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Molecular chaperones: Guardians of tumor suppressor stability and function. 分子伴侣:肿瘤抑制因子稳定性和功能的守护者
Q2 Medicine Pub Date : 2024-10-01 DOI: 10.18632/oncotarget.28653
Jennifer A Heritz, Sarah J Backe, Mehdi Mollapour

The term 'tumor suppressor' describes a widely diverse set of genes that are generally involved in the suppression of metastasis, but lead to tumorigenesis upon loss-of-function mutations. Despite the protein products of tumor suppressors exhibiting drastically different structures and functions, many share a common regulatory mechanism-they are molecular chaperone 'clients'. Clients of molecular chaperones depend on an intracellular network of chaperones and co-chaperones to maintain stability. Mutations of tumor suppressors that disrupt proper chaperoning prevent the cell from maintaining sufficient protein levels for physiological function. This review discusses the role of the molecular chaperones Hsp70 and Hsp90 in maintaining the stability and functional integrity of tumor suppressors. The contribution of cochaperones prefoldin, HOP, Aha1, p23, FNIP1/2 and Tsc1 as well as the chaperonin TRiC to tumor suppressor stability is also discussed. Genes implicated in renal cell carcinoma development-VHL, TSC1/2, and FLCN-will be used as examples to explore this concept, as well as how pathogenic mutations of tumor suppressors cause disease by disrupting protein chaperoning, maturation, and function.

肿瘤抑制因子 "一词描述了一系列种类繁多的基因,这些基因通常参与抑制转移,但一旦发生功能缺失突变,就会导致肿瘤发生。尽管肿瘤抑制因子的蛋白质产物在结构和功能上存在巨大差异,但许多肿瘤抑制因子都有一个共同的调控机制--它们都是分子伴侣的 "客户"。分子伴侣的客户依赖于细胞内的伴侣和辅助伴侣网络来维持稳定性。肿瘤抑制因子的突变会破坏正常的伴侣作用,从而使细胞无法维持足够的蛋白质水平以发挥生理功能。本综述讨论分子伴侣 Hsp70 和 Hsp90 在维持肿瘤抑制因子的稳定性和功能完整性方面的作用。此外,还讨论了辅助伴侣预折叠素、HOP、Aha1、p23、FNIP1/2 和 Tsc1 以及伴侣素 TRiC 对肿瘤抑制因子稳定性的贡献。我们将以与肾细胞癌发展有关的基因--VHL、TSC1/2 和 FLCN 为例,探讨这一概念,以及肿瘤抑制因子的致病突变如何通过破坏蛋白质的伴侣作用、成熟和功能而导致疾病。
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引用次数: 0
Zika virus and brain cancer: Can Zika be an effective treatment for brain cancer? A systematic review. 寨卡病毒与脑癌寨卡病毒能有效治疗脑癌吗?系统综述。
Q2 Medicine Pub Date : 2024-09-30 DOI: 10.18632/oncotarget.28647
Mateus Gonçalves de Sena Barbosa, Beatriz Rodrigues Messias, Rafael Trindade Tatit, Maycon Cristian Gomes de Paula, Valdecir Boeno Spenazato Júnior, Maria Gabriella Borges Braga, Caio Vinícius Marcolino Santos, Luiza D'Ottaviano Cobos, Vinícius Otávio da Silva, Eberval Gadelha Figueiredo, Nicollas Nunes Rabelo, Bipin Chaurasia

Introduction: Many studies have highlighted the use of oncolytic viruses as a new class of therapeutic agents for central nervous system (CNS) tumors, especially glioblastomas (GMB). Zika Virus (ZIKV) proteins targeted to specific stem cells have been studied in vitro and animal models with promising results.

Materials and methods: A systematic review was evaluated the efficacy and safety of the ZIKV use for CNS tumors treatment. Data were extracted and the in vivo studies were evaluated using the Robins-I tool. We assessed bias in each study using criteria such as selection bias, performance bias, detection bias, attrition bias, reporting bias, and others. According to Cochrane guidelines, bias was classified as high, low, or uncertain. High bias occurred when studies did not meet the criteria. Low bias was assigned when criteria were clearly met. Uncertain bias reflected insufficient information for a clear classification.

Results: The 14 included studies shown that ZIKV reduced cell viability or inhibited the growth, proliferation of glioma stem cells (GSCs), and Bcl2 expression - which could potentially enhance the effect of chemotherapy/radiotherapy; caused cytopathic effects, induced tumor cell damage, manifested oncolytic properties, and even selectively safely killed GSCs; ultimately, it led to significant tumor remission and enhanced long-term survival through enhanced T-cell response.

