Amino-acid Transport and the Biology of Human Gliomas

描述（由申请人提供）：谷氨酸是人脑中的主要兴奋性神经递质，是正常神经元信号传导不可或缺的。然而，在能量衰竭的情况下，例如中风后，谷氨酸盐的不受控制的释放可导致神经元的“兴奋性毒性”死亡。谷氨酸中毒可能更常见于神经系统疾病。事实上，最近的研究令人惊讶地表明，星形胶质细胞衍生的原发性脑肿瘤（神经胶质瘤）释放大量谷氨酸进入肿瘤周围空间，并导致假设这种谷氨酸释放可能故意杀死神经元，从而为入侵的肿瘤细胞腾出空间。在这个提议中，我们追求的是另一种假设。我们假设，从胶质瘤细胞释放谷氨酸是一个强制性的副产品，胱氨酸摄取到胶质瘤细胞通过系统XC，胱氨酸-谷氨酸交换。胱氨酸的摄取对于谷胱甘肽（GSH）的产生至关重要，以维持细胞的氧化还原状态。胱氨酸摄取受损会耗尽GSH，导致由于失去对活性氧的防御而导致生长停滞。此外，在该过程中释放的谷氨酸不仅引起兴奋性毒性瘤周神经元损失，而且引起促进神经胶质瘤细胞侵袭的AMPA受体的自分泌/旁分泌激活。该提案旨在表征神经胶质瘤细胞利用的谷氨酸释放/胱氨酸摄取途径，目的是通过抑制这些转运蛋白来抑制肿瘤生长和侵袭。拟议的研究范围从潜在的氨基酸转运蛋白及其在肿瘤生物学中的作用的细胞和分子鉴定到在疾病的动物模型中特异性干扰这些转运蛋白的药物的临床前评价。

DESCRIPTION (provided by applicant): Glutamate is the major excitatory neurotransmitter in the human brain and is indispensable for normal neuronal signaling. However, under conditions of energy failure, for example following a stroke, uncontrolled release of glutamate can cause "excitotoxic" death of neurons. Glutamate toxicity may be more commonly associated with diseases of the nervous system. Indeed, recent studies surprisingly demonstrated that astrocyte-derived primary brain tumors (gliomas) release large quantities of glutamate into the peritumoral space and led to the hypothesis that this glutamate release may purposely kill neurons thereby vacating space for invading tumor cells. In this proposal we are pursuing an alternate hypothesis. We hypothesize that glutamate release from glioma cells is an obligatory byproduct of cystine uptake into glioma cells via system Xc, a cystine-glutamate exchanger. Cystine uptake is essential for the production of glutathione (GSH) to maintain the cells redox status. Impairment of cystine uptake depletes GSH leading to growth arrest due to loss of defense against reactive oxygen species. Furthermore, glutamate released in the process not only causes excitotoxic pertiumoral neuronal loss but causes the autocrine/paracrine activation of AMPA receptors that promote glioma cell invasion. This proposal seeks to characterize the glutamate release/cystine uptake pathway(s) utilized by glioma cells with the objective to suppress tumor growth and invasion by inhibiting these transporters. The proposed studies range from a cellular and molecular identification of the underlying amino acid transporters and their role in tumor biology to the preclinical evaluation of drugs that specifically interfere with these transporters in animal models of the disease.