Annual Review of Cancer Biology最新文献

英文中文

RAS and SHOC2 Roles in RAF Activation and Therapeutic Considerations RAS和SHOC2在RAF激活和治疗中的作用

Annual Review of Cancer Biology

Pub Date : 2023-12-06 DOI: 10.1146/annurev-cancerbio-062822-030450

Daniel A. Bonsor, Dhirendra K. Simanshu

Mutations in RAS proteins play a pivotal role in the development of human cancers, driving persistent RAF activation and deregulating the mitogen-activated protein kinase (MAPK) signaling pathway. While progress has been made in targeting specific oncogenic RAS proteins, effective drug-based therapies for most RAS mutations remain limited. Recent investigations into RAS–RAF complexes and the SHOC2–MRAS–PP1C holoenzyme complex have provided crucial insights into the structural and functional aspects of RAF activation within the MAPK signaling pathway. Moreover, these studies have also unveiled new blueprints for developing inhibitors, allowing us to think beyond the current RAS and MEK inhibitors. In this review, we explore the roles of RAS and SHOC2 in activating RAF and discuss potential therapeutic strategies to target these proteins. A comprehensive understanding of the molecular interactions involved in RAF activation and their therapeutic implications can potentially drive innovative approaches in combating RAS-/RAF-driven cancers.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

RAS蛋白的突变在人类癌症的发展中起着关键作用，驱动持续的RAF激活和解除对丝裂原活化蛋白激酶(MAPK)信号通路的调节。虽然在靶向特异性致癌RAS蛋白方面取得了进展，但针对大多数RAS突变的有效药物治疗仍然有限。最近对RAS-RAF复合物和SHOC2-MRAS-PP1C全酶复合物的研究为MAPK信号通路中RAF激活的结构和功能方面提供了重要的见解。此外，这些研究还揭示了开发抑制剂的新蓝图，使我们能够超越当前的RAS和MEK抑制剂。在这篇综述中，我们探讨了RAS和SHOC2在激活RAF中的作用，并讨论了针对这些蛋白的潜在治疗策略。全面了解RAF活化过程中涉及的分子相互作用及其治疗意义，可以潜在地推动对抗RAS-/RAF驱动的癌症的创新方法。预计《癌症生物学年度评论》第8卷的最终在线出版日期是2024年4月。修订后的估计数请参阅http://www.annualreviews.org/page/journal/pubdates。

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引用次数: 0

Deciphering the Warburg Effect: Metabolic Reprogramming, Epigenetic Remodeling, and Cell Dedifferentiation 解读Warburg效应:代谢重编程、表观遗传重塑和细胞去分化

Annual Review of Cancer Biology

Pub Date : 2023-12-06 DOI: 10.1146/annurev-cancerbio-062822-120857

Albert M. Li, Jiangbin Ye

A century ago, Otto Heinrich Warburg made a seminal discovery now known as the Warburg effect. This metabolic signature, prevalent across all cancer cells, is characterized by the prominent shift of glucose metabolism toward lactate production instead of oxidative respiration. Warburg's pioneering theory suggested that the induction of the Warburg effect instigates dedifferentiation and the process of tumorigenesis, illuminating a fundamental mechanism underlying cancer development. To celebrate the centennial anniversary of Warburg's monumental finding, it is an appropriate moment to reflect upon and commemorate his revolutionary contributions to the fields of metabolism and cancer research. In this review, we explore the role of mitochondria in epigenetic regulation and the decisions governing cell fate from an evolutionary standpoint. Moreover, we summarize metabolic and genetic factors that trigger the Warburg effect, underscoring the therapeutic potential of mitochondrial uncoupling as a strategy to counter this metabolic aberration. Our goal is to elucidate the means to induce tumor differentiation through metabolic therapy, thereby laying a foundation toward the cure for cancer.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

一个世纪前，奥托·海因里希·沃伯格做出了一个开创性的发现，现在被称为沃伯格效应。这种代谢特征普遍存在于所有癌细胞中，其特征是葡萄糖代谢向乳酸生成的显著转变，而不是氧化呼吸。Warburg的开创性理论表明，Warburg效应的诱导引发去分化和肿瘤发生过程，阐明了癌症发展的基本机制。为了庆祝华宝的重大发现一百周年，这是一个恰当的时刻来反思和纪念他在新陈代谢和癌症研究领域的革命性贡献。在这篇综述中，我们从进化的角度探讨线粒体在表观遗传调控中的作用和决定细胞命运的决定。此外，我们总结了触发Warburg效应的代谢和遗传因素，强调了线粒体解偶联作为对抗这种代谢畸变的策略的治疗潜力。我们的目标是阐明通过代谢治疗诱导肿瘤分化的手段，从而为癌症的治疗奠定基础。预计《癌症生物学年度评论》第8卷的最终在线出版日期是2024年4月。修订后的估计数请参阅http://www.annualreviews.org/page/journal/pubdates。

