Journalartikel

Jahr der Veröffentlichung: 2015

Seiten: 437-447

Zeitschrift: American Journal of Respiratory and Critical Care Medicine

Bandnummer: 191

Heftnummer: 4

ISSN: 1073-449X

eISSN: 1535-4970

DOI Link: https://doi.org/10.1164/rccm.201406-1137OC

Verlag: American Thoracic Society

Abstract: 

Rationale: Recent studies indicate that tumor-associated macrophages (M Phi) 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 M Phi in lung cancer.

Methods: Coculturing of M Phi 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 M Phi.

Measurements and Main Results: In the M Phi-tumor cell system, IL-10 drove CCR2 and CX3CR1 up-regulation, whereas CCL1, granulocyte colony-stimulating factor, and MIP1 alpha were required for the up-regulation of CCL2 and CX3CL1. Downstream phenotypic effects included enhanced LLC1 proliferation and migration and M Phi M2 polarization. In vivo, M(13 depletion (clodronate, M Phi Fas-induced apoptosis mice) and genetic ablation of CCR2 and CX3CR1 all inhibited LLC1 tumor growth and metastasis, shifted tumor-associated M Phi 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 M Phi infiltration and CCR2 expression correlated with tumor stage and metastasis.

Conclusions: Tumor-associated M Phi play a central role in lung cancer growth and metastasis, with bidirectional cross-talk between M Phi 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.

Harvard-Zitierstil: Schmall, A., Al-tamari, H., Herold, S., Kampschulte, M., Weigert, A., Wietelmann, A., et al. (2015) Macrophage and Cancer Cell Cross-talk via CCR2 and CX3CR1 Is a Fundamental Mechanism Driving Lung Cancer, American Journal of Respiratory and Critical Care Medicine, 191(4), pp. 437-447. https://doi.org/10.1164/rccm.201406-1137OC

APA-Zitierstil: Schmall, A., Al-tamari, H., Herold, S., Kampschulte, M., Weigert, A., Wietelmann, A., Vipotnik, N., Grimminger, F., Seeger, W., Pullamsetti, S., & Savai, R. (2015). Macrophage and Cancer Cell Cross-talk via CCR2 and CX3CR1 Is a Fundamental Mechanism Driving Lung Cancer. American Journal of Respiratory and Critical Care Medicine. 191(4), 437-447. https://doi.org/10.1164/rccm.201406-1137OC