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N-acetylglucosaminyltransferase V drives colorectal cancer metastasis by facilitating ZO-1 ubiquitination and degradation. N-乙酰葡糖胺基转移酶V通过促进ZO-1的泛素化和降解来推动结直肠癌转移。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-11-07 DOI: 10.1186/s12935-024-03551-7
Yueping Zhan, Chenjun Huang, Rong Wang, Xiao Xiao, Xuewen Xu, Chunfang Gao

Increasing evidence supports the crucial role of Epithelial-Mesenchymal Transition (EMT) in cancer invasion and metastasis. N-acetylglucosaminyltransferase V (MGAT5), which is associated with multiantenna glycosylation, can contribute to tumorigenesis, yet its specific role in promoting colorectal cancer (CRC) metastasis remains unclear. Bioinformatics analysis of CRC datasets revealed that elevated MGAT5 expression was associated with EMT and a poor prognosis. In vitro experiments confirmed the pivotal role of MGAT5 as an EMT regulator in CRC cells. MGAT5 overexpression stimulated cell proliferation and migration, while MGAT5 knockdown had the opposite effect. Mechanistically, MGAT5 promoted EMT through multiantenna glycosylation of ZO-1, promoting its ubiquitination and reducing its expression. Clinically, MGAT5 upregulation in the CRC TMA correlated negatively with ZO-1 expression, which is indicative of malignancy and a poor prognosis. This study revealed that MGAT5 promotes EMT in CRC via interactions between multiple antenna glycosylation products and ZO-1 ubiquitination/degradation, indicating that MGAT5 could serve as a promising therapeutic target for CRC.

越来越多的证据支持上皮-间质转化(EMT)在癌症侵袭和转移中的关键作用。与多天线糖基化相关的N-乙酰葡糖胺基转移酶V(MGAT5)可促进肿瘤发生,但它在促进结直肠癌(CRC)转移中的具体作用仍不清楚。对 CRC 数据集进行的生物信息学分析表明,MGAT5 表达的升高与 EMT 和不良预后有关。体外实验证实了 MGAT5 在 CRC 细胞中作为 EMT 调节因子的关键作用。MGAT5过表达刺激细胞增殖和迁移,而MGAT5敲除则产生相反的效果。从机制上讲,MGAT5 通过对 ZO-1 进行多天线糖基化,促进其泛素化并降低其表达,从而促进 EMT。临床上,MGAT5在CRC TMA中的上调与ZO-1的表达呈负相关,而ZO-1的表达预示着恶性程度和不良预后。这项研究揭示了MGAT5通过多种天线糖基化产物与ZO-1泛素化/降解之间的相互作用促进了CRC的EMT,表明MGAT5可作为CRC的一个有前景的治疗靶点。
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引用次数: 0
Life history dynamics of evolving tumors: insights into task specialization, trade-offs, and tumor heterogeneity. 不断演变的肿瘤的生命史动态:对任务专业化、权衡和肿瘤异质性的见解。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-11-06 DOI: 10.1186/s12935-024-03538-4
Mahmoud Ahmed, Deok Ryong Kim

The evolution of cancer cells parallels species evolution in numerous ways. Variations arise and spread under the pressure of competition between cancer cells. Current investigations of tumor evolution echo earlier debates between biologists. These include the role of non-Darwinian mechanisms, the contribution of neutral evolution, and life history dynamics. The trade-off between proliferation and metastasis is the most well-studied application of life history theory to cancer evolution. This article briefly introduces some parallels between cancer and species evolution, focusing on the life history of evolving tumors. Next, we review evidence from simulation and experimental studies supporting task specialization and trade-offs in cancer. We also cover recent work on inferring tumor tasks from data. We then turn to the implications of multi-tasking and the utility of the theory in explaining critical aspects of tumor heterogeneity. Finally, we discuss some of the criticism and future directions of this research topic.

癌细胞的进化在许多方面与物种进化相似。变异是在癌细胞之间竞争的压力下产生和扩散的。目前对肿瘤进化的研究与生物学家之间早先的争论不谋而合。这些争论包括非达尔文机制的作用、中性进化的贡献以及生命史动态。增殖与转移之间的权衡是生命史理论在癌症进化中最深入的应用。本文简要介绍了癌症与物种进化之间的一些相似之处,重点关注不断进化的肿瘤的生命史。接下来,我们回顾了模拟和实验研究中支持癌症中任务专业化和权衡的证据。我们还介绍了从数据中推断肿瘤任务的最新研究成果。然后,我们将讨论多任务的意义以及该理论在解释肿瘤异质性关键方面的实用性。最后,我们将讨论这一研究课题的一些批评意见和未来发展方向。
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引用次数: 0
Exploiting acquired vulnerability to develop novel treatments for cholangiocarcinoma. 利用后天脆弱性开发治疗胆管癌的新疗法。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-11-05 DOI: 10.1186/s12935-024-03548-2
Sirayot Areewong, Orawan Suppramote, Sunisa Prasopporn, Siwanon Jirawatnotai

Cholangiocarcinoma (CCA) presents a formidable therapeutic challenge due to its extensive heterogeneity and plasticity, which inevitably lead to acquired resistance to current treatments. However, recent evidence suggests that acquired drug resistance is associated with a fitness cost resulting from the myriad of acquired alterations under the selective pressure of the primary treatment. Consequently, CCA patients with acquired resistance are more susceptible to alternative therapies that are ineffective as monotherapies. This phenomenon, termed "acquired vulnerability," has garnered significant interest in drug development, as the acquired alterations could potentially be exploited therapeutically. This review elucidates the modes of acquired vulnerability, methods for identifying and exploiting acquired vulnerabilities in cancer (particularly in CCA), and strategies to enhance the clinical efficacy of drug combinations by leveraging the principle of acquired vulnerability. Identifying acquired vulnerabilities may pave the way for novel drug combinations to effectively treat highly heterogeneous and adaptable malignancies such as CCA.

