Influence of Hyaluronic Acid Transitions in Tumor Microenvironment on Glioblastoma Malignancy and Invasive Behavior.

Brendan A. C. Harley,Jee-Wei E. Chen,Peter Shyu,Yuhang Hu,Jann N. Sarkaria,Sara Pedron

doi:10.3389/fmats.2018.00039

Brendan A. C. Harley, Jee-Wei E. Chen + Show 4 more

Open Access

https://doi.org/10.3389/fmats.2018.00039

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Abstract

The extracellular matrix (ECM) is critical in tumor growth and invasive potential of cancer cells. In glioblastoma tumors, some components of the native brain ECM such as hyaluronic acid (HA) have been suggested as key regulators of processes associated with poor patient outlook such as invasion and therapeutic resistance. Given the importance of cell-mediated remodeling during invasion, it is likely that the molecular weight of available HA polymer may strongly influence GBM progression. Biomaterial platforms therefore provide a unique opportunity to systematically examine the influence of the molecular weight distribution of HA on GBM cell activity. Here we report the relationship between the molecular weight of matrix-bound HA within a methacrylamidefunctionalized gelatin (GelMA) hydrogel, the invasive phenotype of a patient-derived xenograft GBM population that exhibits significant in vivo invasivity, and the local production of soluble HA during GBM cell invasion. Hyaluronic acid of different molecular weights spanning a range associated with cell-mediated remodeling (10, 60, and 500 kDa) was photopolymerized into GelMA hydrogels, with cell activity compared to GelMA only conditions (-HA). Polymerization conditions were tuned to create a homologous series of GelMA hydrogels with conserved poroelastic properties (i.e., shear modulus, Poisson's ratio, and diffusivity). GBM migration was strongly influenced by HA molecular weight; while markers associated with active remodeling of HA (hyaluronan synthase and hyaluronidase) were found to be uninfluenced. These results provide new information regarding the importance of local hyaluronic acid content on the invasive phenotype of GBM.

Highlights

Glioblastoma (GBM), a WHO grade IV astrocytoma, is the most common and deadly form of brain cancer and accounts for more than 50% of primary brain tumors (Furnari et al, 2007; Nakada et al, 2007; Wen and Kesari, 2008)
While the presence of hyaluronic acid (HA) has been shown to be important to tumor progression (Toole, 2004; Stern, 2008; Kim and Kumar, 2014), significant investigation is needed to explore the role of the molecular weight (MW) of HA on processes associated with GBM invasion, progression, and therapeutic response
GelMA hydrogels containing the largest molecular weight HA (500 K) showed significantly reduced invasion compared to all other hydrogel groups (-HA, 10, and 60 K) throughout the entire period studied

Summary

Introduction

Glioblastoma (GBM), a WHO grade IV astrocytoma, is the most common and deadly form of brain cancer and accounts for more than 50% of primary brain tumors (Furnari et al, 2007; Nakada et al, 2007; Wen and Kesari, 2008). Processes of GBM invasion, in the perivascular niche in the tumor margins, involve exposure to HA but a range of fibrillar protein content and significant matrix remodeling, resulting in GBM cell exposure to HA and a wide range of molecular weights of HA (Bayin et al, 2014; Lathia et al, 2015; Paw et al, 2015) In this context, the amount and molecular weight distribution of HA, associated with constant turnover from oligosaccharides to high MW HA, across the tumor microenvironment is believed as an important regulator of GBM invasion (Itano and Kimata, 2008). While the presence of HA has been shown to be important to tumor progression (Toole, 2004; Stern, 2008; Kim and Kumar, 2014), significant investigation is needed to explore the role of the molecular weight (MW) of HA on processes associated with GBM invasion, progression, and therapeutic response

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