title: Foxm1 transcription factor is required for macrophage migration during lung inflammation and tumor formation.
abstract: 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-1α), 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.
authors.affiliation: Division of Pulmonary Biology, Perinatal Institute of Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA.
authors.forename: D
authors.initials: D
authors.lastname: Balli
authors.forename: X
authors.initials: X
authors.lastname: Ren
authors.forename: F-S
authors.initials: FS
authors.lastname: Chou
authors.forename: E
authors.initials: E
authors.lastname: Cross
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: V V
authors.initials: VV
authors.lastname: Kalinichenko
authors.forename: T V
authors.initials: TV
authors.lastname: Kalin
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002084:Butylated Hydroxytoluene / Q000031:analogs & derivatives; D000073883:CX3C Chemokine Receptor 1; D002465:Cell Movement / Q000235:genetics*; D054405:Chemokine CCL3 / Q000235:genetics / Q000378:metabolism; D054426:Chemokine CXCL2 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D053508:Matrix Metalloproteinase 12 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism / Q000637:transplantation; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D011014:Pneumonia / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism; D015728:Receptors, HIV / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000073883:CX3C Chemokine Receptor 1; C514936:CXCR4 protein, mouse; C496534:Ccl3 protein, mouse; D054405:Chemokine CCL3; D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D053583:Interleukin-1beta; D015850:Interleukin-6; D019718:Receptors, CXCR4; D018121:Receptors, Cytokine; D015728:Receptors, HIV; D002084:Butylated Hydroxytoluene; C037667:3,5-di-tert-butyl-4-hydroxytoluene; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D053508:Matrix Metalloproteinase 12