Conclusions: Although current evidence suggests ZIKV as a promising treatment for CNS tumors and may improve survival when combined with surgery and radiotherapy. Despite limited human evidence, it shows potential benefits. Further research is needed to confirm safety, efficacy, and optimize treatment in humans.

导言:许多研究都强调将溶瘤病毒作为治疗中枢神经系统(CNS)肿瘤,尤其是胶质母细胞瘤(GMB)的新型药物。针对特定干细胞的寨卡病毒(ZIKV)蛋白已在体外和动物模型中进行了研究,并取得了可喜的成果:对使用 ZIKV 治疗中枢神经系统肿瘤的有效性和安全性进行了系统性评估。采用罗宾斯-I工具提取数据并评估体内研究。我们使用选择偏倚、表现偏倚、检测偏倚、自然减员偏倚、报告偏倚等标准评估了每项研究的偏倚。根据 Cochrane 指南,偏倚分为高、低和不确定。当研究不符合标准时,就会出现高偏倚。当研究明显符合标准时,偏倚程度为低。不确定偏倚反映了信息不足,无法进行明确分类:纳入的14项研究表明,ZIKV可降低细胞活力或抑制胶质瘤干细胞(GSCs)的生长、增殖和Bcl2的表达--这有可能增强化疗/放疗的效果;ZIKV可引起细胞病理效应、诱导肿瘤细胞损伤、表现出溶瘤特性,甚至可选择性地安全杀死GSCs;最终,ZIKV可通过增强T细胞反应使肿瘤显著缓解并提高长期生存率:结论:尽管目前的证据表明,ZIKV 是一种治疗中枢神经系统肿瘤的有前途的药物,与手术和放疗相结合可提高生存率。尽管人类证据有限,但它仍显示出潜在的益处。还需要进一步的研究来确认其安全性和有效性,并优化人体治疗。
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引用次数: 0
UBA1 dysfunction in VEXAS and cancer. VEXAS 和癌症中的 UBA1 功能障碍
Q2 Medicine Pub Date : 2024-09-30 DOI: 10.18632/oncotarget.28646
Maki Sakuma, Torsten Haferlach, Wencke Walter

UBA1, an X-linked gene, encodes one of the only two ubiquitin E1 enzymes, playing a pivotal role in initiating one of the most essential post-translational modifications. In late 2020, partial loss-of-function mutations in UBA1 within hematopoietic stem and progenitor cells were found to be responsible for VEXAS Syndrome, a previously unidentified hematoinflammatory disorder predominantly affecting older males. The condition is characterized by severe inflammation, cytopenias, and an association to hematologic malignancies. In this research perspective, we comprehensively review the molecular significance of UBA1 loss of function as well as advancements in VEXAS research over the past four years for each of the VEXAS manifestations - inflammation, cytopenias, clonality, and possible oncogenicity. Special attention is given to contrasting the M41 and non-M41 mutations, aiming to elucidate their differential effects and to identify targetable mechanisms responsible for each of the symptoms. Finally, we explore the therapeutic landscape for VEXAS Syndrome, discussing the efficacy and potential of clone-targeting drugs based on the pathobiology of VEXAS. This includes azacitidine, currently approved for myelodysplastic neoplasms (MDS), novel UBA1 inhibitors being developed for a broad spectrum of cancers, Protein Kinase R-like Endoplasmic Reticulum Kinase (PERK) inhibitors, and auranofin, a long-established drug for rheumatoid arthritis. This perspective bridges basic research to clinical symptoms and therapeutics.

