Involvement of Heparan Sulfate and Heparanase in Neural Development and Pathogenesis of Brain Tumors

Xiong, Anqi; Spyrou, Argyris; Forsberg-Nilsson, Karin

doi:10.1007/978-3-030-34521-1_14

Cited by 11 publications

(12 citation statements)

References 199 publications

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“…SS, which is also considered a stem cell malignancy resulting from dysregulation of self-renewal and multilineage differentiation capacities induced by SS18-SSX oncoproteins, displays expression of neural tissuerelated genes [1,44,53,125]. Noteworthy, ERK pathway and EGR1 are known to play a relevant role in neuronal survival and plasticity [109] and heparanase has been implicated in brain development and neural cellular differentiation [126]. Our observations in SS models are reminiscent of findings in the AML context showing that the chimeric proteins PLZF/RARa and AML-Eto mediated the reduction or loss of heparanase activity, likely as a consequence of impaired myeloid differentiation, and that treatment with the HDACi trichostatin A reversed the downregulation of heparanase expression induced by the AML-Eto [127].…”

Section: Discussionmentioning

confidence: 99%

Upregulation of ERK-EGR1-heparanase axis by HDAC inhibitors provides targets for rational therapeutic intervention in synovial sarcoma

Lanzi

Favini

et al. 2021

J Exp Clin Cancer Res

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Background Synovial sarcoma (SS) is an aggressive soft tissue tumor with limited therapeutic options in advanced stage. SS18-SSX fusion oncogenes, which are the hallmarks of SS, cause epigenetic rewiring involving histone deacetylases (HDACs). Promising preclinical studies supporting HDAC targeting for SS treatment were not reflected in clinical trials with HDAC inhibitor (HDACi) monotherapies. We investigated pathways implicated in SS cell response to HDACi to identify vulnerabilities exploitable in combination treatments and improve the therapeutic efficacy of HDACi-based regimens. Methods Antiproliferative and proapoptotic effects of the HDACi SAHA and FK228 were examined in SS cell lines in parallel with biochemical and molecular analyses to bring out cytoprotective pathways. Treatments combining HDACi with drugs targeting HDACi-activated prosurvival pathways were tested in functional assays in vitro and in a SS orthotopic xenograft model. Molecular mechanisms underlying synergisms were investigated in SS cells through pharmacological and gene silencing approaches and validated by qRT-PCR and Western blotting. Results SS cell response to HDACi was consistently characterized by activation of a cytoprotective and auto-sustaining axis involving ERKs, EGR1, and the β-endoglycosidase heparanase, a well recognized pleiotropic player in tumorigenesis and disease progression. HDAC inhibition was shown to upregulate heparanase by inducing expression of the positive regulator EGR1 and by hampering negative regulation by p53 through its acetylation. Interception of HDACi-induced ERK-EGR1-heparanase pathway by cell co-treatment with a MEK inhibitor (trametinib) or a heparanase inhibitor (SST0001/roneparstat) enhanced antiproliferative and pro-apoptotic effects. HDAC and heparanase inhibitors had opposite effects on histone acetylation and nuclear heparanase levels. The combination of SAHA with SST0001 prevented the upregulation of ERK-EGR1-heparanase induced by the HDACi and promoted caspase-dependent cell death. In vivo, the combined treatment with SAHA and SST0001 potentiated the antitumor efficacy against the CME-1 orthotopic SS model as compared to single agent administration. Conclusions The present study provides preclinical rationale and mechanistic insights into drug combinatory strategies based on the use of ERK pathway and heparanase inhibitors to improve the efficacy of HDACi-based antitumor therapies in SS. The involvement of classes of agents already clinically available, or under clinical evaluation, indicates the transferability potential of the proposed approaches.

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Section: Discussionmentioning

confidence: 99%

Upregulation of ERK-EGR1-heparanase axis by HDAC inhibitors provides targets for rational therapeutic intervention in synovial sarcoma

Lanzi

Favini

et al. 2021

J Exp Clin Cancer Res

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“…Heparan sulfate proteoglycans (HSPGs) represent one of the main components of the neurogenic niche. Tight involvement of both the polysaccharide heparan sulfate (HS) chains and their degrading enzyme heparanase in the development of the nervous system and growth and invasion of glioma tumors are comprehensively described by Xiong et al ( 44 , 45 ). Among the main brain HSPGs are syndecan (1-4) and glypican (1-6) families, perlecan/HSPG2, agrin, and collagen XVIII.…”

Section: Proteoglycansmentioning

confidence: 99%

“…Heparanase (HPSE) is the main enzyme responsible for the degradation of polysaccharide chains of HS at the cell surface and ECM of all tissues. It involved in normal physiology and pathological reorganization of ECM into TME and cancer progression and metastasis ( 31 , 45 , 49 ).…”

Section: Ecm Modifying Enzymesmentioning

confidence: 99%

Radiation Effects on Brain Extracellular Matrix

Grigorieva

2020

Front. Oncol.

