Influence of Hyaluronic Acid Transitions in Tumor Microenvironment on Glioblastoma Malignancy and Invasive Behavior
Influence of Hyaluronic Acid Transitions in Tumor Microenvironment on Glioblastoma Malignancy and Invasive Behavior
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DOI：
10.3389/fmats.2018.00039
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发表时间：
2018-06-26
影响因子：
3.2
通讯作者：
Harley, Brendan A. C.
中科院分区：
文献类型：
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作者：
Chen, Jee-Wei E.;Pedron, Sara;Harley, Brendan A. C.
细胞外基质（ECM）在肿瘤生长和癌细胞的侵袭潜力中至关重要。在胶质母细胞瘤肿瘤中，天然脑ECM的一些组分如透明质酸（HA）已被认为是与患者前景不佳相关的过程的关键调节剂，如侵袭和治疗抗性。鉴于细胞介导的重塑在侵袭过程中的重要性，可能可用的HA聚合物的分子量可能强烈影响GBM进展。因此，生物材料平台提供了一个独特的机会，系统地检查HA的分子量分布对GBM细胞活性的影响。在这里，我们报告的基质结合HA的分子量内的甲基丙烯酰胺功能化明胶（GelMA）水凝胶，患者来源的异种移植GBM人口，表现出显着的体内侵袭性的侵袭表型，和GBM细胞入侵过程中的可溶性HA的本地生产之间的关系。将跨越与细胞介导的重塑相关的范围（10、60和500 kDa）的不同分子量的透明质酸光聚合成GelMA水凝胶，与仅GelMA条件（-HA）相比具有细胞活性。调整聚合条件以产生具有保守的多孔弹性性质的同源系列GelMA水凝胶（即，剪切模量、泊松比和扩散率）。GBM迁移受到HA分子量的强烈影响，而与HA（透明质酸合酶和透明质酸酶）的主动重塑相关的标志物被发现不受影响。这些结果提供了关于局部透明质酸含量对GBM侵袭性表型的重要性的新信息。
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 methacrylamide-functionalized 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 hyaluromdase) were found to be uninfluenced. These results provide new information regarding the importance of local hyaluronic acid content on the invasive phenotype of GBM.