Heparanase Promotes Glioma Progression and Is Inversely Correlated with Patient Survival

Kundu, Soumi; Xiong, Anqi; Spyrou, Argyris; Wicher, Grzegorz; Marinescu, Voichita D.; Edqvist, Per‐Henrik; Zhang, Lei; Essand, Magnus; Dimberg, Anna; Smits, Anja; Ilan, Neta; Vlodavsky, Israël; Li, Jinping; Forsberg-Nilsson, Karin

doi:10.1158/1541-7786.mcr-16-0223

Cited by 55 publications

(48 citation statements)

References 49 publications

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“…In multiple myeloma HPSE promotes tumor cell adhesion and invasion via SDC1 ectodomain shedding and subsequent alterations in receptor tyrosine kinase signaling and integrin binding (10,23,54). Few studies have investigated the role for HPSE in primary brain tumors (28–31,46), but the data suggest HPSE can promote tumor growth and progression in vivo. HPSE knockdown in human GBM43 cells cultured under neural stem cell conditions did not alter proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…HPSE knockdown in human GBM43 cells cultured under neural stem cell conditions did not alter proliferation. The role for HPSE in proliferation in vitro may be complex and potential modifiers include cell culture conditions, cell lines used, and method to alter HPSE levels (31,46). In human GBM, HPSE is most highly expressed in the mesenchymal GBM subtype.…”

Section: Discussionmentioning

confidence: 99%

“…In multiple myeloma, a number of oncogenic functions for HPSE have been identified including direct effects on tumor cells and indirect effects on tumor-associated endothelial cells (10,23,23–25). In the brain, HPSE has been implicated in metastatic tumor cell invasion and medulloblastoma cell signaling (26–28), but its role in GBM is less established (29,30) although recent studies suggest its importance in tumor progression (31). …”

Section: Introductionmentioning

confidence: 99%

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Heparan Sulfate Glycosaminoglycans in Glioblastoma Promote Tumor Invasion

Tran

Wade

McKinney

et al. 2017

Molecular Cancer Research

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Glioblastoma (GBM) is the most common primary malignant brain tumor of adults and confers a poor prognosis due, in part, to diffuse invasion of tumor cells. Heparan sulfate (HS) glycosaminoglycans, present on the cell surface and in the extracellular matrix, regulate cell signaling pathways and cell-microenvironment interactions. In GBM, the expression of HS glycosaminoglycans and the enzymes that regulate their function are altered but the actual HS content and structure are unknown. However, inhibition of HS glycosaminoglycan function is emerging as a promising therapeutic strategy for some cancers. In this study, we use liquid chromatography-mass spectrometry (LC/MS) analysis to demonstrate differences in HS disaccharide content and structure across four patient-derived tumorsphere lines (GBM1, 5, 6, 43) and between two murine tumorsphere lines derived from murine GBM with enrichment of mesenchymal and proneural gene expression (mMES and mPN, respectively) markers. In GBM, the heterogeneous HS content and structure across patient-derived tumorsphere lines suggested diverse functions in the GBM tumor microenvironment (TME). In GBM5 and mPN, elevated expression of sulfatase 2 (SULF2), an extracellular enzyme that alters ligand binding to HS, was associated with low trisulfated HS disaccharides, a substrate of SULF2. In contrast, other primary tumorsphere lines had elevated expression of the HS-modifying enzyme heparanase (HPSE). Using gene editing strategies to inhibit HPSE a role for HPSE in promoting tumor cell adhesion and invasion was identified. These studies characterize the heterogeneity in HS glycosaminoglycan content and structure across GBM and reveal their role in tumor cell invasion.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Heparan Sulfate Glycosaminoglycans in Glioblastoma Promote Tumor Invasion

Tran

Wade

McKinney

et al. 2017

Molecular Cancer Research

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“…Nonetheless, from candidate-based analyses of individual ECM components, it is known that significant increases in HSPG production occur in gliomas (Lemjabbar-Alaoui et al, 2015; Wade et al, 2013). These macromolecules can serve as a reservoir for heparin-binding angiogenic growth factors, such as fibroblast growth factors (FGFs) and VEGFs, which are subsequently released in a localized manner by heparanase (Kundu et al, 2016). Vessel-associated macromolecules, which are upregulated on the glioma vasculature include tenascin C (TNC) and periostin (Brosicke and Faissner, 2015; Mustafa et al, 2012), which interestingly are also critical niche factors for promoting cancer cell survival (Oskarsson et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

The Microenvironmental Landscape of Brain Tumors

2017

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The brain tumor microenvironment (TME) is emerging as a critical regulator of cancer progression in primary and metastatic brain malignancies. The unique properties of this organ require a specific framework for designing TME-targeted interventions. Here we discuss a number of these distinct features, including brain-resident cell types, the blood-brain barrier, and various aspects of the immune-suppressive environment. We also highlight recent advances in therapeutically targeting the brain TME in cancer. By developing a comprehensive understanding of the complex and interconnected microenvironmental landscape of brain malignancies we will greatly expand the range of therapeutic strategies available to target these deadly diseases.

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“…HPSE expression is elevated and associated with clinical characteristics in several types of carcinomas in addition to breast cancer [47–52]. For example, a meta-analysis of 27 studies confirmed that HPSE expression was correlated with clinicopathological features in gastric cancer patients [53].…”

Section: Discussionmentioning

confidence: 99%

Elevated heparanase expression is associated with poor prognosis in breast cancer: a study based on systematic review and TCGA data

et al. 2017

Self Cite

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Heparanase promotes tumorigenesis, angiogenesis, and metastasis. Here, we conducted a study based on systematic review and the Cancer Genome Atlas (TCGA) data that examined heparanase expression in clinical samples to determine its prognostic value. According to the meta-analysis and TCGA data, we found that heparanase expression was up-regulated in most breast cancer specimens, and elevated heparanase expression was associated with increased lymph node metastasis, larger tumor size, higher histological grade, and poor survival. These results suggest that targeting heparanase might improve treatments for breast cancer patients.

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Heparanase Promotes Glioma Progression and Is Inversely Correlated with Patient Survival

Abstract: This study aims to target both the malignant brain tumor cells per se and their microenvironment by changing the level of an enzyme, HPSE, that breaks down modified sugar chains on cell surfaces and in the extracellular space. Mol Cancer Res; 14(12); 1243-53. ©2016 AACR.

Cited by 55 publications

References 49 publications

Heparan Sulfate Glycosaminoglycans in Glioblastoma Promote Tumor Invasion

Heparan Sulfate Glycosaminoglycans in Glioblastoma Promote Tumor Invasion

The Microenvironmental Landscape of Brain Tumors

Elevated heparanase expression is associated with poor prognosis in breast cancer: a study based on systematic review and TCGA data

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