胆管癌(CCA)具有广泛的异质性和可塑性,不可避免地会对目前的治疗方法产生获得性耐药性,这给治疗带来了巨大挑战。然而,最近的证据表明,获得性耐药性与在主要治疗方法的选择性压力下发生的无数获得性改变所导致的健康成本有关。因此,具有获得性耐药性的 CCA 患者更容易接受作为单一疗法无效的替代疗法。这种现象被称为 "获得性易感性",引起了药物开发的极大兴趣,因为获得性改变有可能被用于治疗。本综述阐明了获得性易损性的模式、识别和利用癌症(尤其是 CCA)中获得性易损性的方法,以及利用获得性易损性原理提高联合用药临床疗效的策略。识别获得性易损性可为新型药物组合铺平道路,从而有效治疗高度异质性和适应性恶性肿瘤(如 CCA)。
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引用次数: 0
Systematic multiomics analysis and in vitro experiments suggest that ITGA5 could serve as a promising therapeutic target for ccRCC. 系统的多组学分析和体外实验表明,ITGA5 可作为治疗 ccRCC 的一个有前途的靶点。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-11-05 DOI: 10.1186/s12935-024-03546-4
Xiangxian Che, Xi Tian, Zhenda Wang, Shuxuan Zhu, Shiqi Ye, Yue Wang, Yihan Chen, Yiyun Huang, Aihetaimujiang Anwaier, Peifeng Yao, Yijia Chen, Keting Wu, Yifei Liu, Wenhao Xu, Hailiang Zhang, Dingwei Ye

Background: Integrin alpha 5 (ITGA5) was previously confirmed to be related to prognosis in several cancer types; however, its function in clear cell renal cell carcinoma (ccRCC) and how this molecule regulates tumor progression and the tumor microenvironment (TME) remain to be elucidated.

Methods: We investigated the prognostic implications of ITGA5 with a machine learning model and evaluated biological behaviors of different levels of ITGA5 expression in vitro. Bioinformatic analysis was performed to explain the comprehensive effect of ITGA5 on the TME and drug sensitivity.

Results: We constructed a machine learning model to elaborate the prognostic implication of ITGA5. As tumorigenesis of ccRCC was tightly relevant with several mutant genes, we investigated the correlation between ITGA5 expression and frequent mutations and found ITGA5 upregulation in VHL mutant ccRCC (P = 0.016). Through overexpressing, silencing, and blocking ITGA5, we verified the role of ITGA5 in promoting ccRCC adverse biological activities; and the potential functions of ITGA5 in ccRCC were bioinformatically demonstrated, summarizing as cell proliferation, migration, and angiogenesis. The localization of ITGA5 primarily in endothelia and macrophages further verified its magnitude in angiogenesis and aroused our excavation in ITGA5 regulation of immune infiltration landscape. Generally, ITGA5-high ccRCC presented an immunosuppressive TME by inducing a lower level of CD8 + T cell infiltration. For the last part we predicted drug sensitivity relevant to ITGA5 and concluded that a joint medication of ITGA5 inhibitors and VEGFR-target drugs (including sunitinib, axitinib, pazopanib, and motesanib) might be a promising therapeutic strategy.

Conclusion: Our findings clarified the adverse outcome induced by high expression of ITGA5 in ccRCC patients. In vitro experiments and bioinformatical analysis identified ITGA5 function as predominantly cell proliferation, migration, angiogenesis, and macrophage recruitment. Further, we predicted immune infiltration and medication sensitivity regulation by ITGA5 and proposed a joint use of ITGA5 inhibitors and anti-angiogenetic drugs as a potential potent therapeutic strategy.

背景:然而,它在透明细胞肾细胞癌(ccRCC)中的功能以及该分子如何调控肿瘤进展和肿瘤微环境(TME)仍有待阐明:我们利用机器学习模型研究了ITGA5对预后的影响,并在体外评估了ITGA5不同表达水平的生物学行为。我们进行了生物信息学分析,以解释ITGA5对TME和药物敏感性的综合影响:我们构建了一个机器学习模型来阐述 ITGA5 的预后意义。由于ccRCC的肿瘤发生与多个突变基因密切相关,我们研究了ITGA5表达与频繁突变之间的相关性,发现ITGA5在VHL突变的ccRCC中上调(P = 0.016)。通过过表达、沉默和阻断ITGA5,我们验证了ITGA5在促进ccRCC不良生物学活性中的作用,并通过生物信息学方法证明了ITGA5在ccRCC中的潜在功能,概括为细胞增殖、迁移和血管生成。ITGA5 主要定位于内皮细胞和巨噬细胞,这进一步证实了其在血管生成中的重要作用,同时也引起了我们对 ITGA5 调控免疫浸润景观的探索。一般来说,ITGA5高的ccRCC通过诱导较低水平的CD8 + T细胞浸润而呈现出免疫抑制的TME。最后,我们预测了与ITGA5相关的药物敏感性,并得出结论:ITGA5抑制剂和VEGFR靶向药物(包括舒尼替尼、阿西替尼、帕唑帕尼和莫替沙尼)联合用药可能是一种很有前景的治疗策略:我们的研究结果阐明了ITGA5在ccRCC患者中的高表达所诱发的不良后果。体外实验和生物信息学分析确定 ITGA5 的功能主要是细胞增殖、迁移、血管生成和巨噬细胞招募。此外,我们还预测了 ITGA5 对免疫浸润和药物敏感性的调节作用,并建议联合使用 ITGA5 抑制剂和抗血管生成药物作为一种潜在的有效治疗策略。
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引用次数: 0
The efficacy of immunotherapy in non-small cell lung cancer with KRAS mutation: a systematic review and meta-analysis. 免疫疗法对 KRAS 突变非小细胞肺癌的疗效:系统综述与荟萃分析。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-11-01 DOI: 10.1186/s12935-024-03498-9
Rui Zhao, Yang Shu, Wei Xu, Fengxian Jiang, Pancen Ran, Liying Pan, Jingliang Wang, Weihao Wang, Jing Zhao, Yahui Wang, Guobin Fu

