Title: A novel hypoxia-associated subset of FN1(high)MITF(low) melanoma cells: identification, characterization, and prognostic value
Authors: Wouters, Jasper ×
Stas, Marguerite
Govaere, Olivier
Barrette, Kathleen
Dudek, Aleksandra
Vankelecom, Hugo
Haydu, Lauren E
Thompson, John F
Scolyer, Richard A
van den Oord, Joost #
Issue Date: 2014
Publisher: Williams & Wilkins
Series Title: Modern Pathology vol:27 issue:8 pages:1088-1100
Abstract: In many human cancers, the epithelial-to-mesenchymal transition has an important role in the induction of cancer stem-like cells, and hence, in the causation of intratumoral heterogeneity. This process, also referred to as mesenchymal mimicry, is, however, only poorly understood in melanoma and histological correlation is still lacking. In an immunohistochemical analysis of a large prospective series of 220 primary and metastatic melanomas for the well-known epithelial-to-mesenchymal transition marker FN1, we observed melanoma cells with high FN1 expression in metastases with ischemic necrosis, but rarely or not at all in samples lacking evidence of hypoxia. In a blinded, retrospective series of 82 melanoma metastases with 10-year follow-up, the presence of clusters of these FN1(high) melanoma cells correlated significantly with shortened melanoma-specific survival, highlighting the prognostic value of their presence. We describe in detail the unique light- and electron-microscopic features of these FN1(high) melanoma cells, enabling their identification in routinely hematoxylin-and-eosin-stained sections. In addition, by laser microdissection and subsequent gene expression analysis and immunohistochemistry, we highlight their distinctive, molecular phenotype that includes expression of various markers of the epithelial-to-mesenchymal transition (eg, ZEB1) and of melanoma stem-like cells (eg, NGFR), and lack of immunoreactivity for the melanocytic marker MITF. This phenotype could be reproduced in vitro by culturing melanoma cells under hypoxic conditions. Functionally, the hypoxic microenvironment was shown to induce a more migratory and invasive cell type. In conclusion, we identified a novel clinically relevant FN1(high)MITF(low) cell type in melanoma associated with ischemic necrosis, and propose that these cells reside at the crossroad of the epithelial-to-mesenchymal transition and stem-like cell induction, plausibly triggered by the hypoxic environment.
ISSN: 0893-3952
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Surgical Oncology
Translational Cell & Tissue Research
Laboratory of Dermatology
Laboratory of Cell Death Research & Therapy
Stem Cell Biology and Embryology (+)
× corresponding author
# (joint) last author

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