Molecular Cancer最新文献_第9页

Programmed death receptor (PD-)1/PD-ligand (L)1 in urological cancers : the “all-around warrior” in immunotherapy 泌尿系统癌症中的程序性死亡受体（PD-）1/PD-配体（L）1：免疫疗法中的 "全能战士

IF 37.3 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cancer

Pub Date : 2024-09-02 DOI: 10.1186/s12943-024-02095-8

Qiang Liu, Yujing Guan, Shenglong Li

Programmed death receptor-1 (PD-1) and its ligand, programmed death ligand-1 (PD-L1) are essential molecules that are key in modulating immune responses. PD-L1 is constitutively expressed on various immune cells, epithelial cells, and cancer cells, where it functions as a co-stimulatory molecule capable of impairing T-cell mediated immune responses. Upon binding to PD-1 on activated T-cells, the PD-1/PD-L1 interaction triggers signaling pathways that can induce T-cell apoptosis or anergy, thereby facilitating the immune escape of tumors. In urological cancers, including bladder cancer (BCa), renal cell carcinoma (RCC), and prostate cancer (PCa), the upregulation of PD-L1 has been demonstrated. It is linked to poor prognosis and enhanced tumor immune evasion. Recent studies have highlighted the significant role of the PD-1/PD-L1 axis in the immune escape mechanisms of urological cancers. The interaction between PD-L1 and PD-1 on T-cells further contributes to immunosuppression by inhibiting T-cell activation and proliferation. Clinical applications of PD-1/PD-L1 checkpoint inhibitors have shown promising efficacy in treating advanced urological cancers, significantly improving patient outcomes. However, resistance to these therapies, either intrinsic or acquired, remains a significant challenge. This review aims to provide a comprehensive overview of the role of the PD-1/PD-L1 signaling pathway in urological cancers. We summarize the regulatory mechanism underlying PD-1 and PD-L1 expression and activity, including genetic, epigenetic, post-transcriptional, and post-translational modifications. Additionally, we discuss current clinical research on PD-1/PD-L1 inhibitors, their therapeutic potential, and the challenges associated with resistance. Understanding these mechanisms is crucial for developing new strategies to overcome therapeutic limitations and enhance the efficacy of cancer immunotherapy.

程序性死亡受体-1（PD-1）及其配体程序性死亡配体-1（PD-L1）是调节免疫反应的重要分子。PD-L1 在各种免疫细胞、上皮细胞和癌细胞上都有表达，它是一种协同刺激分子，能够损害 T 细胞介导的免疫反应。与活化 T 细胞上的 PD-1 结合后，PD-1/PD-L1 相互作用会触发信号通路，诱导 T 细胞凋亡或失活，从而促进肿瘤的免疫逃逸。在膀胱癌（BCa）、肾细胞癌（RCC）和前列腺癌（PCa）等泌尿系统癌症中，PD-L1 的上调已得到证实。这与预后不良和肿瘤免疫逃避能力增强有关。最近的研究强调了 PD-1/PD-L1 轴在泌尿系统癌症免疫逃避机制中的重要作用。T 细胞上的 PD-L1 和 PD-1 之间的相互作用通过抑制 T 细胞的活化和增殖进一步促进了免疫抑制。PD-1/PD-L1 检查点抑制剂的临床应用已显示出治疗晚期泌尿系统癌症的良好疗效，显著改善了患者的预后。然而，这些疗法的耐药性，无论是内在的还是后天获得的，仍然是一个重大挑战。本综述旨在全面概述 PD-1/PD-L1 信号通路在泌尿系统癌症中的作用。我们总结了 PD-1 和 PD-L1 表达和活性的调控机制，包括遗传、表观遗传、转录后和翻译后修饰。此外，我们还讨论了目前有关 PD-1/PD-L1 抑制剂的临床研究、其治疗潜力以及与耐药性相关的挑战。了解这些机制对于开发新的策略以克服治疗限制和提高癌症免疫疗法的疗效至关重要。

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引用次数: 0

Cellular senescence and SASP in tumor progression and therapeutic opportunities 肿瘤进展中的细胞衰老和 SASP 以及治疗机会

