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

Abstract

Macrophages play a key role in tumor-associated pulmonary inflammation that supports proliferation of tumor cells and promotes lung tumor growth. Although increased numbers of tumor-associated macrophages (TAM) 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 TAM, a mouse line with macrophage-specific Foxm1 deletion was generated (macFoxm1−/−). Lung tumorigenesis was induced using a MCA/BHT 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. Expression levels of pro-inflammatory genes iNOS, Cox-2, IL-1b and IL-6, as well as migration related genes 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, CX3CR1 and CXCR4, were decreased in Foxm1-deficient monocytes. In co-transfection experiments, Foxm1 directly bound to and transcriptionally activated CX3CR1 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.