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.

中文翻译：

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肿瘤微环境中透明质酸转变对胶质母细胞瘤恶性和侵袭行为的影响。

细胞外基质（ECM）对于肿瘤生长和癌细胞的侵袭潜力至关重要。在胶质母细胞瘤中，天然脑 ECM 的某些成分（例如透明质酸（HA））被认为是与患者预后不良（例如侵袭和治疗抵抗）相关过程的关键调节因子。鉴于细胞介导的重塑在侵袭过程中的重要性，可用的 HA 聚合物的分子量可能会强烈影响 GBM 的进展。因此，生物材料平台提供了一个独特的机会来系统地研究 HA 分子量分布对 GBM 细胞活性的影响。在这里，我们报告了甲基丙烯酰胺功能化明胶（GelMA）水凝胶内基质结合的HA的分子量、表现出显着体内侵袭性的患者来源的异种移植GBM群体的侵袭表型以及GBM期间可溶性HA的局部产生之间的关系细胞侵袭。将不同分子量的透明质酸（涵盖与细胞介导的重塑相关的范围（10、60 和 500 kDa））光聚合成 GelMA 水凝胶，与仅 GelMA 条件（-HA）相比，其细胞活性。调整聚合条件以创建具有保守的多孔弹性特性（即剪切模量、泊松比和扩散率）的同源系列 GelMA 水凝胶。GBM迁移受到HA分子量的强烈影响；而与 HA 主动重塑相关的标记物（乙酰透明质酸合酶和透明质酸酶）被发现不受影响。这些结果提供了关于局部透明质酸含量对 GBM 侵袭表型重要性的新信息。