Department of Microbiology and Immunology.
Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, and.
J Neurosci. 2019 May 29;39(22):4387-4402. doi: 10.1523/JNEUROSCI.1118-18.2019. Epub 2019 Mar 29.
Glioblastoma (GB) is one of the deadliest brain cancers to afflict humans, and it has a very poor survival rate even with treatment. The extracellular adenosine-generating enzyme CD73 is involved in many cellular functions that can be usurped by tumors, including cell adhesion, proliferation, invasion, and angiogenesis. We set out to determine the role of CD73 in GB pathogenesis. To do this, we established a unique GB mouse model (CD73-FLK) in which we spatially expressed CD73 on endothelial cells in CD73 mice. This allowed us to elucidate the mechanism of host CD73 versus GB-expressed CD73 by comparing GB pathogenesis in WT, CD73, and CD73-FLK mice. GB in CD73 mice had decreased tumor size, decreased tumor vessel density, and reduced tumor invasiveness compared with GB in WT mice. Interestingly, GBs in CD73-FLK mice were much more invasive and caused complete distortion of the brain morphology. We showed a 20-fold upregulation of A AR on GB compared with sham, and its activation induced matrix metalloproteinase-2, which enhanced GB pathogenesis. Inhibition of A AR signaling decreased multidrug resistance transporter protein expression, including permeability glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1). Further, we showed that blockade of A AR signaling potently increased GB cell death induced by the chemotherapeutic drug temozolomide. Together, these findings suggest that CD73 and A AR play a multifaceted role in GB pathogenesis and progression and that targeting the CD73-A AR axis can benefit GB patients and inform new approaches for therapy to treat GB patients. Glioblastoma (GB) is the most devastating primary brain tumor. GB patients' median survival is 16 months even with treatment. It is critical that we develop prophylaxes to advance GB treatment and improve patient survival. CD73-generated adenosine has been implicated in cancer pathogenesis, but its role in GB was not ascertained. Here, we demonstrated that host CD73 plays a prominent role in multiple areas of glioblastoma pathogenesis, including promoting GB growth, its angiogenesis, and its invasiveness. We found a 20-fold increase in A adenosine receptor (AR) expression on GB compared with sham, and its inhibition increased GB chemosensitivity to temozolomide. These findings strongly indicate that blockade or inhibition of CD73 and the A AR are prime targets for future GB therapy.
胶质母细胞瘤（GB）是一种最致命的侵袭人类大脑的癌症，即使经过治疗，其存活率也非常低。细胞外产生腺苷的酶 CD73 参与许多细胞功能，这些功能可被肿瘤篡夺，包括细胞黏附、增殖、侵袭和血管生成。我们着手确定 CD73 在 GB 发病机制中的作用。为此，我们在 CD73 小鼠中建立了一种独特的 GB 小鼠模型（CD73-FLK），在该模型中，我们在 CD73 小鼠的内皮细胞上空间表达 CD73。这使我们能够通过比较 WT、CD73 和 CD73-FLK 小鼠中的 GB 发病机制来阐明宿主 CD73 与 GB 表达的 CD73 的机制。与 WT 小鼠相比，CD73 小鼠中的 GB 肿瘤体积减小，肿瘤血管密度降低，肿瘤侵袭性降低。有趣的是，CD73-FLK 小鼠中的 GB 侵袭性更强，导致大脑形态完全扭曲。我们发现与假手术相比，GB 中 A1 腺苷受体（A AR）的表达上调了 20 倍，其激活诱导了基质金属蛋白酶-2，从而增强了 GB 的发病机制。A AR 信号通路的抑制降低了多药耐药转运蛋白的表达，包括血脑屏障通透性糖蛋白（P-gp）和多药耐药相关蛋白 1（MRP1）。此外，我们还发现 A AR 信号通路的阻断可强烈增加替莫唑胺诱导的 GB 细胞死亡。综上所述，这些发现表明 CD73 和 A AR 在 GB 的发病机制和进展中发挥着多方面的作用，靶向 CD73-A AR 轴可以使 GB 患者受益，并为治疗 GB 患者提供新的治疗方法。胶质母细胞瘤（GB）是最具破坏性的原发性脑肿瘤。即使经过治疗，GB 患者的中位生存期也只有 16 个月。因此，我们必须开发预防措施来推进 GB 的治疗并提高患者的生存率。CD73 产生的腺苷已被牵涉到癌症的发病机制中，但它在 GB 中的作用尚未确定。在这里，我们证明宿主 CD73 在 GB 发病机制的多个方面发挥着突出作用，包括促进 GB 的生长、血管生成和侵袭。我们发现与假手术相比，GB 上的 A1 腺苷受体（A AR）表达增加了 20 倍，其抑制作用增加了替莫唑胺对 GB 的化疗敏感性。这些发现强烈表明，CD73 和 A AR 的阻断或抑制是未来 GB 治疗的主要靶点。
