CD44 enhances tumor aggressiveness by promoting tumor cell plasticity
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Yvette W.J. Paulis1,2,*, Elisabeth J.M. Huijbers2,*, Daisy W.J. van der Schaft1,4,*, Patricia M.M.B. Soetekouw1, Patrick Pauwels3, Vivianne C.G. Tjan-Heijnen1 and Arjan W. Griffioen2
1 Division of Medical Oncology, Department of Internal Medicine, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
2 Department of Medical Oncology, Angiogenesis Laboratory, VU University Medical Center, Amsterdam, The Netherlands
3 Laboratory of Pathology, University of Antwerp, Antwerp, Belgium
4 Department of Biomedical Engineering, Soft Tissue Biomechanics and Engineering, Eindhoven University of Technology, Den Dolech, Eindhoven, The Netherlands
* These authors have contribution equally to this work
Arjan W. Griffioen, email:
Keywords: cancer, CD44, ewing sarcoma, c-Met, vasculogenic mimicry
Received: November 08, 2014 Accepted: March 19, 2015 Published: April 15, 2015
Aggressive tumor cells can obtain the ability to transdifferentiate into cells with endothelial features and thus form vasculogenic networks. This phenomenon, called vasculogenic mimicry (VM), is associated with increased tumor malignancy and poor clinical outcome. To identify novel key molecules implicated in the process of vasculogenic mimicry, microarray analysis was performed to compare gene expression profiles of aggressive (VM+) and non-aggressive (VM-) cells derived from Ewing sarcoma and breast carcinoma. We identified the CD44/c-Met signaling cascade as heavily relevant for vasculogenic mimicry. CD44 was at the center of this cascade, and highly overexpressed in aggressive tumors. Both CD44 standard isoform and its splice variant CD44v6 were linked to increased aggressiveness in VM. Since VM is most abundant in Ewing sarcoma tumors functional analyses were performed in EW7 cells. Overexpression of CD44 allowed enhanced adhesion to its extracellular matrix ligand hyaluronic acid. CD44 expression also facilitated the formation of vasculogenic structures in vitro, as CD44 knockdown experiments repressed migration and vascular network formation. From these results and the observation that CD44 expression is associated with vasculogenic structures and blood lakes in human Ewing sarcoma tissues, we conclude that CD44 increases aggressiveness in tumors through the process of vasculogenic mimicry.
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