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Transcriptional regulation of hypoxic cancer cell metabolism and artificial intelligence. 缺氧癌细胞新陈代谢的转录调控与人工智能。
IF 14.3 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-30 DOI: 10.1016/j.trecan.2024.10.003
Luana Schito, Sergio Rey-Keim

Gene expression regulation in hypoxic tumor microenvironments is mediated by O2 responsive transcription factors (O2R-TFs), fine-tuning cancer cell metabolic demand for O2 according to its availability. Here, we discuss key O2R-TFs and emerging artificial intelligence (AI)-based applications suitable for the interrogation of O2R-TF relationships specifying cancer cell metabolic adaptations to hypoxia.

缺氧肿瘤微环境中的基因表达调控是由氧气反应性转录因子(O2R-TFs)介导的,根据氧气的可用性微调癌细胞对氧气的代谢需求。在此,我们将讨论关键的 O2R-TFs 和基于人工智能 (AI) 的新兴应用,这些应用适用于研究 O2R-TF 关系,从而确定癌细胞对缺氧的代谢适应性。
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引用次数: 0
The UPRising connection between endoplasmic reticulum stress and the tumor microenvironment. 内质网应激与肿瘤微环境之间的联系日益突出。
IF 14.3 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-29 DOI: 10.1016/j.trecan.2024.09.011
Hery Urra, Raúl Aravena, Lucas González-Johnson, Claudio Hetz

The tumor microenvironment (TME) represents a dynamic network of cancer cells, stromal cells, immune mediators, and extracellular matrix components, crucial for cancer progression. Stress conditions such as oncogene activation, nutrient deprivation, and hypoxia disrupt the endoplasmic reticulum (ER), activating the unfolded protein response (UPR), the main adaptive mechanism to restore ER function. The UPR regulates cancer progression by engaging cell-autonomous and cell-non-autonomous mechanisms, reprogramming the stroma and promoting immune evasion, angiogenesis, and invasion. This review explores the role of UPR beyond cancer cells, focusing on how ER stress signaling reshapes the TME, supporting tumor growth. The therapeutic potential of targeting the UPR is also discussed.

肿瘤微环境(TME)是由癌细胞、基质细胞、免疫介质和细胞外基质成分组成的动态网络,对癌症的进展至关重要。癌基因激活、营养匮乏和缺氧等应激条件会破坏内质网(ER),激活未折叠蛋白反应(UPR),这是恢复ER功能的主要适应机制。UPR 通过调动细胞自主和细胞非自主机制、重塑基质以及促进免疫逃避、血管生成和侵袭来调控癌症进展。本综述探讨了 UPR 在癌细胞之外的作用,重点关注 ER 应激信号如何重塑 TME,从而支持肿瘤生长。此外,还讨论了针对 UPR 的治疗潜力。
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引用次数: 0
Nonrepair functions of DNA mismatch repair proteins: new avenues for precision oncology. DNA 错配修复蛋白的非修复功能:精准肿瘤学的新途径。
IF 14.3 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-25 DOI: 10.1016/j.trecan.2024.10.001
Jerry Tyler DeWitt, Megha Raghunathan, Svasti Haricharan

DNA damage repair (DDR) proteins are well recognized as guardians of the genome that are frequently lost during malignant transformation of normal cells across cancer types. To date, their tumor suppressor functions have been generally regarded as a consequence of their roles in maintaining genomic stability: more genomic instability increases the risk of oncogenic transformation events. However, recent discoveries centering around DNA mismatch repair (MMR) proteins suggest a broader impact of the loss of DDR proteins on cellular processes beyond genomic instability. Here, we explore the clinical implications of nonrepair roles for DDR proteins, using the growing evidence supporting roles for DNA MMR proteins in cell cycle and apoptosis regulation, metabolic function, the cellular secretome, and immunomodulation.

DNA 损伤修复(DDR)蛋白被公认为基因组的守护者,在正常细胞向各种癌症类型恶性转化的过程中,它们经常丢失。迄今为止,人们普遍认为它们的抑瘤功能是维持基因组稳定性的结果:基因组越不稳定,致癌转化的风险就越大。然而,最近围绕 DNA 错配修复(MMR)蛋白的发现表明,除基因组不稳定性外,DDR 蛋白的缺失还会对细胞过程产生更广泛的影响。在这里,我们利用越来越多的证据支持 DNA MMR 蛋白在细胞周期和凋亡调节、代谢功能、细胞分泌组和免疫调节中的作用,探讨 DDR 蛋白的非修复作用对临床的影响。
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引用次数: 0
Neoadjuvant combination immunotherapy in MSI/dMMR colorectal cancer. MSI/dMMR 大肠癌的新辅助联合免疫疗法。
IF 14.3 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-24 DOI: 10.1016/j.trecan.2024.10.006
Meggy Suarez-Carmona, Niels Halama

Neoadjuvant immune checkpoint inhibition (ICI) is a new approach to treat patients with colorectal cancer (CRC). The effects of combined neoadjuvant ICI in locally advanced, DNA mismatch repair (dMMR)-deficient/microsatellite instable (MSI) CRC were recently reported by de Gooyer et al. from the NICHE-3 trial. Further studies will determine whether these impressive pathological responses lead to long-term clinical benefit.

