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Int. J. Mol. Sci. 2016, 17(6), 980; doi:10.3390/ijms17060980

Melanoma-Derived BRAFV600E Mutation in Peritumoral Stromal Cells: Implications for in Vivo Cell Fusion

1
Department of Dermatology and Allergology, University of Szeged, Szeged 6720, Hungary
2
MTA-SZTE Dermatological Research Group, Szeged 6720, Hungary
3
Institute of Immunology & Experimental Oncology, Witten/Herdecke University, Witten 58453, Germany
These authors contributed equally to this work.
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Academic Editor: Terrence Piva
Received: 31 March 2016 / Revised: 7 June 2016 / Accepted: 13 June 2016 / Published: 21 June 2016
(This article belongs to the Special Issue Cell Fusion in Cancer)
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Abstract

Melanoma often recurs in patients after the removal of the primary tumor, suggesting the presence of recurrent tumor-initiating cells that are undetectable using standard diagnostic methods. As cell fusion has been implicated to facilitate the alteration of a cell’s phenotype, we hypothesized that cells in the peritumoral stroma having a stromal phenotype that initiate recurrent tumors might originate from the fusion of tumor and stromal cells. Here, we show that in patients with BRAFV600E melanoma, melanoma antigen recognized by T-cells (MART1)-negative peritumoral stromal cells express BRAFV600E protein. To confirm the presence of the oncogene at the genetic level, peritumoral stromal cells were microdissected and screened for the presence of BRAFV600E with a mutation-specific polymerase chain reaction. Interestingly, cells carrying the BRAFV600E mutation were not only found among cells surrounding the primary tumor but were also present in the stroma of melanoma metastases as well as in a histologically tumor-free re-excision sample from a patient who subsequently developed a local recurrence. We did not detect any BRAFV600E mutation or protein in the peritumoral stroma of BRAFWT melanoma. Therefore, our results suggest that peritumoral stromal cells contain melanoma-derived oncogenic information, potentially as a result of cell fusion. These hybrid cells display the phenotype of stromal cells and are therefore undetectable using routine histological assessments. Our results highlight the importance of genetic analyses and the application of mutation-specific antibodies in the identification of potentially recurrent-tumor-initiating cells, which may help better predict patient survival and disease outcome. View Full-Text
Keywords: cell fusion; melanoma; mutation detection; macrophage; fibroblast; BRAFV600E cell fusion; melanoma; mutation detection; macrophage; fibroblast; BRAFV600E
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Kurgyis, Z.; Kemény, L.V.; Buknicz, T.; Groma, G.; Oláh, J.; Jakab, Á.; Polyánka, H.; Zänker, K.; Dittmar, T.; Kemény, L.; Németh, I.B. Melanoma-Derived BRAFV600E Mutation in Peritumoral Stromal Cells: Implications for in Vivo Cell Fusion. Int. J. Mol. Sci. 2016, 17, 980.

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