Purpose: The KRAS mutation is highly prevalent in NSCLC and is associated with poor efficacy of immunotherapy. Nevertheless, the impact of KRAS mutation, mutation subtypes, and co-mutations on the effectiveness of immunotherapy remains uncertain. This study aimed to assess the influence of the KRAS mutation on the effectiveness of immunotherapy in NSCLC, specifically examining different subtypes of KRAS mutations and co-mutations.

Methods: We performed an extensive search of multiple databases, covering the period from January 1, 2000, to December 5, 2023. A total of 24 articles met our inclusion criteria and were included in this study. A comparative analysis assessed the influence of different subgroups, including KRAS mutation, KRAS wild-type, KRAS G12C mutation, KRAS G12D mutation, and KRAS with co-mutations in NSCLC with immunotherapy. The study outcomes include HR, with corresponding 95% CI and P-values for OS and PFS using Review Manager 5.4 software for the meta-analysis.

Result: The KRAS mutation appears to have a more beneficial impact on OS (HR 0.54 [95% CI: 0.41-0.71]; P < 0.00001) and PFS (HR 0.63 [95% CI: 0.53-0.76]; P < 0.00001) in NSCLC patients receiving immunotherapy compared to those without immunotherapy. The presence of KRASG12C mutation has been found to have a positive impact on PFS (HR 0.39 [95% CI: 0.25-0.62]; P < 0.0001) in NSCLC patients who undergo immunotherapy, compared to those who did not receive immunotherapy. KRAS non-G12D mutation is considerably associated with longer OS (HR 1.52 [95% CI: 1.10-2.10]; P = 0.01). The clinical benefit in OS between patients without STK11 co-mutation and those who have KRAS mutation with STK11 is significant (HR 1.46 [95% CI: 1.10-1.93]; P = 0.008). Comparing the impact of OS patients without KEAP1/NFE2L2 mutation to those with KRAS and KEAP1/NFE2L2 co-mutations showed a significant impact (HR 1.89 [95% CI: 1.33-2.68]; P = 0.0004).

Conclusion: The KRAS mutation and KRAS G12C mutation confer benefits that impact OS and PFS in NSCLC patients treated with immunotherapy. However, the KRAS G12D mutation negatively impacts OS compared to the KRAS non-G12D mutation. Furthermore, KRAS co-mutations involving STK11 and KEAP1/NFE2L2 are associated with a negative impact on the efficacy of immunotherapy in NSCLC patients.

目的:KRAS突变在NSCLC中非常普遍,与免疫疗法疗效不佳有关。然而,KRAS突变、突变亚型和共突变对免疫疗法疗效的影响仍不确定。本研究旨在评估KRAS突变对NSCLC免疫治疗效果的影响,特别是研究KRAS突变的不同亚型和共突变:我们对 2000 年 1 月 1 日至 2023 年 12 月 5 日期间的多个数据库进行了广泛检索。共有 24 篇文章符合我们的纳入标准并被纳入本研究。比较分析评估了不同亚组(包括KRAS突变、KRAS野生型、KRAS G12C突变、KRAS G12D突变和KRAS共突变)对接受免疫疗法的NSCLC的影响。研究结果包括HR,以及OS和PFS的相应95% CI和P值,使用Review Manager 5.4软件进行荟萃分析:结果:KRAS突变似乎对OS有更有利的影响(HR为0.54 [95% CI:0.41-0.71];P结论:KRAS突变和KRAS突变对OS和PFS有更有利的影响:KRAS突变和KRAS G12C突变对接受免疫疗法治疗的NSCLC患者的OS和PFS有益处。然而,与 KRAS 非 G12D 突变相比,KRAS G12D 突变会对 OS 产生负面影响。此外,涉及 STK11 和 KEAP1/NFE2L2 的 KRAS 共突变也会对 NSCLC 患者接受免疫疗法的疗效产生负面影响。
{"title":"The efficacy of immunotherapy in non-small cell lung cancer with KRAS mutation: a systematic review and meta-analysis.","authors":"Rui Zhao, Yang Shu, Wei Xu, Fengxian Jiang, Pancen Ran, Liying Pan, Jingliang Wang, Weihao Wang, Jing Zhao, Yahui Wang, Guobin Fu","doi":"10.1186/s12935-024-03498-9","DOIUrl":"10.1186/s12935-024-03498-9","url":null,"abstract":"<p><strong>Purpose: </strong>The KRAS mutation is highly prevalent in NSCLC and is associated with poor efficacy of immunotherapy. Nevertheless, the impact of KRAS mutation, mutation subtypes, and co-mutations on the effectiveness of immunotherapy remains uncertain. This study aimed to assess the influence of the KRAS mutation on the effectiveness of immunotherapy in NSCLC, specifically examining different subtypes of KRAS mutations and co-mutations.</p><p><strong>Methods: </strong>We performed an extensive search of multiple databases, covering the period from January 1, 2000, to December 5, 2023. A total of 24 articles met our inclusion criteria and were included in this study. A comparative analysis assessed the influence of different subgroups, including KRAS mutation, KRAS wild-type, KRAS G12C mutation, KRAS G12D mutation, and KRAS with co-mutations in NSCLC with immunotherapy. The study outcomes include HR, with corresponding 95% CI and P-values for OS and PFS using Review Manager 5.4 software for the meta-analysis.</p><p><strong>Result: </strong>The KRAS mutation appears to have a more beneficial impact on OS (HR 0.54 [95% CI: 0.41-0.71]; P < 0.00001) and PFS (HR 0.63 [95% CI: 0.53-0.76]; P < 0.00001) in NSCLC patients receiving immunotherapy compared to those without immunotherapy. The presence of KRASG12C mutation has been found to have a positive impact on PFS (HR 0.39 [95% CI: 0.25-0.62]; P < 0.0001) in NSCLC patients who undergo immunotherapy, compared to those who did not receive immunotherapy. KRAS non-G12D mutation is considerably associated with longer OS (HR 1.52 [95% CI: 1.10-2.10]; P = 0.01). The clinical benefit in OS between patients without STK11 co-mutation and those who have KRAS mutation with STK11 is significant (HR 1.46 [95% CI: 1.10-1.93]; P = 0.008). Comparing the impact of OS patients without KEAP1/NFE2L2 mutation to those with KRAS and KEAP1/NFE2L2 co-mutations showed a significant impact (HR 1.89 [95% CI: 1.33-2.68]; P = 0.0004).</p><p><strong>Conclusion: </strong>The KRAS mutation and KRAS G12C mutation confer benefits that impact OS and PFS in NSCLC patients treated with immunotherapy. However, the KRAS G12D mutation negatively impacts OS compared to the KRAS non-G12D mutation. Furthermore, KRAS co-mutations involving STK11 and KEAP1/NFE2L2 are associated with a negative impact on the efficacy of immunotherapy in NSCLC patients.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"24 1","pages":"361"},"PeriodicalIF":5.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11529330/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Exosome therapeutics for non-small cell lung cancer tumorigenesis. 针对非小细胞肺癌肿瘤发生的外泌体疗法。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-10-30 DOI: 10.1186/s12935-024-03544-6
Niloufar Orooji, Manouchehr Fadaee, Tohid Kazemi, Bahman Yousefi

