C5a receptors C5aR1 and C5aR2 mediate opposing pathologies in a mouse model of melanoma
| Autor: | Barbara E. Rolfe, Nadya Panagides, Jamileh A. Nabizadeh, Glen M. Boyle, John D. Lee, Stephen M. Taylor, Helga D. Manthey, Fazrena Nadia Md Akhir, Weiyu Chen, Frederik J. Steyn, Trent M. Woodruff, Xaria X. Li |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Chemokine MAP Kinase Signaling System CD3 medicine.medical_treatment Complement C5a medicine.disease_cause Biochemistry Interferon-gamma Mice 03 medical and health sciences Lymphocytes Tumor-Infiltrating 0302 clinical medicine Cell Movement Tumor Microenvironment Genetics medicine Animals RNA Messenger Receptor Melanoma Receptor Anaphylatoxin C5a Molecular Biology Cells Cultured Chemokine CCL2 Cell Proliferation Tumor microenvironment biology medicine.disease Mice Inbred C57BL 030104 developmental biology Cytokine biology.protein Cancer research Female Carcinogenesis Complement component 5a 030217 neurology & neurosurgery Biotechnology |
| Zdroj: | The FASEB Journal. 33:11060-11071 |
| ISSN: | 1530-6860 0892-6638 |
| DOI: | 10.1096/fj.201800980rr |
| Popis: | The canonical complement component 5a (C5a) receptor (C5aR) 1 has well-described roles in tumorigenesis but the contribution of the second receptor, C5aR2, is unclear. The present study demonstrates that B16.F0 melanoma cells express mRNA for both C5aR1 and C5aR2 and signal through ERK and p38 MAPKs in response to C5a. Despite this, C5a had no impact on melanoma cell proliferation or migration in vitro. In vivo studies demonstrated that the growth of B16.F0 melanoma tumors was increased in C5aR2-/- mice but reduced in C5aR1-/- mice and wild-type mice treated with a C5aR1 antagonist. Analysis of tumor-infiltrating leukocyte populations showed no significant differences between wild-type and C5aR2-/- mice. Conversely, percentages of myeloid-derived suppressor cells, macrophages, and regulatory T lymphocytes were lower in tumors from C5aR1-/- mice, whereas total (CD3+) T lymphocytes and CD4+ subsets were higher. Analysis of cytokine and chemokine levels also showed plasma IFN-γ was higher and tumor C-C motif chemokine ligand 2 was lower in the absence of C5aR1. The results suggest that C5aR1 signaling supports melanoma growth by promoting infiltration of immunosuppressive leukocyte populations into the tumor microenvironment, whereas C5aR2 has a more restricted but beneficial role in limiting tumor growth. Overall, these data support the potential of C5aR1-inhibitory therapies for melanoma.-Nabizadeh, J. A., Manthey, H. D., Panagides, N., Steyn, F. J., Lee, J. D., Li, X. X., Akhir, F. N. M., Chen, W., Boyle, G. M., Taylor, S. M., Woodruff, T. M., Rolfe, B. E. C5a receptors C5aR1 and C5aR2 mediate opposing pathologies in a mouse model of melanoma. |
| Databáze: | OpenAIRE |
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