Human breast cancer metastases to the brain display GABAergic properties in the neural niche
Human breast cancer metastases to the brain display GABAergic properties in the neural niche
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DOI：
10.1073/pnas.1322098111
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发表时间：
2014-01-21
影响因子：
11.1
通讯作者：
Jandial, Rahul
中科院分区：
文献类型：
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作者：
Neman, Josh;Termini, John;Jandial, Rahul
肿瘤在全身的扩散是一种肿瘤过程，是绝大多数癌症死亡的原因。尽管作为恶性侦察兵扩散到远处器官，但大多数肿瘤细胞在到达后未能保持活力。脑的生理微环境必须成为循环乳腺癌细胞成功转移定植的肿瘤有利微环境。乳腺癌细胞和天然脑细胞在转移中的双向相互作用知之甚少，也很少研究。我们有难得的机会来研究罕见的匹配的新鲜乳腺到脑转移组织标本和来自神经外科切除患者的衍生细胞。我们假设，转移，乳腺癌可能会逃脱其规范的遗传约束，容纳和共同居住的神经生态位。乳腺癌细胞获得或表达类脑特性可能是脑定植所需的恶性适应。事实上，我们发现乳腺-脑转移组织和细胞显示出与神经元细胞相似的GABA能表型。GABA（A）受体、GABA转运体、GABA转氨酶、小白蛋白和reelin在乳腺癌脑转移灶中均高度表达。乳腺-脑转移瘤摄取GABA并将其分解代谢为琥珀酸的能力赋予了这种优势，从而形成NADH作为通过GABA分流的生物合成来源。结果表明，乳腺癌在占据脑微环境时表现出神经特征，并将GABA作为肿瘤代谢物。
Dispersion of tumors throughout the body is a neoplastic process responsible for the vast majority of deaths from cancer. Despite disseminating to distant organs as malignant scouts, most tumor cells fail to remain viable after their arrival. The physiologic microenvironment of the brain must become a tumor-favorable microenvironment for successful metastatic colonization by circulating breast cancer cells. Bidirectional interplay of breast cancer cells and native brain cells in metastasis is poorly understood and rarely studied. We had the rare opportunity to investigate uncommonly available specimens of matched fresh breast-to-brain metastases tissue and derived cells from patients undergoing neurosurgical resection. We hypothesized that, to metastasize, breast cancers may escape their normative genetic constraints by accommodating and coinhabiting the neural niche. This acquisition or expression of brainlike properties by breast cancer cells could be a malignant adaptation required for brain colonization. Indeed, we found breast-to-brain metastatic tissue and cells displayed a GABAergic phenotype similar to that of neuronal cells. The GABA(A) receptor, GABA transporter, GABA transaminase, parvalbumin, and reelin were all highly expressed in breast cancer metastases to the brain. Proliferative advantage was conferred by the ability of breast-to-brain metastases to take up and catabolize GABA into succinate with the resultant formation of NADH as a biosynthetic source through the GABA shunt. The results suggest that breast cancers exhibit neural characteristics when occupying the brain microenvironment and co-opt GABA as an oncometabolite.