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引用次数: 0

Complex Roles of PTPN11/SHP2 in Carcinogenesis and Prospect of Targeting SHP2 in Cancer Therapy PTPN11/SHP2 在癌症发生过程中的复杂作用以及靶向 SHP2 治疗癌症的前景

Annual Review of Cancer Biology

Pub Date : 2023-12-06 DOI: 10.1146/annurev-cancerbio-062722-013740

Alexander Scheiter, Li-Chun Lu, Lilian H. Gao, Gen-Sheng Feng

The nonreceptor tyrosine phosphatase SHP2 has been at the center of cell signaling research for three decades. SHP2 is required to fully activate the RTK/RAS/ERK signaling cascade, although the underlying mechanisms are not completely understood. PTPN11 , which encodes SHP2, is the first identified proto-oncogene that encodes a tyrosine phosphatase, with dominantly activating mutations detected in leukemias and solid tumors. However, SHP2 has pro- and antioncogenic effects, and the most recent data reveal opposite activities of SHP2 in tumor cells and microenvironment cells. Allosteric SHP2 inhibitors show promising antitumor effects and overcome resistance to inhibitors of RAS/ERK signaling in animal models. Many clinical trials with orally bioactive SHP2 inhibitors, alone or combined with other regimens, are ongoing for a variety of cancers worldwide, with therapeutic outcomes yet unknown. This review discusses the multifaceted functions of SHP2 in oncogenesis, preclinical studies, and clinical trials with SHP2 inhibitors in oncological treatment.Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

三十年来，非受体酪氨酸磷酸酶 SHP2 一直是细胞信号传导研究的中心。SHP2是完全激活RTK/RAS/ERK信号级联的必要条件，但其潜在机制尚未完全明了。编码 SHP2 的 PTPN11 是第一个被发现的编码酪氨酸磷酸酶的原癌基因，在白血病和实体瘤中发现了显性激活突变。然而，SHP2 具有促癌和抗癌作用，最新数据显示，SHP2 在肿瘤细胞和微环境细胞中具有相反的活性。异位SHP2抑制剂显示出良好的抗肿瘤效果，并能克服动物模型对RAS/ERK信号抑制剂的耐药性。口服生物活性 SHP2 抑制剂（单独使用或与其他疗法联合使用）的许多临床试验正在全球范围内针对各种癌症进行，但治疗效果尚不清楚。这篇综述讨论了SHP2在肿瘤发生中的多方面功能、临床前研究以及SHP2抑制剂在肿瘤治疗中的临床试验。《癌症生物学年度综述》第8卷的最终在线出版日期预计为2024年4月。修订后的预计日期请参见 http://www.annualreviews.org/page/journal/pubdates。

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引用次数: 0

Central Role of the Antigen-Presentation and Interferon-γ Pathways in Resistance to Immune Checkpoint Blockade 抗原呈递和干扰素γ途径在免疫检查点阻断抵抗中的核心作用

Annual Review of Cancer Biology

Pub Date : 2022-04-11 DOI: 10.1146/annurev-cancerbio-070220-111016

Annette Paschen, Ignacio Melero, Antoni Ribas

Resistance to immunotherapy is due in some instances to the acquired stealth mechanisms of tumor cells that lose expression of MHC class I antigen–presenting molecules or downregulate their class I antigen–presentation pathways. Most dramatically, biallelic β2-microglobulin (B2M) loss leads to complete loss of MHC class I expression and to invisibility to CD8⁺ T cells. MHC class I expression and antigen presentation are potently upregulated by interferon-γ (IFNγ) in a manner that depends on IFNγ receptor (IFNGR) signaling via JAK1 and JAK2. Mutations in these molecules lead to IFNγ unresponsiveness and mediate loss of recognition and killing by cytotoxic T lymphocytes. Loss of MHC class I augments sensitivity of tumor cells to be killed by natural killer (NK) lymphocytes, and this mechanism could be exploited to revert resistance, for instance, with interleukin-2 (IL-2)-based agents. Moreover, in some experimental models,potent local type I interferon responses, such as those following intratumoral injection of Toll-like receptor 9 (TLR9) or TLR3 agonists, revert resistance due to mutations of JAKs.

