Yakubov Eduard, Schmid Sebastian, Hammer Alexander, Chen Daishi, Dahlmanns Jana Katharina, Mitrovic Ivana, Zurabashvili Luka, Savaskan Nicolai, Steiner Hans-Herbert, Dahlmanns Marc
Department of Neurosurgery, Paracelsus Medical University, Nuremberg, Germany.
Department of Trauma, Orthopaedics, Plastic and Hand Surgery, University Hospital Augsburg, Augsburg, Germany.
Front Oncol. 2023 Jul 24;13:1176038. doi: 10.3389/fonc.2023.1176038. eCollection 2023.
Human malignant brain tumors such as gliomas are devastating due to the induction of cerebral edema and neurodegeneration. A major contributor to glioma-induced neurodegeneration has been identified as glutamate. Glutamate promotes cell growth and proliferation in variety of tumor types. Intriguently, glutamate is also an excitatory neurotransmitter and evokes neuronal cell death at high concentrations. Even though glutamate signaling at the receptor and its downstream effectors has been extensively investigated at the molecular level, there has been little insight into how glutamate enters the tumor microenvironment and impacts on metabolic equilibration until recently. Surprisingly, the 12 transmembrane spanning tranporter xCT (SLC7A11) appeared to be a major player in this process, mediating glutamate secretion and ferroptosis. Also, PPARγ is associated with ferroptosis in neurodegeneration, thereby destroying neurons and causing brain swelling. Although these data are intriguing, tumor-associated edema has so far been quoted as of vasogenic origin. Hence, glutamate and PPARγ biology in the process of glioma-induced brain swelling is conceptually challenging. By inhibiting xCT transporter or AMPA receptors in vivo, brain swelling and peritumoral alterations can be mitigated. This review sheds light on the role of glutamate in brain tumors presenting the conceptual challenge that xCT disruption causes ferroptosis activation in malignant brain tumors. Thus, interfering with glutamate takes center stage in forming the basis of a metabolic equilibration approach.
人类恶性脑肿瘤，如神经胶质瘤，由于会引发脑水肿和神经退行性变，因而具有极大的破坏性。已确定神经胶质瘤诱导神经退行性变的一个主要因素是谷氨酸。谷氨酸在多种肿瘤类型中促进细胞生长和增殖。有趣的是，谷氨酸也是一种兴奋性神经递质，在高浓度时会引发神经元细胞死亡。尽管在分子水平上已经对谷氨酸在受体及其下游效应器处的信号传导进行了广泛研究，但直到最近，对于谷氨酸如何进入肿瘤微环境并影响代谢平衡仍知之甚少。令人惊讶的是，具有12个跨膜结构域的转运体xCT（SLC7A11）似乎是这一过程中的主要参与者，介导谷氨酸分泌和铁死亡。此外，PPARγ与神经退行性变中的铁死亡有关，从而破坏神经元并导致脑肿胀。尽管这些数据很有趣，但迄今为止，肿瘤相关水肿一直被认为是血管源性的。因此，神经胶质瘤诱导脑肿胀过程中的谷氨酸和PPARγ生物学在概念上具有挑战性。通过在体内抑制xCT转运体或AMPA受体，可以减轻脑肿胀和瘤周改变。本综述揭示了谷氨酸在脑肿瘤中的作用，提出了xCT破坏导致恶性脑肿瘤中铁死亡激活这一概念性挑战。因此，干扰谷氨酸在形成代谢平衡方法的基础中占据核心地位。
