Neoplastic Cells are the Major Source of MT-MMPs in IDH1-Mutant Glioma, Thus Enhancing Tumor-Cell Intrinsic Brain Infiltration.

Ina Thome,Jörg W Bartsch,Nina Timmesfeld,Ralf Jacob,Raphael Lacle,Catharina Conrad,Ginette Bortolussi,Ansgar Schmidt,Georgios Pantazis,Andreas Voß,Axel Pagenstecher

doi:10.3390/cancers12092456

Ina Thome, Jörg W Bartsch + Show 9 more

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https://doi.org/10.3390/cancers12092456

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Abstract

Simple SummaryMost primary brain tumors infiltrate the surrounding brain even before the time of diagnosis and therefore cannot be removed completely. Matrix metalloproteases can degrade the extracellular proteins of the brain and thereby allow for the brain infiltration of glioma cells. Here, we demonstrate that tumor cells are the major source of several metalloproteases and as such responsible for the malignant behavior of gliomas. Our findings suggest that, controlling metalloproteases might be a promising therapeutic avenue in the treatment of glioma.Tumor-cell infiltration is a major obstacle to successful therapy for brain tumors. Membrane-type matrix metalloproteinases (MT-MMPs), a metzincin subfamily of six proteases, are important mediators of infiltration. The cellular source of MT-MMPs and their role in glioma biology, however, remain controversial. Thus, we comprehensively analyzed the expression of MT-MMPs in primary brain tumors. All MT-MMPs were differentially expressed in primary brain tumors. In diffuse gliomas, MT-MMP1, -3, and -4 were predominantly expressed by IDH1mutated tumor cells, while macrophages/microglia contributed significantly less to MT-MMP expression. For functional analyses, individual MT-MMPs were expressed in primary mouse p53−/− astrocytes. Invasion and migration potential of MT-MMP-transduced astrocytes was determined via scratch, matrigel invasion, and novel organotypic porcine spinal slice migration (OPoSSM) and invasion assays. Overall, MT-MMP-transduced astrocytes showed enhanced migration compared to controls. MMP14 was the strongest mediator of migration in scratch assays. However, in the OPoSSM assays, the glycosylphosphatidylinositol (GPI)-anchored MT-MMPs MMP17 and MMP25, not MMP14, mediated the highest infiltration rates of astrocytes. Our data unequivocally demonstrate for the first time that glioma cells, not microglia, are the predominant producers of MT-MMPs in glioma and can act as potent mediators of tumor-cell infiltration into CNS tissue. These proteases are therefore promising targets for therapeutic interventions.

Highlights

Diffuse infiltration of the surrounding brain tissue is a hallmark of diffuse astrocytoma and glioblastoma, and regularly prevents the complete resection of these tumors [1]
We investigated the effects of individual Membrane-type matrix metalloproteinases (MT-matrix metalloprotease (MMP)) on the migration of primary astrocytes in various substrates, including via a novel CNS infiltration assay termed organotypic porcine spinal slice migration (OPoSSM) assay, which is an in-vivo-like, laboratory-animal-saving test system that allows for the determination of white-matter infiltration by genetically altered cells
MT-MMPs are pleiotropic factors with a multitude of biological actions ranging from the activation of other MMPs and the shedding of membrane-bound proteins to cell migration

Summary

Introduction

Diffuse infiltration of the surrounding brain tissue is a hallmark of diffuse astrocytoma and glioblastoma, and regularly prevents the complete resection of these tumors [1]. These tumors are relatively insensitive to radiation therapy and chemotherapy (for review, see Reference [2]). Since the migration of glioma cells is crucial to the malignant behavior of these tumors, the factors that confer this potential have been extensively studied [4]. Some of the protease members of the matrix metalloprotease (MMP) family have been shown to enhance glioma cell mobility [5].

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