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Radiotherapy is an important therapeutic approach to treating malignant tumors of different localization, including brain cancer. Glioblastoma multiforme (GBM) represents the most aggressive brain tumor, which develops relapsed disease during the 1st year after the surgical removal of the primary node, in spite of active adjuvant radiochemotherapy. More and more evidence suggests that the treatment's success might be determined by the balance of expected antitumor effects of the treatment and its non-targeted side effects on the surrounding brain tissue. Radiation-induced damage of the GBM microenvironment might create tumor-susceptible niche facilitating proliferation and invasion of the residual glioma cells and the disease relapse. Understanding of molecular mechanisms of radiation-induced changes in brain ECM might help to reconsider and improve conventional anti-glioblastoma radiotherapy, taking into account the balance between its antitumor and ECM-destructing activities. Although little is currently known about the radiation-induced changes in brain ECM, this review summarizes current knowledge about irradiation effects onto the main components of brain ECM such as proteoglycans, glycosaminoglycans, glycoproteins, and the enzymes responsible for their modification and degradation.

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“…This chapter highlights the roles of chondroitin sulfate (CS) and dermatan sulfate (DS)-proteoglycans (PGs) in neural biology, heparan sulfate (HS)-PGs were outside the scope of this review and thus are only briefly touched on. However many excellent reviews exist on HS-PGs and their interactions with extracellular matrix (ECM) components in neural development, neural function and potential in neural repair biology ( Condomitti and de Wit, 2018 ; Zhang P. et al, 2018 ; Roppongi et al, 2020 ; Xiong et al, 2020 ; Kamimura and Maeda, 2021 ; Sakamoto et al, 2021 ). Roles for HS-PGs in model developmental organisms such as Drosophila melanogaster and Caenorhabditis elegans have also been reviewed ( Díaz-Balzac et al, 2014 ; Blanchette et al, 2017 ; Kamimura and Maeda, 2017 ; Saied-Santiago et al, 2017 ) and the interested reader is referred to these excellent publications for further information.…”

Section: Introductionmentioning

confidence: 99%

Neural Tissue Homeostasis and Repair Is Regulated via CS and DS Proteoglycan Motifs

Hayes

Melrose

2021

Front. Cell Dev. Biol.

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Chondroitin sulfate (CS) is the most abundant and widely distributed glycosaminoglycan (GAG) in the human body. As a component of proteoglycans (PGs) it has numerous roles in matrix stabilization and cellular regulation. This chapter highlights the roles of CS and CS-PGs in the central and peripheral nervous systems (CNS/PNS). CS has specific cell regulatory roles that control tissue function and homeostasis. The CNS/PNS contains a diverse range of CS-PGs which direct the development of embryonic neural axonal networks, and the responses of neural cell populations in mature tissues to traumatic injury. Following brain trauma and spinal cord injury, a stabilizing CS-PG-rich scar tissue is laid down at the defect site to protect neural tissues, which are amongst the softest tissues of the human body. Unfortunately, the CS concentrated in gliotic scars also inhibits neural outgrowth and functional recovery. CS has well known inhibitory properties over neural behavior, and animal models of CNS/PNS injury have demonstrated that selective degradation of CS using chondroitinase improves neuronal functional recovery. CS-PGs are present diffusely in the CNS but also form denser regions of extracellular matrix termed perineuronal nets which surround neurons. Hyaluronan is immobilized in hyalectan CS-PG aggregates in these perineural structures, which provide neural protection, synapse, and neural plasticity, and have roles in memory and cognitive learning. Despite the generally inhibitory cues delivered by CS-A and CS-C, some CS-PGs containing highly charged CS disaccharides (CS-D, CS-E) or dermatan sulfate (DS) disaccharides that promote neural outgrowth and functional recovery. CS/DS thus has varied cell regulatory properties and structural ECM supportive roles in the CNS/PNS depending on the glycoform present and its location in tissue niches and specific cellular contexts. Studies on the fruit fly, Drosophila melanogaster and the nematode Caenorhabditis elegans have provided insightful information on neural interconnectivity and the role of the ECM and its PGs in neural development and in tissue morphogenesis in a whole organism environment.

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Involvement of Heparan Sulfate and Heparanase in Neural Development and Pathogenesis of Brain Tumors

Cited by 11 publications

References 199 publications

Upregulation of ERK-EGR1-heparanase axis by HDAC inhibitors provides targets for rational therapeutic intervention in synovial sarcoma

Upregulation of ERK-EGR1-heparanase axis by HDAC inhibitors provides targets for rational therapeutic intervention in synovial sarcoma

Radiation Effects on Brain Extracellular Matrix

Neural Tissue Homeostasis and Repair Is Regulated via CS and DS Proteoglycan Motifs

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