肺癌症致瘤调节因子Akt/mTOR的激活及其作为生物标志物的潜在价值

Onco Pub Date : 2022-02-25 DOI:10.3390/onco2010004
C. Sousa, B. Silva‐Lima, M. Videira
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引用次数: 2

摘要

癌症的高发病率和适度的治疗结果促使在涉及细胞恶性肿瘤的复杂相互作用网络中识别细胞分子靶点/生物标志物。大多数与EMT相关的调节介质强调了患者的生物学变异、治疗难治性事件和肿瘤细胞异质性。基于对相关途径的理解的患者分层,如对EMT启动至关重要的PI3K/Akt轴,可以有利地改变疾病管理。当过表达的Akt酪氨酸激酶(Akt2)被认为是指导临床管理决策的恶性生物标志物,改善癌症患者的预后时,可以预期显著的临床优势。此外,不应错过将其用作药物靶点的机会,该靶点旨在抑制细胞增殖和存活、干性标志物表达和耐药性的下游复杂性。mTOR作为Akt的下游靶点的价值,以及EMT转录因子Twist、Snail和Zeb1的进一步激活,在这篇综述中被重新审视。一项深入的最新评估提供了其在上皮标记物(如E-钙粘蛋白和miR-200)的机制抑制中的作用的证据,同时诱导间充质标记物(例如波形蛋白、N-钙粘蛋白、和miR-21)的表达。最后,分析了另一种转录因子FOXM1作为PI3K/Akt和Wnt/β-catenin通路之间的联系,通过调节p70S6K促进细胞代谢的证据。建议采用更现实的方法来解决未满足的临床需求,并支持临床层面的决策。考虑到几种复杂的细胞内相互作用可能会进一步改善患者分层,并产生更好的结果。
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Akt/mTOR Activation in Lung Cancer Tumorigenic Regulators and Their Potential Value as Biomarkers
The high incidence and modest therapeutic outcomes of lung cancer have prompted the identification of cell molecular targets/biomarkers within the complex networks of interactions involved in cell malignancy. Most of the EMT-related regulatory mediators underline patients’ biologic variations, therapeutic refractory events, and tumor cell heterogeneity. Patient stratification based on the understanding of the relevant pathways, such as the PI3K/Akt axis crucial in EMT initiation, could favorably alter disease management. Significant clinical advantage could be expected when overexpressed Akt tyrosine kinase (Akt2) is addressed as a malignant biomarker to guide clinical management decisions, improving prognosis in lung cancer patients. Moreover, one should not miss the opportunity of using it as a druggable target aiming at the inhibition of the downstream complexity that underlies cell proliferation and survival, expression of stemness markers and drug resistance. The value of mTOR, as a downstream target of Akt, and the further activation of EMT transcription factors Twist, Snail and Zeb1 are revisited in this review. An in-depth state-of-the-art assessment provides evidence of its role in the mechanistic inhibition of epithelial markers, such as E-cadherin and miR-200, while inducing the expression of the mesenchymal ones, such as vimentin, N-cadherin, and miR-21. Lastly, evidence suggesting another transcription factor, FOXM1, as the link between the PI3K/Akt and Wnt/β-catenin pathways, prompting cell metabolism through the regulation of p70S6K, is analyzed. A more realistic approach is advised to address unmet clinical needs and support decision making at a clinical level. Taking into consideration several complex intracellular interactions might further improve patient stratification and result in better outcomes.
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