Sloan Anthony R, Lee-Poturalski Christine, Hoffman Harry C, Harris Peggy L, Elder Theresa E, Richardson Brian, Kerstetter-Fogle Amber, Cioffi Gino, Schroer Julia, Desai Ansh, Cameron Mark, Barnholtz-Sloan Jill, Rich Jeremy, Jankowsky Eckhard, Sen Gupta Anirban, Sloan Andrew E
Department of Neurological Surgery, Case Western Reserve University, Cleveland, Ohio, USA.
Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio, USA.
Neurooncol Adv. 2022 Nov 7;4(1):vdac172. doi: 10.1093/noajnl/vdac172. eCollection 2022 Jan-Dec.
The interaction between platelets and cancer cells has been underexplored in solid tumor models that do not metastasize, for example, glioblastoma (GBM) where metastasis is rare. Histologically, it is known that glioma stem cells (GSCs) are found in perivascular and pseudsopalisading regions of GBM, which are also areas of platelet localization. High platelet counts have been associated with poor clinical outcomes in many cancers. While platelets are known to promote the progression of other tumors, mechanisms by which platelets influence GBM oncogenesis are unknown. Here, we aimed to understand how the bidirectional interaction between platelets and GSCs drives GBM oncogenesis.
Male and female NSG mice were transplanted with GSC lines and treated with antiplatelet and anti-thrombin inhibitors. Immunofluorescence, qPCR, and Western blots were used to determine expression of coagulation mechanism in GBM tissue and subsequent GSC lines.
We show that GSCs activate platelets by endogenous production of all the factors of the intrinsic and extrinsic coagulation cascades in a plasma-independent manner. Therefore, GSCs produce thrombin resulting in platelet activation. We further demonstrate that the endogenous coagulation cascades of these cancer stem cells are tumorigenic: they activate platelets to promote stemness and proliferation and pharmacological inhibition delays tumor growth .
Our findings uncover a specific preferential relationship between platelets and GSCs that drive GBM malignancies and identify a therapeutically targetable novel interaction.
在不发生转移的实体瘤模型中，例如转移罕见的胶质母细胞瘤（GBM），血小板与癌细胞之间的相互作用尚未得到充分研究。从组织学上看，已知在GBM的血管周围和假栅栏状区域发现了胶质瘤干细胞（GSCs），而这些区域也是血小板定位的区域。在许多癌症中，高血小板计数与不良临床结果相关。虽然已知血小板会促进其他肿瘤的进展，但血小板影响GBM肿瘤发生的机制尚不清楚。在此，我们旨在了解血小板与GSCs之间的双向相互作用如何驱动GBM肿瘤发生。
将雄性和雌性NSG小鼠移植GSC系，并使用抗血小板和抗凝血酶抑制剂进行治疗。采用免疫荧光、qPCR和蛋白质印迹法测定GBM组织及后续GSC系中凝血机制的表达。
我们发现GSCs通过内源性产生内源性和外源性凝血级联反应的所有因子，以不依赖血浆的方式激活血小板。因此，GSCs产生凝血酶导致血小板激活。我们进一步证明，这些癌症干细胞的内源性凝血级联反应具有致瘤性：它们激活血小板以促进干性和增殖，并且药物抑制会延迟肿瘤生长。
我们的研究结果揭示了血小板与GSCs之间驱动GBM恶性肿瘤的特定优先关系，并确定了一个可用于治疗的新型相互作用靶点。