Non-small cell lung cancer (NSCLC) remains an ongoing health concern, with poor treatment options and prognosis for many patients. Typically, individuals with lung cancer are detected at the middle and terminal stages, resulting in poor medical results due to lack of initial diagnosis and treatment. So, finding the initial specific and effective therapy options for lung cancer is necessary. In addition, exosomes are generally small lipid vesicles with a diameter in the nanometer range that are created and released by different cell types. Exosomes have therapeutic potential through delivering bioactive compounds including microRNAs, siRNAs, and therapeutic proteins to tumor cells, modifying the tumor microenvironment, and promoting anti-tumor immune responses. In recent years, exosome-based therapy has become known as an appropriate approach for NSCLC treatment. This review offers an overview of the possibility of exosome-based therapy for NSCLC, with an emphasis on mechanisms of action, preclinical research, and current clinical trials. Preclinical studies have shown that exosome-based therapy can decrease tumor growth, metastasis, and drug resistance in NSCLC models. Furthermore, ongoing clinical trials are looking at the safety and efficacy of exosome-based therapies in NSCLC patients, offering important insights into their translational prospects. Despite promising preclinical evidences, significant obstacles remain, including optimizing exosome isolation and purification techniques, standardizing production strategies, and developing scalable manufacturing processes. Overall, exosome-based therapy shows significant promise as a novel and various methods for treating NSCLC, with the potential to enhance patient outcomes and evolution cancer treatment.

