Department of Laboratory Medicine, Calcutta School of Tropical Medicine, Kolkata, West Bengal, India.
Department of Clinical and Experimental Pharmacology, School of Tropical Medicine, Kolkata, West Bengal, India.
J Cell Physiol. 2018 Jan;233(1):269-290. doi: 10.1002/jcp.25874. Epub 2017 Mar 24.
Combating gliomagenic global immunosuppression is one of the emerging key for improving prognosis in malignant glioma. Apoptosis plays a pivotal role within the adult hematopoietic system particularly in regulating the cells of immune system. Gliomagenic regulation of apoptotic mediators within bone marrow milieu has not been elucidated. We previously demonstrated that administration of membrane glycopeptides T11 target structure (T11TS) not only rejuvenate bone marrow hematopoietic stem cells (BMHSCs) from glioma mediated hibernation by inhibiting gliomagenic overexpression of Ang-1/Tie-2 but also stimulate glioma mediated diminution of expression CD34, c-kit, and Sca-1 markers. In the present study, we investigated the impact of glioma on apoptotic signaling cascades of BMHSCs and consequences following T11TS therapy. Bone marrow smear and Annexin V staining confirm gliomagenic acceleration of apoptotic fate of BMHSCs whereas T11TS treatment in glioma-bearing rats disrupted apoptosis of BMHSCs. Flowcytometry, immunoblotting, and immunofluorescence imagining results revealed multi potent T11TS not only significantly downregulates gliomagenic overexpression of Fas, Fas L, Bid, and caspase-8, the pro-apoptotic extrinsic mediators but also strongly inhibits cytosolic release of cytochrome-c, Apf-1, and Bax to deactivate gliomagenic caspase-9, 3 the key intrinsic apoptotic mediators followed by up modulation of anti-apoptotic Bcl-2 in glioma associated HSCs. T11TS is also able to diminish the perforin-granzyme B mediated apoptotic verdict of BMHSCs during gliomagenesis. The anti-apoptotic action of T11TS on glioma associated BMHSCs provide a crucial insight into how T11TS exerts its immunomodulatory action against glioma mediated immune devastation.
对抗神经胶质瘤导致的全身性免疫抑制是改善恶性神经胶质瘤预后的新兴关键之一。细胞凋亡在成人造血系统中起着关键作用，特别是在调节免疫系统细胞方面。骨髓微环境中神经胶质瘤对凋亡介质的调节作用尚未阐明。我们之前的研究表明，给予膜糖肽 T11 靶向结构（T11TS）不仅可以通过抑制神经胶质瘤过度表达的 Ang-1/Tie-2 使受神经胶质瘤影响而休眠的骨髓造血干细胞（BMHSCs）恢复活力，还可以刺激神经胶质瘤导致的 CD34、c-kit 和 Sca-1 标志物表达减少。在本研究中，我们研究了神经胶质瘤对 BMHSCs 凋亡信号级联的影响以及 T11TS 治疗后的后果。骨髓涂片和 Annexin V 染色证实神经胶质瘤加速了 BMHSCs 的凋亡命运，而 T11TS 治疗在荷神经胶质瘤大鼠中破坏了 BMHSCs 的凋亡。流式细胞术、免疫印迹和免疫荧光成像结果表明，多功能 T11TS 不仅显著下调了神经胶质瘤过度表达的 Fas、FasL、Bid 和 caspase-8 等促凋亡外源性介质，而且强烈抑制了细胞质中细胞色素-c、Apf-1 和 Bax 的释放，从而使神经胶质瘤 caspase-9 和 3 等关键内在凋亡介质失活，随后上调了神经胶质瘤相关 HSCs 中的抗凋亡 Bcl-2。T11TS 还能够减少在神经胶质瘤发生过程中穿孔素-颗粒酶 B 介导的 BMHSCs 凋亡。T11TS 对神经胶质瘤相关 BMHSCs 的抗凋亡作用为了解 T11TS 如何发挥其针对神经胶质瘤介导的免疫破坏的免疫调节作用提供了重要的见解。
