Mahatma Gandhi Medical Advanced Research Institute (MGMARI), Sri Balaji Vidyapeeth (Deemed to-be University), Puducherry, India.
Mahatma Gandhi Medical Advanced Research Institute (MGMARI), Sri Balaji Vidyapeeth (Deemed to-be University), Puducherry, India.
Cell Signal. 2022 Jul;95:110350. doi: 10.1016/j.cellsig.2022.110350. Epub 2022 May 4.
Glioblastoma multiforme is one of the calamitous primary glial brain tumors with extensive heterogeneity at cellular and molecular levels. While maximal surgical resection trailed by radio and chemotherapy employing temozolomide remains the gold-standard treatment for malignant glioma patients, the overall prognosis remains dismal and there exists an unmet need for effective therapeutic strategies. In this context, we hypothesize that proper understanding of signaling pathways responsible for glioblastoma multiforme proliferation would be the first trump card while searching for novel targeted therapies. Among the pathways aberrantly activated, PI3K/AKT/mTOR is the most significant pathway, that is clinically implicated in malignancies such as high-grade glioma. Further, the WNT/β-Catenin cascade is well-implicated in several malignancies, while its role in regulating glioma pathogenesis has only emerged recently. Nevertheless, oncogenic activation of both these pathways is a frequent event in malignant glioma that facilitates tumor proliferation, stemness and chemo-resistance. Recently, it has been reported that the cross-talk of PI3K/AKT/mTOR pathway with multiple signaling pathways could promote glioma progression and reduce the sensitivity of glioma cells to the standard therapy. However, very few studies had focused on the relationship between PI3K/AKT/mTOR and WNT/β-Catenin pathways in glioblastoma multiforme. Interestingly, in homeostatic and pathologic circumstances, both these pathways depict fine modulation and are connected at multiple levels by upstream and downstream effectors. Thus, gaining deep insights on the collusion between these pathways would help in discovering unique therapeutic targets for glioblastoma multiforme management. Hence, the current review aims to address, "the importance of inter-play between PI3K/AKT/mTOR and WNT/β-Catenin pathways", and put forward, "the possibility of combinatorially targeting them", for glioblastoma multiforme treatment enhancement.
多形性胶质母细胞瘤是具有广泛细胞和分子异质性的灾难性原发性神经胶质瘤之一。虽然最大限度的手术切除，随后进行放射和化疗，联合替莫唑胺，仍然是恶性神经胶质瘤患者的金标准治疗，但总体预后仍然不佳，需要有效的治疗策略。在这种情况下，我们假设，正确理解导致胶质母细胞瘤增殖的信号通路将是寻找新的靶向治疗方法的首要关键。在异常激活的通路中，PI3K/AKT/mTOR 是最重要的通路，该通路在高级别胶质瘤等恶性肿瘤中具有临床意义。此外，WNT/β-连环蛋白级联在多种恶性肿瘤中都有很好的作用，而其在调节神经胶质瘤发病机制中的作用最近才出现。然而，这两条通路的致癌激活在恶性神经胶质瘤中是一种常见事件，它促进了肿瘤的增殖、干性和化疗耐药性。最近有报道称，PI3K/AKT/mTOR 通路与多种信号通路的交叉对话可以促进神经胶质瘤的进展，并降低神经胶质瘤细胞对标准治疗的敏感性。然而，很少有研究关注 PI3K/AKT/mTOR 和 WNT/β-连环蛋白通路在胶质母细胞瘤中的关系。有趣的是，在生理和病理情况下，这两条通路都描绘了精细的调节，并通过上游和下游效应器在多个水平上连接。因此，深入了解这些通路之间的相互作用将有助于发现胶质母细胞瘤管理的独特治疗靶点。因此，本综述旨在探讨“PI3K/AKT/mTOR 和 WNT/β-连环蛋白通路之间相互作用的重要性”，并提出“联合靶向它们的可能性”，以增强胶质母细胞瘤的治疗效果。