非小细胞肺癌(NSCLC)一直是人们关注的健康问题,许多患者的治疗方案和预后都很差。肺癌患者通常在中期和晚期才被发现,由于缺乏初期诊断和治疗,导致医疗效果不佳。因此,找到肺癌最初的特异性有效治疗方案十分必要。此外,外泌体一般是直径在纳米范围内的小型脂质囊泡,由不同类型的细胞产生和释放。外泌体具有治疗潜力,可将生物活性化合物(包括 microRNA、siRNA 和治疗蛋白)输送到肿瘤细胞,改变肿瘤微环境,促进抗肿瘤免疫反应。近年来,基于外泌体的疗法已成为治疗 NSCLC 的一种适当方法。本综述概述了外泌体疗法治疗 NSCLC 的可能性,重点介绍其作用机制、临床前研究和当前的临床试验。临床前研究表明,基于外泌体的疗法可以减少 NSCLC 模型中的肿瘤生长、转移和耐药性。此外,正在进行的临床试验正在研究基于外泌体的疗法对 NSCLC 患者的安全性和疗效,为其转化前景提供了重要见解。尽管临床前证据前景看好,但仍存在重大障碍,包括优化外泌体分离和纯化技术、标准化生产策略以及开发可扩展的生产工艺。总之,基于外泌体的疗法作为治疗 NSCLC 的一种新颖、多样的方法前景广阔,有望改善患者的预后并促进癌症治疗的发展。
{"title":"Exosome therapeutics for non-small cell lung cancer tumorigenesis.","authors":"Niloufar Orooji, Manouchehr Fadaee, Tohid Kazemi, Bahman Yousefi","doi":"10.1186/s12935-024-03544-6","DOIUrl":"10.1186/s12935-024-03544-6","url":null,"abstract":"<p><p>Non-small cell lung cancer (NSCLC) remains an ongoing health concern, with poor treatment options and prognosis for many patients. Typically, individuals with lung cancer are detected at the middle and terminal stages, resulting in poor medical results due to lack of initial diagnosis and treatment. So, finding the initial specific and effective therapy options for lung cancer is necessary. In addition, exosomes are generally small lipid vesicles with a diameter in the nanometer range that are created and released by different cell types. Exosomes have therapeutic potential through delivering bioactive compounds including microRNAs, siRNAs, and therapeutic proteins to tumor cells, modifying the tumor microenvironment, and promoting anti-tumor immune responses. In recent years, exosome-based therapy has become known as an appropriate approach for NSCLC treatment. This review offers an overview of the possibility of exosome-based therapy for NSCLC, with an emphasis on mechanisms of action, preclinical research, and current clinical trials. Preclinical studies have shown that exosome-based therapy can decrease tumor growth, metastasis, and drug resistance in NSCLC models. Furthermore, ongoing clinical trials are looking at the safety and efficacy of exosome-based therapies in NSCLC patients, offering important insights into their translational prospects. Despite promising preclinical evidences, significant obstacles remain, including optimizing exosome isolation and purification techniques, standardizing production strategies, and developing scalable manufacturing processes. Overall, exosome-based therapy shows significant promise as a novel and various methods for treating NSCLC, with the potential to enhance patient outcomes and evolution cancer treatment.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"24 1","pages":"360"},"PeriodicalIF":5.3,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11523890/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Machine learning and single-cell RNA sequencing reveal relationship between intratumor CD8+ T cells and uveal melanoma metastasis. 机器学习和单细胞 RNA 测序揭示了肿瘤内 CD8+ T 细胞与葡萄膜黑色素瘤转移之间的关系。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-10-30 DOI: 10.1186/s12935-024-03539-3
Shuming Chen, Zichun Tang, Qiaoqian Wan, Weidi Huang, Xie Li, Xixuan Huang, Shuyan Zheng, Caiyang Lu, Jinzheng Wu, Zhuo Li, Xiao Liu
<p><strong>Purpose: </strong>Uveal melanoma (UM) is adults' most common primary intraocular malignant tumor. It has been observed that 40% of patients experience distant metastasis during subsequent treatment. While there exist multigene models developed using machine learning methods to assess metastasis and prognosis, the immune microenvironment's specific mechanisms influencing the tumor microenvironment have not been clarified. Single-cell transcriptome sequencing can accurately identify different types of cells in a tissue for precise analysis. This study aims to develop a model with fewer genes to evaluate metastasis risk in UM patients and provide a theoretical basis for UM immunotherapy.</p><p><strong>Methods: </strong>RNA-seq data and clinical information from 79 μm patients from TCGA were used to construct prognostic models. Mechanisms were probed using two single-cell datasets derived from the GEO database. After screening for metastasis-related genes, enrichment analysis was performed using GO and KEGG. Prognostic genes were screened using log-rank test and one-way Cox regression, and prognostic models were established using LASSO regression analysis and multifactor Cox regression analysis. The TCGA-UVM dataset was used as internal validation and dataset GSE22138 as external validation data. A time-dependent subject work characteristic curve (time-ROC) was established to assess the predictive ability of the model. Subsequently, dimensionality reduction, clustering, pseudo-temporal analysis and cellular communication analysis were performed on GSE138665 and GSE139829 to explore the underlying mechanisms involved. Cellular experiments were also used to validate the relevant findings.</p><p><strong>Results: </strong>Based on clinical characteristics and RNA-seq transcriptomic data from 79 samples in the TCGA-UVM cohort, 247 metastasis-related genes were identified. Survival models for three genes (SLC25A38, EDNRB, and LURAP1) were then constructed using lasso regression and multifactorial cox regression. Kaplan-Meier survival analysis showed that the high-risk group was associated with poorer overall survival (OS) and metastasis-free survival (MFS) in UM patients. Time-dependent ROC curves demonstrated high predictive performance in 6 m, 18 m, and 30 m prognostic models. Cell scratch assay showed that the 24 h and 48 h migration rates of cells with reduced expression of the three genes were significantly higher than those of the si-NC group. CD8 + T cells may play an important role in tumour metastasis as revealed by immune infiltration analysis. An increase in the percentage of cytotoxic CD8 + T cells in the metastatic high-risk group was found in the exploration of single-cell transcriptome data. The communication intensity of cytotoxic CD8 was significantly enhanced. It was also found that the CD8 + T cells in the two groups were in different states, although the number of CD8 + T cells in the high-risk group increased, they were most
