BRAFV600E melanoma cells secrete factors that activate stromal fibroblasts and enhance tumourigenicity |
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Authors: | C A Whipple C E Brinckerhoff |
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Institution: | 1.Departments of Medicine, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, and Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA;2.Departments of Biochemistry, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, and Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA |
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Abstract: | Background: Melanoma, the most lethal form of skin cancer, is responsible for over 80% of all skin cancer deaths and is highly metastatic, readily spreading to the lymph nodes or metastasising to other organs. The frequent genetic mutation found in metastatic melanoma, BRAFV600E, results in constitutive activation of the mitogen-activated protein kinase pathway.Methods: In this study, we utilised genetically engineered melanoma cell lines and xenograft mouse models to investigate how BRAFV600E affected cytokine (IL-1β, IL-6, and IL-8) and matrix metalloproteinase-1 (MMP-1) expression in tumour cells and in human dermal fibroblasts.Results: We found that BRAFV600E melanoma cells expressed higher levels of these cytokines and of MMP-1 than wild-type counterparts. Further, conditioned medium from the BRAFV600E melanoma cells promoted the activation of stromal fibroblasts, inducing expression of SDF-1 and its receptor CXCR4. This increase was mitigated when the conditioned medium was taken from melanoma cells treated with the BRAFV600E specific inhibitor, vemurafenib.Conclusions: Our findings highlight the role of BRAFV600E in activating the stroma and suggest a mechanistic link between BRAFV600E and MMP-1 in mediating melanoma progression and in activating adjacent fibroblasts in the tumour microenvironment. |
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Keywords: | MMP-1 cytokines chemokines tumour microenvironment carcinoma-like associated fibroblasts vemurafenib PLX4032 stromal fibroblasts |
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