Varricchio Alanah, Ramesh Sunita A, Yool Andrea J
School of Biomedicine, University of Adelaide, Adelaide, SA 5005, Australia.
College of Science and Engineering, Flinders University, Bedford Park, SA 5042, Australia.
Int J Mol Sci. 2021 Nov 2;22(21):11909. doi: 10.3390/ijms222111909.
Comprising more than half of all brain tumors, glioblastoma multiforme (GBM) is a leading cause of brain cancer-related deaths worldwide. A major clinical challenge is presented by the capacity of glioma cells to rapidly infiltrate healthy brain parenchyma, allowing the cancer to escape control by localized surgical resections and radiotherapies, and promoting recurrence in other brain regions. We propose that therapies which target cellular motility pathways could be used to slow tumor dispersal, providing a longer time window for administration of frontline treatments needed to directly eradicate the primary tumors. An array of signal transduction pathways are known to be involved in controlling cellular motility. Aquaporins (AQPs) and voltage-gated ion channels are prime candidates as pharmacological targets to restrain cell migration in glioblastoma. Published work has demonstrated AQPs 1, 4 and 9, as well as voltage-gated potassium, sodium and calcium channels, chloride channels, and acid-sensing ion channels are expressed in GBM and can influence processes of cell volume change, extracellular matrix degradation, cytoskeletal reorganization, lamellipodial and filopodial extension, and turnover of cell-cell adhesions and focal assembly sites. The current gap in knowledge is the identification of optimal combinations of targets, inhibitory agents, and drug delivery systems that will allow effective intervention with minimal side effects in the complex environment of the brain, without disrupting finely tuned activities of neuro-glial networks. Based on published literature, we propose that co-treatments using AQP inhibitors in addition to other therapies could increase effectiveness, overcoming some limitations inherent in current strategies that are focused on single mechanisms. An emerging interest in nanobodies as drug delivery systems could be instrumental for achieving the selective delivery of combinations of agents aimed at multiple key targets, which could enhance success in vivo.
多形性胶质母细胞瘤（GBM）占所有脑肿瘤的一半以上，是全球脑癌相关死亡的主要原因。胶质瘤细胞能够迅速浸润健康的脑实质，使得癌症能够逃避局部手术切除和放射治疗的控制，并促使其在其他脑区复发，这带来了一项重大的临床挑战。我们提出，针对细胞运动途径的疗法可用于减缓肿瘤扩散，为直接根除原发性肿瘤所需的一线治疗提供更长的给药时间窗。已知一系列信号转导途径参与控制细胞运动。水通道蛋白（AQP）和电压门控离子通道是抑制胶质母细胞瘤细胞迁移的主要药理学靶点候选物。已发表的研究表明，AQP 1、4和9以及电压门控钾、钠和钙通道、氯通道和酸敏感离子通道在GBM中表达，并可影响细胞体积变化、细胞外基质降解、细胞骨架重组、片状伪足和丝状伪足延伸以及细胞间粘附和粘着斑位点周转等过程。目前知识上的差距在于确定靶点、抑制剂和药物递送系统的最佳组合，以便在脑的复杂环境中进行有效干预，同时副作用最小，且不破坏神经胶质网络的精细调节活动。基于已发表的文献，我们提出，除其他疗法外，联合使用AQP抑制剂可能会提高疗效，克服目前专注于单一机制的策略所固有的一些局限性。作为药物递送系统，纳米抗体的新兴研究兴趣可能有助于实现针对多个关键靶点的药物组合的选择性递送，从而提高体内治疗的成功率。
