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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Yearbook 2016     Display Documents

ID: 723929.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook 2016
Macrophage and cancer cell cross-talk via CCR2 and CX3CR1 is a fundamental mechanism driving lung cancer
Authors:Schmall, A.; Al-Tamari, H. M.; Herold, S.; Kampschulte, M.; Weigert, A.; Wietelmann, A.; Vipotnik, N.; Grimminger, F.; Seeger, W.; Pullamsetti, S. S.; Savai, R.
Date of Publication (YYYY-MM-DD):2015-02-15
Title of Journal:Am J Respir Crit Care Med
Issue / Number:4
Start Page:437
End Page:447
Audience:Not Specified
Abstract / Description:RATIONALE: Recent studies indicate that tumor-associated macrophages (MPhi) with an M2 phenotype can influence cancer progression and metastasis, but the regulatory pathways remain poorly characterized. OBJECTIVES: This study investigated the role of tumor-associated MPhi in lung cancer. METHODS: Coculturing of MPhi with mouse Lewis lung carcinoma (LLC1) and 10 different human lung cancer cell lines (adenocarcinoma, squamous cell carcinoma, and large cell carcinoma) caused up-regulation of CCR2/CCL2 and CX3CR1/CX3CL1 in both the cancer cells and the MPhi. MEASUREMENTS AND MAIN RESULTS: In the MPhi-tumor cell system, IL-10 drove CCR2 and CX3CR1 up-regulation, whereas CCL1, granulocyte colony-stimulating factor, and MIP1alpha were required for the up-regulation of CCL2 and CX3CL1. Downstream phenotypic effects included enhanced LLC1 proliferation and migration and MPhi M2 polarization. In vivo, MPhi depletion (clodronate, MPhi Fas-induced apoptosis mice) and genetic ablation of CCR2 and CX3CR1 all inhibited LLC1 tumor growth and metastasis, shifted tumor-associated MPhi toward M1 polarization, suppressed tumor vessel growth, and enhanced survival (metastasis model). Furthermore, mice treated with CCR2 antagonist mimicked genetic ablation of CCR2, showing reduced tumor growth and metastasis. In human lung cancer samples, tumor MPhi infiltration and CCR2 expression correlated with tumor stage and metastasis. CONCLUSIONS: Tumor-associated MPhi play a central role in lung cancer growth and metastasis, with bidirectional cross-talk between MPhi and cancer cells via CCR2 and CX3CR1 signaling as a central underlying mechanism. These findings suggest that the therapeutic strategy of blocking CCR2 and CX3CR1 may prove beneficial for halting lung cancer progression.
Free Keywords:Adenocarcinoma/*metabolism/pathology; Animals; Biomarkers, Tumor/*metabolism; Carcinoma, Large Cell/*metabolism/pathology; Carcinoma, Squamous Cell/*metabolism/pathology; Cell Line, Tumor; Chemokine CCL2/metabolism; Chemokine CX3CL1/metabolism; Humans; Lung Neoplasms/*metabolism/pathology; Macrophages/*metabolism; Mice; Neoplasm Metastasis; Neoplasm Staging; Receptor Cross-Talk; Receptors, CCR2/metabolism; Receptors, Chemokine/metabolism; Up-Regulation; Ccr2; Cx3cr1; lung cancer; macrophages; microenvironment
External Publication Status:published
Document Type:Article
Communicated by:n.n.
Affiliations:MPI für physiologische und klinische Forschung
Identifiers:ISSN:1535-4970 (Electronic) 1073-449X (Linking) %R 10.1164/rccm.201406-1137OC
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