Sivakumar Hemamylammal, Strowd Roy, Skardal Aleksander
Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
Department of Neurology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
Gels. 2017 Jul 13;3(3):28. doi: 10.3390/gels3030028.
Glioblastoma (GBM) is one of most aggressive forms of brain cancer, with a median survival time of 14.6 months following diagnosis. This low survival rate could in part be attributed to the lack of model systems of this type of cancer that faithfully recapitulate the tumor architecture and microenvironment seen in vivo in humans. Therapeutic studies would provide results that could be translated to the clinic efficiently. Here, we assess the role of the tumor microenvironment physical parameters on the tumor, and its potential use as a biomarker using a hyaluronic acid hydrogel system capable of elastic modulus tuning and dynamic elastic moduli changes. Experiments were conducted to assess the sensitivity of glioblastoma cell populations with different mutations to varying elastic moduli. Cells with aberrant epithelial growth factor receptor (EGFR) expression have a predilection for a stiffer environment, sensing these parameters through focal adhesion kinase (FAK). Importantly, the inhibition of FAK or EGFR generally resulted in reversed elastic modulus preference. Lastly, we explore the concept of therapeutically targeting the elastic modulus and dynamically reducing it via chemical or enzymatic degradation, both showing the capability to reduce or stunt proliferation rates of these GBM populations.
胶质母细胞瘤（GBM）是最具侵袭性的脑癌形式之一，诊断后的中位生存时间为14.6个月。这种低生存率部分可归因于缺乏能忠实地重现人类体内所见肿瘤结构和微环境的此类癌症模型系统。治疗研究将提供可有效转化至临床的结果。在此，我们使用能够调节弹性模量并实现动态弹性模量变化的透明质酸水凝胶系统，评估肿瘤微环境物理参数对肿瘤的作用及其作为生物标志物的潜在用途。进行实验以评估具有不同突变的胶质母细胞瘤细胞群体对不同弹性模量的敏感性。上皮生长因子受体（EGFR）表达异常的细胞倾向于更硬的环境，通过粘着斑激酶（FAK）感知这些参数。重要的是，抑制FAK或EGFR通常会导致弹性模量偏好逆转。最后，我们探索通过化学或酶促降解对弹性模量进行治疗性靶向并动态降低它的概念，两者均显示出降低或抑制这些GBM群体增殖率的能力。
