Garrido Wallys, Rocha Jose Dellis, Jaramillo Catherinne, Fernandez Katia, Oyarzun Carlos, San Martin Rody, Quezada Claudia
Laboratorio de Patologia Molecular, Instituto de Bioquimica y Microbiologia, Facultad de Ciencias, Universidad Austral de Chile, Campus Isla Teja, Valdivia, P.O. Box 567, Chile.
Curr Drug Targets. 2014;15(10):931-42.
Glioblastoma multiforme (GBM) is the most common glial cell-derived brain tumour, with one of the worst prognoses among all cancers. GBM cells are infiltrative and extremely resistant to radio- and chemotherapy, which inevitably leads to recurrence after surgical resection. These inherent GBM properties are the reasons that patient treatment has not seen major improvements in decades. Studies have consistently shown that glioblastoma stem-like cells (GSCs) are responsible for the tumourigenic properties in the GBM population. In fact, their self-renewal and proliferative potential are required for tumour growth, and their extreme chemoresistance leads to early recurrence of this tumour. Among those mechanisms associated with chemoresistance and having the greatest clinical impact in cancer treatment, are the activities of plasma membrane transporters that extrude antitumour drugs from the cell, thus notably decreasing the pharmacological efficiency of these drugs. The multiple drug resistance associated protein-1 (Mrp1) transporter has been shown to be particularly important in GBM, as inhibition of Mrp1 activity notably chemosensitises cells to antiproliferative drugs. As current therapeutic options for GBM offer only a poor improvement in overall survival rate, alternative strategies for overcoming tumour resistance are urgently sought after. To this end, it is of major clinical relevance to know more about the endogenous modulators that control Mrp1 expression within the pathological environment of the tumour. This review describes the particular properties of glioblastoma cells that overcome multimodal therapy and relapse, with an emphasis on the microenvironmental tumour properties that influence the chemoresistance phenotype to antiproliferative drugs. We also discuss alternative methods of reversal of Mrp1-mediated chemoresistance in these cells by targeting extracellular adenosine production or signalling through particular plasma membrane receptors.
多形性胶质母细胞瘤（GBM）是最常见的源自神经胶质细胞的脑肿瘤，在所有癌症中预后最差。GBM细胞具有浸润性，并且对放疗和化疗具有极强的抗性，这不可避免地导致手术切除后复发。GBM的这些固有特性是数十年来患者治疗未见重大改善的原因。研究一直表明，胶质母细胞瘤干细胞（GSCs）是GBM群体中致瘤特性的原因。事实上，它们的自我更新和增殖潜力是肿瘤生长所必需的，并且它们的极端化学抗性导致该肿瘤的早期复发。在与化学抗性相关且在癌症治疗中具有最大临床影响的那些机制中，质膜转运蛋白的活性可将抗肿瘤药物从细胞中排出，从而显著降低这些药物的药理效率。多药耐药相关蛋白1（Mrp1）转运蛋白已被证明在GBM中尤为重要，因为抑制Mrp1活性可显著使细胞对抗增殖药物产生化学敏感性。由于目前GBM的治疗选择仅能使总体生存率有微小提高，因此迫切需要寻求克服肿瘤抗性的替代策略。为此，更多地了解在肿瘤病理环境中控制Mrp1表达的内源性调节剂具有重大临床意义。本综述描述了胶质母细胞瘤细胞克服多模式治疗和复发的特殊特性，重点是影响对抗增殖药物化学抗性表型的微环境肿瘤特性。我们还讨论了通过靶向细胞外腺苷产生或通过特定质膜受体发出信号来逆转这些细胞中Mrp1介导的化学抗性的替代方法。