UBA1是一个X连锁基因,编码仅有的两种泛素E1酶之一,在启动最重要的翻译后修饰中发挥着关键作用。2020 年末,人们发现造血干细胞和祖细胞中 UBA1 的部分功能缺失突变是 VEXAS 综合征的病因,这是一种之前未被发现的主要影响老年男性的血液炎症性疾病。这种疾病的特征是严重的炎症、细胞减少以及与血液恶性肿瘤有关。在这篇研究视角中,我们全面回顾了 UBA1 功能缺失的分子意义,以及过去四年中 VEXAS 研究在炎症、细胞减少症、克隆性和可能的致癌性等每种 VEXAS 表现方面取得的进展。我们特别关注 M41 突变和非 M41 突变的对比,旨在阐明它们的不同影响,并确定导致每种症状的可靶向机制。最后,我们探讨了VEXAS综合征的治疗前景,讨论了基于VEXAS病理生物学的克隆靶向药物的疗效和潜力,其中包括目前被批准用于骨髓增生异常性肿瘤(MDS)的阿扎胞苷、正在开发用于多种癌症的新型UBA1抑制剂、蛋白激酶R样内质网激酶(PERK)抑制剂,以及治疗类风湿性关节炎的历史悠久的药物奥拉诺芬。这一视角是基础研究与临床症状和治疗之间的桥梁。
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引用次数: 0
Linking FOXM1 and PD-L1 to CDK4/6-MEK targeted therapy resistance in malignant peripheral nerve sheath tumors. 将 FOXM1 和 PD-L1 与恶性周围神经鞘瘤的 CDK4/6-MEK 靶向治疗耐药性联系起来。
Q2 Medicine Pub Date : 2024-09-30 DOI: 10.18632/oncotarget.28650
Joshua J Lingo, Ellen Voigt, Dawn E Quelle

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, Ras-driven sarcomas characterized by loss of the NF1 tumor suppressor gene and hyperactivation of MEK and CDK4/6 kinases. MPNSTs lack effective therapies. We recently demonstrated remarkable efficacy of dual CDK4/6-MEK inhibition in mice with de novo MPNSTs, which was heightened by combined targeting of the immune checkpoint protein, PD-L1. The triple combination therapy targeting CDK4/6, MEK, and PD-L1 led to extended MPNST regression and improved survival, although most tumors eventually acquired drug resistance. Here, we consider the immune activation phenotype caused by CDK4/6-MEK inhibition in MPNSTs that uniquely involved intratumoral plasma cell accumulation. We discuss how PD-L1 and FOXM1, a tumor-promoting transcription factor, are functionally linked and may be key mediators of resistance to CDK4/6-MEK targeted therapies. Finally, the role of FOXM1 in suppressing anti-tumor immunity and potentially thwarting immune-based therapies is considered. We suggest that future therapeutic strategies targeting the oncogenic network of CDK4/6, MEK, PD-L1, and FOXM1 represent exciting future treatment options for MPNST patients.

恶性周围神经鞘瘤(MPNSTs)是一种侵袭性 Ras 驱动肉瘤,其特征是 NF1 抑癌基因缺失以及 MEK 和 CDK4/6 激酶过度激活。MPNST 缺乏有效的治疗方法。最近,我们在患有新发 MPNST 的小鼠中证实了 CDK4/6-MEK 双抑制的显著疗效,而联合靶向免疫检查点蛋白 PD-L1 则增强了疗效。针对CDK4/6、MEK和PD-L1的三联疗法延长了MPNST的消退时间并提高了生存率,尽管大多数肿瘤最终会产生耐药性。在此,我们探讨了 CDK4/6-MEK 抑制在 MPNST 中引起的免疫激活表型,这种表型独特地涉及瘤内浆细胞聚集。我们讨论了 PD-L1 和 FOXM1(一种肿瘤促进转录因子)如何在功能上相互关联,并可能成为 CDK4/6-MEK 靶向疗法耐药性的关键介质。最后,我们还考虑了 FOXM1 在抑制抗肿瘤免疫和可能挫败基于免疫的疗法中的作用。我们认为,针对 CDK4/6、MEK、PD-L1 和 FOXM1 等致癌网络的未来治疗策略是未来治疗 MPNST 患者的令人兴奋的选择。
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引用次数: 0
Retraction: Association study of inflammatory cytokine and chemokine expression in hand foot and mouth disease. 撤回:手足口病中炎症细胞因子和趋化因子表达的关联研究。
Q2 Medicine Pub Date : 2024-09-30 DOI: 10.18632/oncotarget.28655
Wenzhong Shang, Suying Qian, Lijuan Fang, Yong Han, Cuiping Zheng
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引用次数: 0
Lessons from the ACDC-RP trial: Clinical trial design for radical prostatectomy neoadjuvant therapy trials. ACDC-RP 试验的经验教训:前列腺癌根治术新辅助治疗试验的临床试验设计。
Q2 Medicine Pub Date : 2024-09-30 DOI: 10.18632/oncotarget.28648
Rashid K Sayyid, Neil E Fleshner
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引用次数: 0
Integrated stress response (ISR) activation and apoptosis through HRI kinase by PG3 and other p53 pathway-restoring cancer therapeutics. PG3和其他可恢复p53通路的癌症治疗药物通过HRI激酶激活综合应激反应(ISR)和细胞凋亡。
Q2 Medicine Pub Date : 2024-09-17 DOI: 10.18632/oncotarget.28637
Xiaobing Tian, Wafik S El-Deiry

