Abstract
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.
Highlights
Vasculogenic mimicry (VM) describes the process in which highly aggressive, plastic tumor cells gain characteristics normally restricted to endothelial cells
In the current study we demonstrated by genomic screening that CD44 standard (CD44s) expression is enhanced in aggressive tumor cells, as compared to nonaggressive tumor cells derived from both Ewing sarcoma and breast carcinoma tissues
Array data were validated by quantitative real-time RT-PCR for a panel of nine genes randomly selected from the list of upregulated genes (Supplementary Figure S2)
Summary
Vasculogenic mimicry (VM) describes the process in which highly aggressive, plastic tumor cells gain characteristics normally restricted to endothelial cells This transdifferentiation allows tumor cells to form matrix-rich vasculogenic tubular structures [1]. After the initial observation of VM in melanoma, evidence for its occurrence has been reported in other tumor types [2,3,4,5,6,7] and research has focused on identifying the molecular mechanism underlying this phenomenon [8] Further understanding of this process revealed that in e.g. glioblastoma it is the stem-like glioblastoma cell subset that is responsible for the capacity to transdifferentiate into endothelial-like cells. It was demonstrated that these cells gain the ability to activate transcriptional programs assumed to be restricted to endothelial cells [9, 10]
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