Microglial lysophosphatidic acid promotes glioblastoma proliferation and migration via LPA1receptor
Microglial lysophosphatidic acid promotes glioblastoma proliferation and migration via LPA1receptor
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DOI：
10.1111/jnc.15097
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发表时间：
2020-06-20
影响因子：
4.7
通讯作者：
Lima, Flavia R. S.
中科院分区：
文献类型：
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作者：
Amaral, Rackele F.;Geraldo, Luiz H. M.;Lima, Flavia R. S.
胶质母细胞瘤是一种高度侵袭性的原发脑肿瘤，具有细胞异质性、对化疗不敏感、患者存活率低等特点。溶血磷脂酸(LPA)是一种溶血磷脂，作为一种生物活性的信号分子，在发育和疾病的各种生物学事件中发挥重要作用，包括几种癌症类型。小胶质细胞是中枢神经系统的驻留巨噬细胞，表达高水平的自体趋化蛋白(ATX，Enpp2)，这是一种合成LPA的酶。我们的研究旨在通过小胶质细胞与基底膜的相互作用来研究LPA在肿瘤生长和侵袭中的作用。首先，通过生物信息学研究，患者数据分析表明，侵袭性更强的GBM表达更高水平的ENPP2，这也与神经性GBM患者预后较差有关。利用GBM-小胶质细胞共培养体系，我们证明了GBM分泌因子能够增加小胶质细胞中LPA(1)和ATX的表达，低氧可进一步增强这种作用。另一方面，与小胶质细胞的相互作用也增加了GBM中ATX的表达。此外，小胶质细胞诱导的GBM增殖和迁移可被LPA(1)的药理抑制作用所抑制，提示小胶质细胞来源的LPA可能支持肿瘤的生长和侵袭。最后，与其他胶质瘤相比，LPA(1)在GBM中的表达增加，也可能与患者的生存期较差有关。这些结果首次显示了小胶质细胞-GBM通过LPA途径的相互作用，并与肿瘤进展相关。更好地了解这种相互作用可以导致开发新的治疗策略，将LPA作为GBM治疗的潜在靶点。
Glioblastomas (GBMs) are highly aggressive primary brain tumors characterized by cellular heterogeneity, insensitivity to chemotherapy and poor patient survival. Lysophosphatidic acid (LPA) is a lysophospholipid that acts as a bioactive signaling molecule and plays important roles in diverse biological events during development and disease, including several cancer types. Microglial cells, the resident macrophages of the central nervous system, express high levels of Autotaxin (ATX,Enpp2), an enzyme that synthetizes LPA. Our study aimed to investigate the role of LPA on tumor growth and invasion in the context of microglia-GBM interaction. First, through bioinformatics studies, patient data analysis demonstrated that more aggressive GBM expressed higher levels of ENPP2, which was also associated with worse patient prognosis with proneural GBM. Using GBM-microglia co-culture system we then demonstrated that GBM secreted factors were able to increase LPA(1)and ATX in microglia, which could be further enhanced by hypoxia. On the other hand, interaction with microglial cells also increased ATX expression in GBM. Furthermore, microglial-induced GBM proliferation and migration could be inhibited by pharmacological inhibition of LPA(1), suggesting that microglial-derived LPA could support tumor growth and invasion. Finally, increased LPA(1)expression was observed in GBM comparing with other gliomas and could be also associated with worse patient survival. These results show for the first time a microglia-GBM interaction through the LPA pathway with relevant implications for tumor progression. A better understanding of this interaction can lead to the development of new therapeutic strategies setting LPA as a potential target for GBM treatment.