目的:葡萄膜黑色素瘤(UM)是成人最常见的原发性眼内恶性肿瘤。据观察,40%的患者在后续治疗中会出现远处转移。虽然已有利用机器学习方法开发的多基因模型来评估转移和预后,但免疫微环境影响肿瘤微环境的具体机制尚未明确。单细胞转录组测序可以准确识别组织中不同类型的细胞,进行精确分析。本研究旨在建立一个基因数量较少的模型,以评估 UM 患者的转移风险,并为 UM 免疫疗法提供理论依据:方法:利用来自 TCGA 的 79 μm 患者的 RNA-seq 数据和临床信息构建预后模型。方法:利用来自GEO数据库的两个单细胞数据集构建预后模型。在筛选出转移相关基因后,利用GO和KEGG进行了富集分析。使用Log-rank检验和单因素Cox回归筛选预后基因,并使用LASSO回归分析和多因素Cox回归分析建立预后模型。TCGA-UVM数据集作为内部验证数据,GSE22138数据集作为外部验证数据。建立了随时间变化的受试者工作特征曲线(time-ROC),以评估模型的预测能力。随后,对 GSE138665 和 GSE139829 进行了降维、聚类、伪时态分析和细胞通讯分析,以探索其中的潜在机制。同时还利用细胞实验验证了相关结论:根据TCGA-UVM队列中79个样本的临床特征和RNA-seq转录组数据,确定了247个转移相关基因。然后利用套索回归和多因素考克斯回归构建了三个基因(SLC25A38、EDNRB和LURAP1)的生存模型。Kaplan-Meier 生存分析表明,高风险组与 UM 患者较差的总生存期(OS)和无转移生存期(MFS)相关。与时间相关的 ROC 曲线显示,6 m、18 m 和 30 m 预后模型的预测性能较高。细胞划痕试验显示,三种基因表达减少的细胞的24小时和48小时迁移率明显高于si-NC组。免疫浸润分析表明,CD8 + T细胞可能在肿瘤转移中发挥重要作用。在对单细胞转录组数据的研究中发现,转移性高危组中细胞毒性 CD8 + T 细胞的比例有所增加。细胞毒性 CD8 的通讯强度明显增强。研究还发现,两组的CD8 + T细胞处于不同的状态,虽然高危组的CD8 + T细胞数量增加,但它们大多处于衰竭和未分化状态,而低危组的CD8 + T细胞大多处于功能状态:我们建立了一个精确而稳定的3基因模型来预测患者的转移风险和预后。肿瘤微环境中的 CD8 + T 细胞衰竭在 UM 转移中起着至关重要的作用。
{"title":"Machine learning and single-cell RNA sequencing reveal relationship between intratumor CD8<sup>+</sup> T cells and uveal melanoma metastasis.","authors":"Shuming Chen, Zichun Tang, Qiaoqian Wan, Weidi Huang, Xie Li, Xixuan Huang, Shuyan Zheng, Caiyang Lu, Jinzheng Wu, Zhuo Li, Xiao Liu","doi":"10.1186/s12935-024-03539-3","DOIUrl":"10.1186/s12935-024-03539-3","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Purpose: &lt;/strong&gt;Uveal melanoma (UM) is adults' most common primary intraocular malignant tumor. It has been observed that 40% of patients experience distant metastasis during subsequent treatment. While there exist multigene models developed using machine learning methods to assess metastasis and prognosis, the immune microenvironment's specific mechanisms influencing the tumor microenvironment have not been clarified. Single-cell transcriptome sequencing can accurately identify different types of cells in a tissue for precise analysis. This study aims to develop a model with fewer genes to evaluate metastasis risk in UM patients and provide a theoretical basis for UM immunotherapy.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;RNA-seq data and clinical information from 79 μm patients from TCGA were used to construct prognostic models. Mechanisms were probed using two single-cell datasets derived from the GEO database. After screening for metastasis-related genes, enrichment analysis was performed using GO and KEGG. Prognostic genes were screened using log-rank test and one-way Cox regression, and prognostic models were established using LASSO regression analysis and multifactor Cox regression analysis. The TCGA-UVM dataset was used as internal validation and dataset GSE22138 as external validation data. A time-dependent subject work characteristic curve (time-ROC) was established to assess the predictive ability of the model. Subsequently, dimensionality reduction, clustering, pseudo-temporal analysis and cellular communication analysis were performed on GSE138665 and GSE139829 to explore the underlying mechanisms involved. Cellular experiments were also used to validate the relevant findings.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Based on clinical characteristics and RNA-seq transcriptomic data from 79 samples in the TCGA-UVM cohort, 247 metastasis-related genes were identified. Survival models for three genes (SLC25A38, EDNRB, and LURAP1) were then constructed using lasso regression and multifactorial cox regression. Kaplan-Meier survival analysis showed that the high-risk group was associated with poorer overall survival (OS) and metastasis-free survival (MFS) in UM patients. Time-dependent ROC curves demonstrated high predictive performance in 6 m, 18 m, and 30 m prognostic models. Cell scratch assay showed that the 24 h and 48 h migration rates of cells with reduced expression of the three genes were significantly higher than those of the si-NC group. CD8 + T cells may play an important role in tumour metastasis as revealed by immune infiltration analysis. An increase in the percentage of cytotoxic CD8 + T cells in the metastatic high-risk group was found in the exploration of single-cell transcriptome data. The communication intensity of cytotoxic CD8 was significantly enhanced. It was also found that the CD8 + T cells in the two groups were in different states, although the number of CD8 + T cells in the high-risk group increased, they were most","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"24 1","pages":"359"},"PeriodicalIF":5.3,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11523669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A multidimensional analysis of the impact of obesity on immune checkpoint inhibitor therapy efficacy. 肥胖对免疫检查点抑制剂疗效影响的多维分析。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-10-29 DOI: 10.1186/s12935-024-03532-w
Wenjing Xu, Yifan Yang, Yue Yu, Lu Wu, Dong Ma, Rongrong Li, Lu Yang, Hengwen Sun

