Polysialic Acid Sustains the Hypoxia-Induced Migration and Undifferentiated State of Human Glioblastoma Cells

Abstract

Gliomas are the most common primary malignant brain tumors. Glioblastoma, IDH-wildtype (GBM, CNS WHO grade 4) is the most aggressive form of glioma and is characterized by extensive hypoxic areas that strongly correlate with tumor malignancy. Hypoxia promotes several processes, including stemness, migration, invasion, angiogenesis, and radio- and chemoresistance, that have direct impacts on treatment failure. Thus, there is still an increasing need to identify novel targets to limit GBM relapse. Polysialic acid (PSA) is a carbohydrate composed of a linear polymer of α2,8-linked sialic acids, primarily attached to the Neural Cell Adhesion Molecule (NCAM). It is considered an oncodevelopmental antigen that is re-expressed in various tumors. High levels of PSA-NCAM are associated with high-grade and poorly differentiated tumors. Here, we investigated the effect of PSA inhibition in GBM cells under low oxygen concentrations. Our main results highlight the way in which hypoxia stimulates polysialylation in U87-MG cells and in a GBM primary culture. By lowering PSA levels with the sialic acid analog, F-NANA, we also inhibited GBM cell migration and interfered with their differentiation influenced by the hypoxic microenvironment. Our findings suggest that PSA may represent a possible molecular target for the development of alternative pharmacological strategies to manage a devastating tumor like GBM.

Therapeutic potential to target sialylation and SIGLECs in neurodegenerative and psychiatric diseases

“…Apparently, the highly negatively charged polySia plays a pivotal role in supporting neuronal outgrowth, regeneration, and synaptic plasticity, thereby facilitating motility and plasticity. However, these functions are also exploited by glioblastomas to promote cancer growth, migration, and metastasis formation, in which polySia-NCAM overexpression is associated with poorer disease-free and overall survival ( 32 , 33 ).…”

Insights into the Role of Sialylation in Cancer Metastasis, Immunity, and Therapeutic Opportunity

“…Moreover, tumor cell migration in a hypoxic environment is maintained by polySia [ 54 ]. The hypoxic microenvironment increases the polysialylation of neural cell adhesion molecule (NCAM), which results in increased glioblastoma cell motility [ 55 ]. Furthermore, steric hindrance caused by cell surface polySia confers the anti-adhesive property to polySia-positive tumors and facilitates metastatic or invasive growth [ 37 ].…”

Next-Generation Sequencing Comparative Analysis of DNA Mutations between Blood-Derived Extracellular Vesicles and Matched Cancer Tissue in Patients with Grade 4 Glioblastoma

“…This classification was recently updated in the fifth edition of the WHO classification of tumors of the Central Nervous System (CNS5), and the novel nomenclature for GBM is glioblastoma, IDH-wildtype (CNS WHO grade 4). In order to provide powerful diagnostic and/or prognostic information, TERT promoter mutations, EGFR amplifications, and chromosome 7 gain/chromosome 10 loss were added as molecular biomarkers [ 6 , 7 ]. Nevertheless, the early diagnosis and, in particular, the possibility of monitoring the progression and the molecular rearrangement of the GBM without resorting to invasive procedures is clearly more complex compared to other types of tumors.…”