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

Oncogene volume 31, pages 3875–3888 (2012)Cite this article

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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, CX3CR1 and CXCR4, were decreased in Foxm1-deficient monocytes. In co-transfection experiments, Foxm1 directly bound to and transcriptionally activated the 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.

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Acknowledgements

We dedicate this work to the memory of Dr Robert H Costa, a pioneer in the discovery and characterization of Forkhead transcription factors. We thank Dr Jeff Whitsett, Dr Sheila Bell and Dr Craig Bolte for critical reading of the manuscript, and Shirin Akhter, Jon Snyder and Alyssa Sproles for technical assistance. This work was supported by a Research Grant from the American Cancer Society, Ohio Division (TVK); a Grant from Concern Foundation 84794 (TVK); Department of Defense Award PC080478 (TVK); and NIH Grants R01 CA142724 (TVK) and R01 HL84151 (VVK).

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Authors and Affiliations

  1. Division of Pulmonary Biology, the Perinatal Institute of Cincinnati Children's Hospital Research Foundation, Cincinnati, OH, USA

    D Balli, X Ren, E Cross, Y Zhang, V V Kalinichenko & T V Kalin

  2. Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Cincinnati, OH, USA

    F-S Chou

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  1. D Balli
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Correspondence to T V Kalin.

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Balli, D., Ren, X., Chou, FS. et al. Foxm1 transcription factor is required for macrophage migration during lung inflammation and tumor formation. Oncogene 31, 3875–3888 (2012). https://doi.org/10.1038/onc.2011.549

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