新辅助免疫检查点抑制(ICI)是治疗结直肠癌(CRC)患者的一种新方法。de Gooyer 等人最近在 NICHE-3 试验中报告了联合新辅助 ICI 对局部晚期、DNA 错配修复(dMMR)缺陷/微卫星不稳定(MSI)型 CRC 的治疗效果。进一步的研究将确定这些令人印象深刻的病理反应是否会带来长期的临床获益。
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引用次数: 0
A new enhancer for anti-PD-1/PD-L1 immunotherapy: PCSK9 inhibition. 抗 PD-1/PD-L1 免疫疗法的新增强剂:PCSK9 抑制剂
IF 14.3 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-24 DOI: 10.1016/j.trecan.2024.10.002
Shengbo Sun, Zhengyang Yang, Hongwei Yao, Zhongtao Zhang

Anti-programmed cell death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1) immunotherapy has shown promising results in cancer treatment, improving clinical outcomes and prolonging patient survival. However, most patients exhibit low response rates to PD-1/PD-L1 blockade, highlighting the urgent need for new enhancers. Increasing data now demonstrate that inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9), a serine proteinase, can enhance the antitumor efficacy of anti-PD-1/PD-L1 immunotherapy.

抗程序性细胞死亡蛋白1(PD-1)/PD-1配体1(PD-L1)免疫疗法在癌症治疗中取得了可喜的成果,改善了临床疗效,延长了患者生存期。然而,大多数患者对 PD-1/PD-L1 阻断剂的反应率较低,这凸显了对新增强剂的迫切需求。目前,越来越多的数据表明,抑制丝氨酸蛋白酶--9 型枯草蛋白酶(PCSK9)可以增强抗 PD-1/PD-L1 免疫疗法的抗肿瘤疗效。
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引用次数: 0
Mitochondrial DNA damage, repair, and replacement in cancer. 癌症中的线粒体 DNA 损伤、修复和替代。
IF 14.3 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-21 DOI: 10.1016/j.trecan.2024.09.010
Pavel Vodicka, Sona Vodenkova, Natalie Danesova, Ludmila Vodickova, Renata Zobalova, Kristyna Tomasova, Stepana Boukalova, Michael V Berridge, Jiri Neuzil

Mitochondria are vital organelles with their own DNA (mtDNA). mtDNA is circular and composed of heavy and light chains that are structurally more accessible than nuclear DNA (nDNA). While nDNA is typically diploid, the number of mtDNA copies per cell is higher and varies considerably during development and between tissues. Compared with nDNA, mtDNA is more prone to damage that is positively linked to many diseases, including cancer. Similar to nDNA, mtDNA undergoes repair processes, although these mechanisms are less well understood. In this review, we discuss the various forms of mtDNA damage and repair and their association with cancer initiation and progression. We also propose horizontal mitochondrial transfer as a novel mechanism for replacing damaged mtDNA.

线粒体是重要的细胞器,有自己的 DNA(mtDNA)。mtDNA 是环状的,由重链和轻链组成,在结构上比核 DNA(nDNA)更易接近。nDNA 通常是二倍体,而每个细胞的 mtDNA 拷贝数更高,而且在发育过程中和不同组织之间有很大差异。与 nDNA 相比,mtDNA 更容易受损,这与包括癌症在内的许多疾病都有正相关。与 nDNA 相似,mtDNA 也会经历修复过程,但对这些机制的了解还不够深入。在这篇综述中,我们将讨论 mtDNA 损伤和修复的各种形式及其与癌症发生和发展的关系。我们还提出线粒体水平转移是一种替代受损 mtDNA 的新机制。
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引用次数: 0
Epigenetic reprogramming in pediatric gliomas: from molecular mechanisms to therapeutic implications. 小儿胶质瘤的表观遗传学重编程:从分子机制到治疗意义。
IF 14.3 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-10 DOI: 10.1016/j.trecan.2024.09.007
Santiago Haase, Stephen Carney, Maria Luisa Varela, Devarshi Mukherji, Ziwen Zhu, Yingxiang Li, Felipe J Nuñez, Pedro R Lowenstein, Maria G Castro

Brain tumors in children and adults differ greatly in patient outcomes and responses to radiotherapy and chemotherapy. Moreover, the prevalence of recurrent mutations in histones and chromatin regulatory proteins in pediatric and young adult gliomas suggests that the chromatin landscape is rewired to support oncogenic programs. These early somatic mutations dysregulate widespread genomic loci by altering the distribution of histone post-translational modifications (PTMs) and, in consequence, causing changes in chromatin accessibility and in the histone code, leading to gene transcriptional changes. We review how distinct chromatin imbalances in glioma subtypes impact on oncogenic features such as cellular fate, proliferation, immune landscape, and radio resistance. Understanding these mechanisms of epigenetic dysregulation carries substantial implications for advancing targeted epigenetic therapies.

