ADAMTS1 Supports Endothelial Plasticity of Glioblastoma Cells with Relevance for Glioma Progression.

Orlando Serrano-Garrido,José Luis Fernandez-Luna,Juan Carlos Rodríguez-Manzaneque,Carlos Peris-Torres,Helena G Asenjo,Silvia Redondo-García,María Del Carmen Plaza-Calonge

doi:10.3390/biom11010044

Abstract

Gliomas in general and the more advanced glioblastomas (GBM) in particular are the most usual tumors of the central nervous system with poor prognosis. GBM patients develop resistance to distinct therapies, in part due to the existence of tumor cell subpopulations with stem-like properties that participate in trans-differentiation events. Within the complex tumor microenvironment, the involvement of extracellular proteases remains poorly understood. The extracellular protease ADAMTS1 has already been reported to contribute to the plasticity of cancer cells. Accordingly, this basic knowledge and the current availability of massive sequencing data from human gliomas, reinforced the development of this work. We first performed an in silico study of ADAMTS1 and endothelial markers in human gliomas, providing the basis to further assess these molecules in several primary glioblastoma-initiating cells and established GBM cells with the ability to acquire an endothelial-like phenotype. Using a co-culture approach of endothelial and GBM cells, we noticed a relevant function of ADAMTS1 in GBM cells leading the organization of endothelial-like networks and, even more significantly, we found a blockade of the formation of tumor-spheres and a deficient response to hypoxia in the absence of ADAMTS1. Our data support a chief role of this protease modulating the phenotypic plasticity of GBM.

Highlights

Gliomas are the most usual and lethal type of primary malignant tumors of the central nervous system
We observed a positive correlation between advanced glioma stages and an increasing ADAMTS1 gene expression in both datasets including a total of 1342 gliomas (Figure 1A)
As we are interested in the acquisition of endothelial-like properties by glioblastoma multiforme (GBM) cells, we found the positive correlation of ADAMTS1 with endothelial markers very encouraging, remarking that these genes are not discovered just in genuine endothelium, but they are expressed in tumor cells

Summary

Introduction

Gliomas are the most usual and lethal type of primary malignant tumors of the central nervous system. (recently classified as IDH-wild type) has a very poor prognosis and a median overall survival of only 14–16 months in newly diagnosed patients [1,2]. GBM is characterized by its invasive properties and they possess a very robust vascularization including abnormal blood vessels [3], favoring the frequent episodes of resistance to chemotherapy, radiotherapy and antiangiogenic drugs. It has been remarked the tremendous plasticity of tumor cells in GBM cases, supported by the existence of tumor cell subpopulations with stem cell-like properties [4]. The acquisition of an endothelial-like (EL) phenotype was introduced with the concept of vasculogenic mimicry [9], revealed in some tumors as an alternative mechanism of vascularization where tumor cells revert to a stem-like state and a consequent conversion to pseudoendothelium [10]

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Discussion

Conclusion