Department of Bioengineering, Stanford University, Stanford, California, USA.
Department of Orthopaedic Surgery, Stanford University, Stanford, California, USA.
J Biomed Mater Res A. 2021 Jun;109(6):1027-1035. doi: 10.1002/jbm.a.37093. Epub 2020 Sep 21.
Brain cancer is a devastating disease given its extreme invasiveness and intricate location. Glioblastoma multiforme (GBM) is one of the most common forms of brain cancer, and cancer progression is often correlated with significantly altered tissue stiffness. To elucidate the effect of matrix stiffness on GBM cell fates, previous research is largely limited to 2D studies using immortalized cell lines, which has limited physiological relevance. The objective of the study is to develop gradient hydrogels with brain-mimicking stiffness range as a 3Din vitro GBM model for screening of the effects of matrix stiffness on GBM. To increase the physiological relevance, patient-derived tumor xenograft (PDTX) GBM cells were used. Our gradient platform allows formation of cell-containing hydrogels with stiffness ranging from 40 Pa to 1,300 Pa within a few minutes. By focusing on a brain-mimicking stiffness range, this gradient hydrogel platform is designed for investigating brain cancer. Increasing stiffness led to decreased GBM proliferation and less spreading, which is accompanied by downregulation of matrix-metalloproteinases (MMPs). Using temozolomide (TMZ) as a model drug, we demonstrate that increasing stiffness led to higher drug resistance by PDTX GBM cells in 3D, suggesting matrix stiffness can directly modulate how GBM cells respond to drug treatment. While the current study focuses on stiffness gradient, the setup may also be adapted for screening other cancer niche cues such as how biochemical ligand gradient modulates brain cancer progression and drug responses using reduced materials and time.
脑癌因其极强的侵袭性和复杂的位置而极具破坏性。多形性胶质母细胞瘤（GBM）是最常见的脑癌之一，癌症的进展通常与组织硬度的显著改变有关。为了阐明基质硬度对 GBM 细胞命运的影响，之前的研究主要局限于使用永生化细胞系的 2D 研究，这在生理相关性方面具有很大的局限性。本研究的目的是开发具有脑模拟硬度范围的梯度水凝胶，作为一种 3D 体外 GBM 模型，用于筛选基质硬度对 GBM 的影响。为了提高生理相关性，使用了患者来源的肿瘤异种移植物（PDTX）GBM 细胞。我们的梯度平台允许在几分钟内形成含有细胞的水凝胶，其硬度范围从 40Pa 到 1300Pa。通过关注脑模拟的硬度范围，这个梯度水凝胶平台是为了研究脑癌而设计的。增加硬度会导致 GBM 增殖减少和扩散减少，这伴随着基质金属蛋白酶（MMPs）的下调。使用替莫唑胺（TMZ）作为模型药物，我们证明在 3D 中增加硬度会导致 PDTX GBM 细胞产生更高的耐药性，这表明基质硬度可以直接调节 GBM 细胞对药物治疗的反应。虽然目前的研究集中在硬度梯度上，但该设置也可以适应筛选其他癌症生态位线索，例如生物化学配体梯度如何通过使用更少的材料和时间来调节脑癌的进展和药物反应。