Restoration of the p53 pathway has been a long-term goal in the field of cancer research to treat tumors with mutated p53 and aggressive clinical behavior. p53 pathway restoration in p53-deficient cancers can be achieved by small molecules via p53-dependent or p53-independent processes. Hereafter p53-independent restoration of p53-pathway-signaling in p53-deficient/mutated tumors is referred to as 'restoration of the p53 pathway'. We compare activation of p53 target genes by novel compounds PG3 and PG3-Oc, that activate p53-target genes in a p53-independent manner, and four mutant p53-activating compounds while Nutlin-3a is used as negative control. PG3 and PG3-Oc upregulate p21, PUMA, and DR5 in five cancer cell lines with various p53 mutational statuses through ATF4 (Activating Transcriptional Factor 4) and integrated stress response (ISR) independent of p53. Mutant p53-targeting compounds induce expression of the 3 major downstream p53 target genes and ATF4 in a highly variable and cell-type-dependent manner. PG3 treatment activates ATF4 through ISR via kinase HRI (Heme-Regulated Inhibitor). ATF4 mediates upregulation of PUMA, p21, and NAG-1/GDF15 (Nonsteroidal anti-inflammatory drug-activated gene 1). We note that PUMA mediates apoptosis through activation of caspase-8 in HT29 cells and potentially caspase-10 in SW480 cells. We provide a novel mechanism engaged by PG3 to induce cell death via the HRI/ATF4/PUMA axis. Our results provide unique insights into the mechanism of action of PG3 as a novel cancer therapeutic targeting p53 pathway-like tumor suppression.

恢复 p53 通路一直是癌症研究领域的一个长期目标,目的是治疗 p53 基因突变并具有侵袭性临床表现的肿瘤。小分子药物可以通过依赖 p53 或不依赖 p53 的过程来实现 p53 通路在 p53 缺失型癌症中的恢复。以下将不依赖于 p53 的 p53 通路信号在 p53 缺失/突变肿瘤中的恢复称为 "p53 通路的恢复"。我们比较了新型化合物 PG3 和 PG3-Oc 和四种突变的 p53 激活化合物对 p53 靶基因的激活情况,PG3 和 PG3-Oc 以不依赖 p53 的方式激活 p53 靶基因,而 Nutlin-3a 则作为阴性对照。PG3 和 PG3-Oc 可通过 ATF4(激活转录因子 4)和独立于 p53 的综合应激反应(ISR)上调具有不同 p53 突变状态的五种癌细胞系中的 p21、PUMA 和 DR5。突变 p53 靶向化合物以高度可变和依赖细胞类型的方式诱导 3 个主要下游 p53 靶基因和 ATF4 的表达。PG3 处理通过激酶 HRI(血红素调节抑制剂)通过 ISR 激活 ATF4。ATF4 介导 PUMA、p21 和 NAG-1/GDF15(非甾体抗炎药激活基因 1)的上调。我们注意到,PUMA 在 HT29 细胞中通过激活 caspase-8 介导细胞凋亡,在 SW480 细胞中可能通过激活 caspase-10 介导细胞凋亡。我们提供了 PG3 通过 HRI/ATF4/PUMA 轴诱导细胞死亡的新机制。我们的研究结果为了解 PG3 的作用机制提供了独特的见解,PG3 是一种新型的癌症治疗药物,以 p53 通路类肿瘤抑制为靶点。
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引用次数: 0
Retraction: Myeloid ecotropic viral integration site 1 inhibits cell proliferation, invasion or migration in human gastric cancer. 撤回:髓样生态病毒整合位点 1 可抑制人胃癌的细胞增殖、侵袭或迁移
Q2 Medicine Pub Date : 2024-09-17 DOI: 10.18632/oncotarget.28649
Fei Song, Hong Wang, Yingying Wang
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引用次数: 0
The emerging role of AI in enhancing intratumoral immunotherapy care. 人工智能在加强肿瘤内免疫疗法护理方面的新兴作用。
Q2 Medicine Pub Date : 2024-09-17 DOI: 10.18632/oncotarget.28643
Abin Sajan, Abdallah Lamane, Asad Baig, Korentin Le Floch, Laurent Dercle