Background: Obesity is a well-known risk factor for developing malignant tumors and promoting tumor cell growth and spread. However, recent studies have shown that obese cancer patients, who typically have a worse prognosis than nonobese cancer patients, show a significant improvement in survival after receiving immune checkpoint inhibitor (ICI) therapy. This phenomenon is known as the "obesity paradox". However, this phenomenon is influenced by tumor type and sex. Therefore, this study aimed to explore the impact of obesity on immunotherapy efficacy from multiple perspectives, aiming to verify this paradox and provide new scientific evidence on the effect of obesity on ICI efficacy.

Methods: This retrospective study evaluated the data of patients who received ICI therapy between June 2019 and August 2023. Automatic segmentation of skeletal muscle, subcutaneous fat, and visceral fat was performed using Slice-O-Matic software, and the corresponding skeletal muscle index (SMI), subcutaneous fat index (SFI) and visceral fat index (VFI) were calculated. The neutrophil-to-lymphocyte ratio (NLR) was determined by dividing the neutrophil count by the lymphocyte count. Univariate and multivariate Cox regression analyses were used to evaluate the correlation between body mass index (BMI), body composition parameters, and the NLR with overall survival (OS) and progression-free survival (PFS) in obese patients receiving ICI therapy.

Results: We analyzed 219 patients with a median age of 60 years (IQR 53-69 years; 155 men and 64 women). Obese patients, particularly those with visceral fat accumulation, exhibited extended OS after ICI therapy (log-rank P = 0.027). Cox multivariate analysis revealed that the NLR (HR = 1.036; 95% CI: 0.996 to 1.078; P = 0.002) was independently associated with OS. Patients with a high NLR had worse OS than those with a low NLR.

Conclusions: This study corroborates the veracity of the "obesity paradox" under specific conditions and identifies NLR as an independent prognostic factor, with elevated NLR indicative of a poor prognosis.

背景:众所周知,肥胖是罹患恶性肿瘤并促进肿瘤细胞生长和扩散的危险因素。然而,最近的研究表明,肥胖癌症患者的预后通常比非肥胖癌症患者更差,但在接受免疫检查点抑制剂(ICI)治疗后,肥胖癌症患者的生存率却显著提高。这一现象被称为 "肥胖悖论"。然而,这一现象受肿瘤类型和性别的影响。因此,本研究旨在从多个角度探讨肥胖对免疫疗法疗效的影响,旨在验证这一悖论,并为肥胖对ICI疗效的影响提供新的科学证据:这项回顾性研究评估了2019年6月至2023年8月期间接受ICI治疗的患者数据。使用 Slice-O-Matic 软件对骨骼肌、皮下脂肪和内脏脂肪进行了自动分割,并计算了相应的骨骼肌指数(SMI)、皮下脂肪指数(SFI)和内脏脂肪指数(VFI)。中性粒细胞与淋巴细胞比值(NLR)通过中性粒细胞计数除以淋巴细胞计数确定。采用单变量和多变量 Cox 回归分析评估接受 ICI 治疗的肥胖患者的体重指数(BMI)、身体成分参数和 NLR 与总生存期(OS)和无进展生存期(PFS)之间的相关性:我们对 219 名患者进行了分析,他们的中位年龄为 60 岁(IQR 53-69 岁;男性 155 人,女性 64 人)。肥胖患者,尤其是内脏脂肪堆积的患者,在接受 ICI 治疗后的 OS 延长(log-rank P = 0.027)。Cox多变量分析显示,NLR(HR = 1.036;95% CI:0.996 至 1.078;P = 0.002)与OS密切相关。与低NLR患者相比,高NLR患者的OS更差:本研究证实了特定条件下 "肥胖悖论 "的真实性,并确定NLR是一个独立的预后因素,NLR升高表明预后不良。
{"title":"A multidimensional analysis of the impact of obesity on immune checkpoint inhibitor therapy efficacy.","authors":"Wenjing Xu, Yifan Yang, Yue Yu, Lu Wu, Dong Ma, Rongrong Li, Lu Yang, Hengwen Sun","doi":"10.1186/s12935-024-03532-w","DOIUrl":"10.1186/s12935-024-03532-w","url":null,"abstract":"<p><strong>Background: </strong>Obesity is a well-known risk factor for developing malignant tumors and promoting tumor cell growth and spread. However, recent studies have shown that obese cancer patients, who typically have a worse prognosis than nonobese cancer patients, show a significant improvement in survival after receiving immune checkpoint inhibitor (ICI) therapy. This phenomenon is known as the \"obesity paradox\". However, this phenomenon is influenced by tumor type and sex. Therefore, this study aimed to explore the impact of obesity on immunotherapy efficacy from multiple perspectives, aiming to verify this paradox and provide new scientific evidence on the effect of obesity on ICI efficacy.</p><p><strong>Methods: </strong>This retrospective study evaluated the data of patients who received ICI therapy between June 2019 and August 2023. Automatic segmentation of skeletal muscle, subcutaneous fat, and visceral fat was performed using Slice-O-Matic software, and the corresponding skeletal muscle index (SMI), subcutaneous fat index (SFI) and visceral fat index (VFI) were calculated. The neutrophil-to-lymphocyte ratio (NLR) was determined by dividing the neutrophil count by the lymphocyte count. Univariate and multivariate Cox regression analyses were used to evaluate the correlation between body mass index (BMI), body composition parameters, and the NLR with overall survival (OS) and progression-free survival (PFS) in obese patients receiving ICI therapy.</p><p><strong>Results: </strong>We analyzed 219 patients with a median age of 60 years (IQR 53-69 years; 155 men and 64 women). Obese patients, particularly those with visceral fat accumulation, exhibited extended OS after ICI therapy (log-rank P = 0.027). Cox multivariate analysis revealed that the NLR (HR = 1.036; 95% CI: 0.996 to 1.078; P = 0.002) was independently associated with OS. Patients with a high NLR had worse OS than those with a low NLR.</p><p><strong>Conclusions: </strong>This study corroborates the veracity of the \"obesity paradox\" under specific conditions and identifies NLR as an independent prognostic factor, with elevated NLR indicative of a poor prognosis.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"24 1","pages":"358"},"PeriodicalIF":5.3,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11523605/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Stearoyl CoA desaturase inhibition can effectively induce apoptosis in bladder cancer stem cells. 硬脂酰辅酶脱饱和酶抑制剂能有效诱导膀胱癌干细胞凋亡。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-10-29 DOI: 10.1186/s12935-024-03540-w
Yuchen Li, Chiyuan Piao, Chuize Kong

Bladder cancer stands as one of the most prevalent cancers worldwide. While our previous research confirmed the significant role of stearoyl-CoA desaturase (SCD) in bladder cancer, the underlying reasons for its abnormal overexpression remain largely unknown. Moreover, the distinct response to SCD inhibitors between cancer stem cells (CSCs) and adherent cultured cell lines lacks clear elucidation. Therefore, in this experiment, we aim to conduct an analysis and screening of the SCD transcription start site, further seeking critical transcription factors involved. Simultaneously, through experimental validation, we aim to explore the pivotal role of endoplasmic reticulum stress/unfolded protein response in drug sensitivity among cancer stem cells. Additionally, our RNA-seq and lipid metabolism analysis revealed the significant impact of nervonic acid on altering the proliferative capacity of bladder cancer cell lines.

