in vitro . The chemokine receptors responsible for monocyte recruitment to the lung, CX 3 CR1 and CXCR4 , were decreased in Foxm1-deficient monocytes. In co-transfection experiments, Foxm1 directly bound to and transcriptionally activated the CX 3 CR1 promoter. Adoptive transfer of wild-type monocytes to macFoxm1 −/− mice restored BHT-induced pulmonary inflammation to the levels observed in control mice. Expression of Foxm1 in macrophages is required for pulmonary inflammation, recruitment of macrophages into tumor sites and lung tumor growth.