在某些情况下，对免疫治疗的抵抗是由于肿瘤细胞失去MHC I类抗原呈递分子的表达或下调其I类抗原呈递途径的获得性隐身机制。最引人注目的是，双等位基因β2-微球蛋白(B2M)的丢失导致MHC I类表达的完全丧失，并且对CD8+ T细胞不可见。干扰素-γ (IFNγ)以依赖于通过JAK1和JAK2信号传导的IFNγ受体(IFNGR)的方式，有效地上调MHC I类表达和抗原呈递。这些分子的突变导致IFNγ无反应性，介导细胞毒性T淋巴细胞识别和杀伤的丧失。MHC I类的缺失增加了肿瘤细胞对自然杀伤(NK)淋巴细胞的敏感性，这种机制可以用来恢复耐药性，例如，使用基于白细胞介素-2 (IL-2)的药物。此外，在一些实验模型中，有效的局部I型干扰素应答，如肿瘤内注射toll样受体9 (TLR9)或TLR3激动剂后的应答，恢复了由于jak突变引起的耐药。

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引用次数: 0

Cancer Genomic Rearrangements and Copy Number Alterations from Errors in Cell Division 癌症基因组重排和细胞分裂错误引起的拷贝数改变

Annual Review of Cancer Biology

Pub Date : 2022-01-18 DOI: 10.1146/annurev-cancerbio-070620-094029

Cheng-Zhong Zhang, David Pellman

Analysis of cancer genomes has shown that a large fraction of chromosomal changes originate from catastrophic events including whole-genome duplication, chromothripsis, breakage-fusion-bridge cycles, and chromoplexy. Through sophisticated computational analysis of cancer genomes and experimental recapitulation of these catastrophic alterations, we have gained significant insights into the origin, mechanism, and evolutionary dynamics of cancer genome complexity. In this review, we summarize this progress and survey the major unresolved questions, with particular emphasis on the relative contributions of chromosome fragmentation and DNA replication errors to complex chromosomal alterations.

对癌症基因组的分析表明，很大一部分染色体变化源于灾难性事件，包括全基因组复制、染色体断裂、断裂-融合桥循环和染色体交错。通过对癌症基因组的复杂计算分析和对这些灾难性改变的实验再现，我们对癌症基因组复杂性的起源、机制和进化动力学有了重要的认识。在这篇综述中，我们总结了这方面的进展，并调查了主要的未解决的问题，特别强调了染色体断裂和DNA复制错误对复杂染色体改变的相对贡献。

引用次数: 0

Caught in a Web: Emerging Roles of Neutrophil Extracellular Traps in Cancer 陷入网络:中性粒细胞细胞外陷阱在癌症中的新角色

Annual Review of Cancer Biology

Pub Date : 2022-01-18 DOI: 10.1146/annurev-cancerbio-080421-015537

Xue-Yan He, David Ng, Mikala Egeblad

Neutrophil extracellular traps (NETs) are meshes of DNA decorated with granular proteins that are extruded from neutrophils during immune responses to pathogens. However, excessive NET formation is negatively associated with many diseases, including cancer. NETs contain, for example, proteases, danger-associated molecular patterns (DAMPs), and DNA. These components can act directly on the cancer cells but also affect the surrounding microenvironment, including altering the extracellular matrix and the immune response to tumors. Here, we discuss the emerging roles of NETs in cancer progression, from their ability to promote primary tumor growth and immune escape to their prometastatic effects. The potential clinical implication of targeting NETs as novel therapeutic strategies in cancer is also discussed.