The emergence of immunotherapy (IO), and more recently intratumoral IO presents a novel approach to cancer treatment which can enhance immune responses while allowing combination therapy and reducing systemic adverse events. These techniques are intended to change the therapeutic paradigm of oncology care, and means that traditional assessment methods are inadequate, underlining the importance of adopting innovative approaches. Artificial intelligence (AI) with machine learning algorithms and radiomics are promising approaches, offering new insights into patient care by analyzing complex imaging data to identify biomarkers to refine diagnosis, guide interventions, predict treatment responses, and adapt therapeutic strategies. In this editorial, we explore how integrating these technologies could revolutionize personalized oncology. We discuss their potential to enhance the survival and quality of life of patients treated with intratumoral IO by improving treatment effectiveness and minimizing side effects, potentially reshaping practice guidelines. We also identify areas for future research and review clinical trials to confirm the efficacy of these promising approaches.

免疫疗法(IO)以及最近出现的肿瘤内免疫疗法为癌症治疗提供了一种新方法,它可以增强免疫反应,同时允许联合治疗并减少全身不良反应。这些技术旨在改变肿瘤护理的治疗模式,这意味着传统的评估方法是不够的,突出了采用创新方法的重要性。人工智能(AI)与机器学习算法和放射组学是前景广阔的方法,通过分析复杂的成像数据来确定生物标记物,从而完善诊断、指导干预、预测治疗反应并调整治疗策略,为患者护理提供新的见解。在这篇社论中,我们将探讨如何整合这些技术来彻底改变个性化肿瘤学。我们讨论了这些技术通过提高治疗效果和减少副作用来提高瘤内 IO 治疗患者的生存率和生活质量的潜力,从而有可能重塑实践指南。我们还确定了未来的研究领域,并回顾了临床试验,以确认这些前景广阔的方法的疗效。
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引用次数: 0
Trained and ready - the case for an inflammatory memory for hematopoietic stem and progenitor cells in the AML niche. 训练有素、蓄势待发--急性髓细胞性白血病龛位中造血干细胞和祖细胞的炎症记忆案例。
Q2 Medicine Pub Date : 2024-09-04 DOI: 10.18632/oncotarget.28642
Ding-Wen Chen, Eric K Wafula, Peter Kurre

Lifelong hematopoiesis is sustained by crosstalk between hematopoietic stem and progenitor cells (HSPCs) and specialized bone marrow niches. Acute myeloid leukemia (AML) upends that balance, as leukemic blasts secrete factors that remodel the bone marrow into a self-reinforcing leukemic niche. The inflammatory secretome behind this compartmental adaptation accounts for a progressive decline in hematopoietic function that leads to diagnosis and persists through early treatment. Not surprisingly, the mediators of an acute inflammatory injury and HSPC suppression have attracted much attention in an effort to alleviate morbidity and improve outcomes. HSPCs typically recover during disease remission and re-expand in the bone marrow (BM), but little is known about potentially lasting consequences for stem cells and progenitors. We recently showed that AML-experienced HSPCs actively participate in the inflammatory process during leukemic progression. HSPCs are constituent components of the innate immune system, and elegant studies of infection and experimental inflammation over the past decade have described the generation of an adoptively transferable, innate immune memory. Building on this paradigm, we discuss the potential translational relevance of a durable legacy in AML-experienced HSPC.

终生造血是通过造血干细胞和祖细胞(HSPCs)与专门的骨髓龛之间的相互作用来维持的。急性髓性白血病(AML)打破了这一平衡,因为白血病爆破细胞分泌的因子将骨髓重塑为一个自我强化的白血病龛位。这种分区适应背后的炎性分泌物导致造血功能逐渐下降,这种下降导致诊断,并持续到早期治疗。毫不奇怪,急性炎症损伤和 HSPC 抑制的介质引起了人们的广泛关注,以减轻发病率和改善预后。HSPC通常在疾病缓解期间恢复,并在骨髓(BM)中重新扩增,但对干细胞和祖细胞的潜在持久后果却知之甚少。我们最近发现,急性髓细胞白血病患者的HSPCs在白血病进展过程中积极参与炎症过程。HSPCs是先天性免疫系统的组成成分,在过去十年中,对感染和实验性炎症的深入研究描述了一种可被收养转移的先天性免疫记忆的产生。在这一范例的基础上,我们讨论了经历过急性髓细胞白血病的 HSPC 的持久遗产的潜在转化意义。
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引用次数: 0
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