The scrambled story between hyaluronan and glioblastoma

Abstract

Advances in cancer biology are revealing the importance of the cancer cell microenvironment on tumorigenesis and cancer progression. Hyaluronan (HA), the main glycosaminoglycan in the extracellular matrix, has been associated with the progression of glioblastoma (GBM), the most frequent and lethal primary tumor in the central nervous system, for several decades. However, the mechanisms by which HA impacts GBM properties and processes have been difficult to elucidate. In this review, we provide a comprehensive assessment of the current knowledge on HA’s effects on GBM biology, introducing its primary receptors CD44 and RHAMM and the plethora of relevant downstream signaling pathways that can scramble efforts to directly link HA activity to biological outcomes. We consider the complexities of studying an extracellular polymer and the different strategies used to try to capture its function, including 2D and 3D in vitro studies, patient samples, and in vivo models. Given that HA affects not only migration and invasion, but also cell proliferation, adherence, and chemoresistance, we highlight the potential role of HA as a therapeutic target. Finally, we review the different existing approaches to diminish its protumor effects, such as the use of 4-methylumbelliferone, HA oligomers, and hyaluronidases and encourage further research along these lines in order to improve the survival and quality of life of GBM patients.

Atomic Force Microscope Nanoindentation Analysis of Diffuse Astrocytic Tumor Elasticity: Relation with Tumor Histopathology

“…It should be noted that in the present study, tumor cell infiltration has not been quantified in the white matter specimens. Nevertheless, exploring the possible association of peritumoral white matter elasticity with prominent traits of its histology, like tumor cell infiltration, as well as myelin and hyaluronan [ 61 ] content and properties, factors that play a key role in the interaction between glioma and extracellular matrix [ 62 , 63 , 64 ], would be an interesting topic for future research.…”

Hyaluronan Functions in Wound Repair That Are Captured to Fuel Breast Cancer Progression

“…Out of these, HYAL1 (present in lysosomes) is mainly responsible for HA degradation into oligo–, di–, and monosaccharides while HYAL2 (localized to the cell surface via a GPI linker) degrades HA into fragments of about 20 kDa. These HYAL2 created fragments are either released into the microenvironment or internalized by HA receptors such as CD44 to be further degraded by HYAL1 [ 44 , 45 , 46 ]. Two additional proteins with hyaluronidase activity have more recently been discovered that process HA into intermediate–sized LMW fragments: the transmembrane protein TMEM2 [ 47 ] and KIAA1199 (CEMIP, HYBID) [ 48 ].…”

Targeting the Tumor Extracellular Matrix by the Natural Molecule 4-Methylumbelliferone: A Complementary and Alternative Cancer Therapeutic Strategy

“…It has been proposed that the aggressiveness of GBM depends on the co-expression of HAS and hyaluronidases (95). In this sense, based on the fact that 4-MU is a small molecule able to cross the blood brain barrier (96), Pibuel et al proposed its use as an interesting therapeutic strategy to complement GBM treatment (65). These authors demonstrated that, in the GL26 murine GBM cell line, 4-MU diminished HA synthesis while increasing apoptosis and decreasing cell proliferation and migration (66).…”