膀胱癌是全球发病率最高的癌症之一。虽然我们之前的研究证实了硬脂酰-CoA 去饱和酶(SCD)在膀胱癌中的重要作用,但其异常过表达的根本原因仍然不为人知。此外,癌症干细胞(CSCs)和粘附培养细胞系对 SCD 抑制剂的不同反应也缺乏明确的解释。因此,在本实验中,我们旨在对SCD转录起始位点进行分析和筛选,进一步寻找参与其中的关键转录因子。同时,通过实验验证,我们旨在探索内质网应激/不折叠蛋白反应在癌症干细胞药物敏感性中的关键作用。此外,我们的 RNA-seq 和脂质代谢分析表明,神经酸对改变膀胱癌细胞株的增殖能力有显著影响。
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引用次数: 0
STAT3: Key targets of growth-promoting receptor positive breast cancer. STAT3:促进生长的受体阳性乳腺癌的关键靶点。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-10-28 DOI: 10.1186/s12935-024-03541-9
Rui-Yuan Jiang, Jia-Yu Zhu, Huan-Ping Zhang, Yuan Yu, Zhi-Xin Dong, Huan-Huan Zhou, Xiaojia Wang

Breast cancer has become the malignant tumor with the first incidence and the second mortality among female cancers. Most female breast cancers belong to luminal-type breast cancer and HER2-positive breast cancer. These breast cancer cells all have different driving genes, which constantly promote the proliferation and metastasis of breast cancer cells. Signal transducer and activator of transcription 3 (STAT3) is an important breast cancer-related gene, which can promote the progress of breast cancer. It has been proved in clinical and basic research that over-expressed and constitutively activated STAT3 is involved in the progress, proliferation, metastasis and chemotherapy resistance of breast cancer. STAT3 is an important key target in luminal-type breast cancer and HER2-positive cancer, which has an important impact on the curative effect of related treatments. In breast cancer, the activation of STAT3 will change the spatial position of STAT3 protein and cause different phenotypic changes of breast cancer cells. In the current basic research and clinical research, small molecule inhibitors activated by targeting STAT3 can effectively treat breast cancer, and enhance the efficacy level of related treatment methods for luminal-type and HER2-positive breast cancers.

乳腺癌已成为女性癌症中发病率第一、死亡率第二的恶性肿瘤。大多数女性乳腺癌属于管腔型乳腺癌和 HER2 阳性乳腺癌。这些乳腺癌细胞都有不同的驱动基因,不断促进乳腺癌细胞的增殖和转移。信号转导和转录激活因子 3(STAT3)是与乳腺癌相关的重要基因,可促进乳腺癌的进展。临床和基础研究证明,过度表达和组成性激活的 STAT3 参与了乳腺癌的进展、增殖、转移和化疗耐药。STAT3 是腔镜型乳腺癌和 HER2 阳性癌症的重要关键靶点,对相关治疗的疗效有重要影响。在乳腺癌中,STAT3 的激活会改变 STAT3 蛋白的空间位置,引起乳腺癌细胞不同的表型变化。在目前的基础研究和临床研究中,通过靶向 STAT3 激活的小分子抑制剂可以有效治疗乳腺癌,提高相关治疗方法对腔隙型乳腺癌和 HER2 阳性乳腺癌的疗效水平。
{"title":"STAT3: Key targets of growth-promoting receptor positive breast cancer.","authors":"Rui-Yuan Jiang, Jia-Yu Zhu, Huan-Ping Zhang, Yuan Yu, Zhi-Xin Dong, Huan-Huan Zhou, Xiaojia Wang","doi":"10.1186/s12935-024-03541-9","DOIUrl":"10.1186/s12935-024-03541-9","url":null,"abstract":"<p><p>Breast cancer has become the malignant tumor with the first incidence and the second mortality among female cancers. Most female breast cancers belong to luminal-type breast cancer and HER2-positive breast cancer. These breast cancer cells all have different driving genes, which constantly promote the proliferation and metastasis of breast cancer cells. Signal transducer and activator of transcription 3 (STAT3) is an important breast cancer-related gene, which can promote the progress of breast cancer. It has been proved in clinical and basic research that over-expressed and constitutively activated STAT3 is involved in the progress, proliferation, metastasis and chemotherapy resistance of breast cancer. STAT3 is an important key target in luminal-type breast cancer and HER2-positive cancer, which has an important impact on the curative effect of related treatments. In breast cancer, the activation of STAT3 will change the spatial position of STAT3 protein and cause different phenotypic changes of breast cancer cells. In the current basic research and clinical research, small molecule inhibitors activated by targeting STAT3 can effectively treat breast cancer, and enhance the efficacy level of related treatment methods for luminal-type and HER2-positive breast cancers.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"24 1","pages":"356"},"PeriodicalIF":5.3,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11520424/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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Cancer Cell International
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