Inhibition of Heparanase in Pediatric Brain Tumor Cells Attenuates their Proliferation, Invasive Capacity, and In Vivo Tumor Growth.

Argyris Spyrou,Edward Hammond,Keith Dredge,Israel Vlodavsky,Di Yu,Soumi Kundu,Uri Barash,Tommie Olofsson,Lulu Haseeb,Karin Forsberg-Nilsson

doi:10.1158/1535-7163.mct-16-0900

Abstract

Curative therapy for medulloblastoma and other pediatric embryonal brain tumors has improved, but the outcome still remains poor and current treatment causes long-term complications. Malignant brain tumors infiltrate the healthy brain tissue and, thus despite resection, cells that have already migrated cause rapid tumor regrowth. Heparan sulfate proteoglycans (HSPG), major components of the extracellular matrix (ECM), modulate the activities of a variety of proteins. The major enzyme that degrades HS, heparanase (HPSE), is an important regulator of the ECM. Here, we report that the levels of HPSE in pediatric brain tumors are higher than in healthy brain tissue and that treatment of pediatric brain tumor cells with HPSE stimulated their growth. In addition, the latent, 65 kDa form of HPSE (that requires intracellular enzymatic processing for activation) enhanced cell viability and rapidly activated the ERK and AKT signaling pathways, before enzymatically active HPSE was detected. The HPSE inhibitor PG545 efficiently killed pediatric brain tumor cells, but not normal human astrocytes, and this compound also reduced tumor cell invasion in vitro and potently reduced the size of flank tumors in vivo Our findings indicate that HPSE in malignant brain tumors affects both the tumor cells themselves and their ECM. In conclusion, HPSE plays a substantial role in childhood brain tumors, by contributing to tumor aggressiveness and thereby represents a potential therapeutic target. Mol Cancer Ther; 16(8); 1705-16. ©2017 AACR.

Highlights

Aggressive childhood medulloblastomas and central nervous system (CNS) embryonal tumors [CNS-ET, previously referred to as supratentorial primitive neuroectodermal tumors] arise from undifferentiated, or poorly differentiated neural cells, which may display divergent differentiation along the neuronal and astrocytic lineages [1]
The quantification of negative and weak areas was more prominent in nontumor tissue than in the medulloblastoma and CNS-ET tissue cores
When PFSK or D283 cells were exposed to conditioned medium (CM) from cells producing the active form of HPSE, or CM from control cells, simultaneously with PG545, we found that the highest concentration of PG545 reduced cell viability extensively and the CM containing enzymatically active HPSE was not able to counteract this effect (Supplementary Fig. S1A)

Summary

Introduction

Aggressive childhood medulloblastomas and central nervous system (CNS) embryonal tumors [CNS-ET, previously referred to as supratentorial primitive neuroectodermal tumors (sPNET)] arise from undifferentiated, or poorly differentiated neural cells, which may display divergent differentiation along the neuronal and astrocytic lineages [1]. Medulloblastomas originate in the cerebellum, whereas CNS-ETs develop above the tentorium and are distributed in the frontal, temporal, and parietal lobes [2]. CNS-ETs are less common, but more aggressive than medulloblastomas, with a poorer survival rate [1]. New classification reveals that CNS-ETs are molecularly highly heterogeneous, some sharing characteristics with already classified entities, and the remainder being distinguishable as four molecular and morphological variants [3]. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

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