儿童和成人脑肿瘤在患者预后以及对放疗和化疗的反应方面存在很大差异。此外,儿童和年轻成人胶质瘤中组蛋白和染色质调控蛋白反复突变的普遍性表明,染色质景观已被重新配线,以支持致癌程序。这些早期体细胞突变通过改变组蛋白翻译后修饰(PTMs)的分布,使广泛的基因组位点失调,进而引起染色质可及性和组蛋白密码的改变,导致基因转录变化。我们回顾了胶质瘤亚型中不同的染色质失衡如何影响致癌特征,如细胞命运、增殖、免疫景观和放射抗性。了解这些表观遗传失调的机制对推进表观遗传靶向治疗具有重要意义。
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引用次数: 0
Engineering growth factor ligands and receptors for therapeutic innovation. 对生长因子配体和受体进行工程设计,以实现治疗创新。
IF 14.3 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-09 DOI: 10.1016/j.trecan.2024.09.006
Xinran An, Justin Paoloni, Yuseong Oh, Jamie B Spangler

Growth factors signal through engagement and activation of their respective cell surface receptors to choreograph an array of cellular functions, including proliferation, growth, repair, migration, differentiation, and survival. Because of their vital role in determining cell fate and maintaining homeostasis, dysregulation of growth factor pathways leads to the development and/or progression of disease, particularly in the context of cancer. Exciting advances in protein engineering technologies have enabled innovative strategies to redesign naturally occurring growth factor ligands and receptors as targeted therapeutics. We review growth factor protein engineering efforts, including affinity modulation, molecular fusion, the design of decoy receptors, dual specificity constructs, and vaccines. Collectively, these approaches are catapulting next-generation drugs to treat cancer and a host of other conditions.

生长因子通过接合和激活各自的细胞表面受体发出信号,从而编排一系列细胞功能,包括增殖、生长、修复、迁移、分化和存活。由于生长因子在决定细胞命运和维持体内平衡方面起着至关重要的作用,因此生长因子通路的失调会导致疾病的发生和/或发展,尤其是癌症。蛋白质工程技术取得了令人振奋的进展,从而能够采用创新策略重新设计天然存在的生长因子配体和受体,将其作为靶向治疗药物。我们回顾了生长因子蛋白质工程方面的工作,包括亲和力调节、分子融合、诱饵受体设计、双重特异性构建物和疫苗。总之,这些方法正在催生治疗癌症和一系列其他疾病的下一代药物。
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引用次数: 0
Aberrant nuclei with amplified DNA in cancer. 癌症中DNA扩增的异常细胞核。
IF 14.3 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-05 DOI: 10.1016/j.trecan.2024.09.005
Venkata Narasimha Kadali, Ofer Shoshani

Gene amplification in the form of extrachromosomal DNA (ecDNA) or intrachromosomal homogenous staining regions (HSRs) is an emerging hallmark in cancer. Recent studies implicate abnormal nuclear structures in the biogenesis and evolution of amplified DNA. Here, we discuss how the interplay between aberrant nuclei and gene amplification drives cancer therapy resistance and metastasis.

染色体外 DNA(ecDNA)或染色体内同源染色区(HSR)形式的基因扩增是癌症的一个新特征。最近的研究表明,核结构异常与扩增 DNA 的生物发生和进化有关。在此,我们将讨论异常细胞核与基因扩增之间的相互作用是如何驱动癌症耐药性和转移的。
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引用次数: 0
Small cell lung cancer profiling: an updated synthesis of subtypes, vulnerabilities, and plasticity. 小细胞肺癌特征分析:亚型、脆弱性和可塑性的最新综述。
IF 14.3 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-19 DOI: 10.1016/j.trecan.2024.07.008
Esther Redin, Álvaro Quintanal-Villalonga, Charles M Rudin

Small cell lung cancer (SCLC) is a devastating disease with high proliferative and metastatic capacity. SCLC has been classified into molecular subtypes based on differential expression of lineage-defining transcription factors. Recent studies have proposed new subtypes that are based on both tumor-intrinsic and -extrinsic factors. SCLC demonstrates substantial intratumoral subtype heterogeneity characterized by highly plastic transcriptional states, indicating that the initially dominant subtype can shift during disease progression and in association with resistance to therapy. Strategies to promote or constrain plasticity and cell fate transitions have nominated novel targets that could prompt the development of more durably effective therapies for patients with SCLC. In this review, we describe the latest advances in SCLC subtype classification and their biological and clinical implications.

小细胞肺癌(SCLC)是一种具有高度增殖和转移能力的毁灭性疾病。小细胞肺癌已被划分为分子亚型,这些亚型基于不同的细胞系界定转录因子的表达。最近的研究提出了基于肿瘤内在和外在因素的新亚型。SCLC表现出大量的瘤内亚型异质性,其特点是转录状态具有高度可塑性,这表明最初占主导地位的亚型会在疾病进展过程中发生转变,并与治疗耐药性有关。促进或限制可塑性和细胞命运转换的策略提出了新的靶点,这些靶点可促使开发出对SCLC患者更持久有效的疗法。在这篇综述中,我们将介绍SCLC亚型分类的最新进展及其生物学和临床意义。
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引用次数: 0
期刊
Trends in cancer
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