中性粒细胞胞外陷阱(NETs)是在对病原体的免疫反应中从中性粒细胞中挤出的带有颗粒蛋白装饰的DNA网。然而，过度的NET形成与包括癌症在内的许多疾病呈负相关。例如，net包含蛋白酶、危险相关分子模式(DAMPs)和DNA。这些成分可以直接作用于癌细胞，但也会影响周围的微环境，包括改变细胞外基质和对肿瘤的免疫反应。在这里，我们讨论了NETs在癌症进展中的新作用，从它们促进原发肿瘤生长和免疫逃逸的能力到它们的前转移作用。本文还讨论了靶向NETs作为癌症治疗新策略的潜在临床意义。

引用次数: 0

RB1, Cancer Lineage Plasticity, and Therapeutic Resistance RB1，肿瘤谱系可塑性和治疗耐药性

Annual Review of Cancer Biology

Pub Date : 2022-01-18 DOI: 10.1146/annurev-cancerbio-070120-092840

Letian Zhang, David W. Goodrich

Lineage plasticity, a cell's capacity to switch lineage-restricted gene expression states, is required for normal tissue homeostasis. Cancer lineage plasticity is increasingly observed as a mechanism of resistance to therapy, particularly molecularly targeted therapies. These therapies often owe their superior efficacy to the lineage-restricted nature of their therapeutic target, so cancers can evade such therapies by changing lineage states. As increasingly effective molecularly targeted therapies are deployed, cancer lineage plasticity is likely to be a growing clinical problem. Lineage plasticity reflects a nongenetic, potentially reversible transcriptional adaptation, but oncogenic genetic mutations likely drive elevated lineage plasticity that is typical of cancer cells. Here key concepts relevant to cancer lineage plasticity are presented, evidence implicating loss of the RB1 tumor-suppressor gene in driving cancer lineage plasticity is reviewed, and possible therapeutic approaches to counter cancer lineage plasticity are discussed.

谱系可塑性是细胞转换谱系限制基因表达状态的能力，是正常组织稳态所必需的。癌症谱系可塑性越来越多地被认为是一种抵抗治疗的机制，特别是分子靶向治疗。这些疗法通常将其优越的疗效归功于其治疗靶点的谱系限制性质，因此癌症可以通过改变谱系状态来逃避这些疗法。随着越来越有效的分子靶向治疗的部署，癌症谱系可塑性可能是一个日益严重的临床问题。谱系可塑性反映了一种非遗传的、潜在可逆的转录适应，但致癌基因突变可能会提高谱系可塑性，这是癌细胞的典型特征。本文介绍了与癌症谱系可塑性相关的关键概念，综述了RB1肿瘤抑制基因缺失在驱动癌症谱系可塑性中的证据，并讨论了对抗癌症谱系可塑性的可能治疗方法。

引用次数: 0

TGFβ: Signaling Blockade for Cancer Immunotherapy. TGFβ:肿瘤免疫治疗的信号阻断剂。

IF 7.7

Annual Review of Cancer Biology

Pub Date : 2022-01-01 Epub Date: 2021-12-22 DOI: 10.1146/annurev-cancerbio-070620-103554

Szu-Ying Chen, Ons Mamai, Rosemary J Akhurst

Discovered over four decades ago, transforming growth factor β (TGFβ) is a potent pleiotropic cytokine that has context-dependent effects on most cell types. It acts as a tumor suppressor in some cancers and/or supports tumor progression and metastasis through its effects on the tumor stroma and immune microenvironment. In TGFβ-responsive tumors it can promote invasion and metastasis through epithelial-mesenchymal transformation, the appearance of cancer stem cell features, and resistance to many drug classes, including checkpoint blockade immunotherapies. Here we consider the biological activities of TGFβ action on different cells of relevance toward improving immunotherapy outcomes for patients, with a focus on the adaptive immune system. We discuss recent advances in the development of drugs that target the TGFβ signaling pathway in a tumor-specific or cell type-specific manner to improve the therapeutic window between response rates and adverse effects.

转化生长因子β (TGFβ)是一种有效的多效性细胞因子，对大多数细胞类型具有环境依赖性作用。它在某些癌症中作为肿瘤抑制因子和/或通过其对肿瘤基质和免疫微环境的影响支持肿瘤的进展和转移。在tgf β应答性肿瘤中，它可以通过上皮-间质转化、癌症干细胞特征的出现以及对许多药物类别(包括检查点阻断免疫疗法)的耐药性来促进侵袭和转移。在这里，我们考虑TGFβ作用于不同细胞的生物活性，与改善患者的免疫治疗结果相关，重点是适应性免疫系统。我们讨论了以肿瘤特异性或细胞类型特异性方式靶向TGFβ信号通路的药物开发的最新进展，以改善反应率和不良反应之间的治疗窗口。

引用次数: 7

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Annual Review of Cancer Biology

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