CXCR4/MIF axis amplifies tumor growth and epithelial-mesenchymal interaction in non-small cell lung cancer
| Autor: | Axel Schambach, Denise Klatt, Philippe Dänzer Barbosa, Benedikt Jäger, Antje Prasse, Stefan Lienenklaus, Heiko Golpon, Linda Plappert |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Receptors CXCR4 Epithelial-Mesenchymal Transition Lung Neoplasms Cell CXCR4 Metastasis 03 medical and health sciences Mice 0302 clinical medicine Mice Inbred NOD Carcinoma Non-Small-Cell Lung medicine Animals Humans Lung cancer Autocrine signalling Macrophage Migration-Inhibitory Factors Cell Proliferation A549 cell Chemistry Interleukin-6 Cell Biology Fibroblasts medicine.disease Chemokine CXCL12 Intramolecular Oxidoreductases 030104 developmental biology medicine.anatomical_structure A549 Cells 030220 oncology & carcinogenesis Cancer cell Cancer research Macrophage migration inhibitory factor |
| Zdroj: | Cellular signalling. 73 |
| ISSN: | 1873-3913 |
| Popis: | Overexpression of C-X-C chemokine receptor type 4 (CXCR4) has been shown in several cancers, including non-small cell lung cancer (NSCLC) and is linked to early metastasis and worse prognosis. The crosstalk between cancer cells and tumor stroma promotes the growth and metastasis and CXCR4 signaling is a key element of this crosstalk. To test the effects of CXCR4 overexpression (CXCR4-OE), we transduced the human NSCLC cell line A549 by using a lentiviral vector. A 3D cell culture model showed generations of tumorspheres and the effects derived by the co-culturing of lung fibroblasts. Using a xenograft mouse model, we also studied the effects of CXCR4-OE in pulmonary cell engraftment and tumor burden in vivo. Our data indicate that CXCR4-OE leads to increased tumorsphere formation and epithelial-mesenchymal transition (EMT). CXCR4-OE by A549 cells resulted in a significant increase in the production of the CXCR4-ligand macrophage migration inhibitory factor (MIF) compared to those transduced with an empty vector (EV) or in which the CXCR4 expression was deleted (KO). In our in vitro system, we did not detect any production of the canonical CXCR4 ligand CXCL12. Autocrine MIF production and CXCR4 signaling are part of a self-perpetuating loop that amplifies tumor growth and EMT. Co-culture with lung fibroblasts further increased tumorsphere formation, partially driven by an increase in IL-6 production. When A549 cells were injected into murine lungs, we observed more abundant and significantly larger tumor lesions in recipients of CXCR4-OE A549 cells compared to those receiving EV or KO cells, consistent with our in vitro findings. Treatment of mice with the MIF antagonist ISO-1 resulted in significantly less tumor burden. In conclusion, our data highlight the role of the CXCR4-OE/MIF/IL-6 axis in epithelial mesenchymal crosstalk and NSCLC progression. |
| Databáze: | OpenAIRE |
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