IF 37.3 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cancer

Pub Date : 2024-08-31 DOI: 10.1186/s12943-024-02096-7

Zening Dong, Yahan Luo, Zhangchen Yuan, Yu Tian, Tianqiang Jin, Feng Xu

Cellular senescence (CS), a permanent and irreversible arrest of the cell cycle and proliferation leading to the degeneration of cellular structure and function, has been implicated in various key physiological and pathological processes, particularly in cancer. Initially, CS was recognized as a barrier to tumorigenesis, serving as an intrinsic defense mechanism to protect cells from malignant transformation. However, increasing evidence suggests that senescent cells can promote tumor progression to overt malignancy, primarily through a set of factors known as senescence-associated secretory phenotypes (SASPs), including chemokines, growth factors, cytokines, and stromal metalloproteinases. These factors significantly reshape the tumor microenvironment (TME), enabling tumors to evade immune destruction. Interestingly, some studies have also suggested that SASPs may impede tumor development by enhancing immunosurveillance. These opposing roles highlight the complexity and heterogeneity of CS and SASPs in diverse cancers. Consequently, there has been growing interest in pharmacological interventions targeting CS or SASPs in cancer therapy, such as senolytics and senomorphics, to either promote the clearance of senescent cells or mitigate the harmful effects of SASPs. In this review, we will interpret the concept of CS, delve into the role of SASPs in reshaping the TME, and summarize recent advances in anti-tumor strategies targeting CS or SASPs.

细胞衰老（CS）是细胞周期和增殖的一种永久性、不可逆转的停滞，会导致细胞结构和功能的退化。最初，CS 被认为是肿瘤发生的屏障，是保护细胞免受恶性转化的内在防御机制。然而，越来越多的证据表明，衰老细胞可促进肿瘤进展为明显的恶性肿瘤，主要是通过一系列称为衰老相关分泌表型（SASPs）的因子，包括趋化因子、生长因子、细胞因子和基质金属蛋白酶。这些因子极大地重塑了肿瘤微环境（TME），使肿瘤得以逃避免疫破坏。有趣的是，一些研究还表明 SASPs 可通过增强免疫监视来阻碍肿瘤的发展。这些相反的作用凸显了 CS 和 SASPs 在不同癌症中的复杂性和异质性。因此，人们越来越关注在癌症治疗中针对 CS 或 SASPs 的药物干预，如衰老剂和衰老形态剂，以促进衰老细胞的清除或减轻 SASPs 的有害影响。在这篇综述中，我们将解读CS的概念，深入探讨SASPs在重塑TME中的作用，并总结针对CS或SASPs的抗肿瘤策略的最新进展。

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引用次数: 0

Joint single-cell genetic and transcriptomic analysis reveal pre-malignant SCP-like subclones in human neuroblastoma 单细胞遗传学和转录组学联合分析揭示了人类神经母细胞瘤的恶性前 SCP 样亚克隆

IF 37.3 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cancer

Pub Date : 2024-08-31 DOI: 10.1186/s12943-024-02091-y

Thale K. Olsen, Jörg Otte, Shenglin Mei, Bethel Tesfai Embaie, Polina Kameneva, Huaitao Cheng, Teng Gao, Vasilios Zachariadis, Ioanna Tsea, Åsa Björklund, Emil Kryukov, Ziyi Hou, Anna Johansson, Erik Sundström, Tommy Martinsson, Susanne Fransson, Jakob Stenman, Shahrzad Shirazi Fard, John Inge Johnsen, Per Kogner, Igor Adameyko, Martin Enge, Peter V. Kharchenko, Ninib Baryawno

Neuroblastoma (NB) is a heterogeneous embryonal malignancy and the deadliest tumor of infancy. It is a complex disease that can result in diverse clinical outcomes. In some children, tumors regress spontaneously. Others respond well to existing treatments. But for the high-risk group, which constitutes approximately 40% of all patients, the prognosis remains dire despite collaborative efforts in basic and clinical research. While its exact cellular origin is still under debate, NB is assumed to arise from the neural crest cell lineage including multipotent Schwann cell precursors (SCPs), which differentiate into sympatho-adrenal cell states eventually producing chromaffin cells and sympathoblasts. To investigate clonal development of neuroblastoma cell states, we performed haplotype-specific analysis of human tumor samples using single-cell multi-omics, including joint DNA/RNA sequencing of sorted single cells (DNTR-seq). Samples were also assessed using immunofluorescence stainings and fluorescence in-situ hybridization (FISH). Beyond adrenergic tumor cells, we identify subpopulations of aneuploid SCP-like cells, characterized by clonal expansion, whole-chromosome 17 gains, as well as expression programs of proliferation, apoptosis, and a non-immunomodulatory phenotype. Aneuploid pre-malignant SCP-like cells represent a novel feature of NB. Genetic evidence and tumor phylogeny suggest that these clones and malignant adrenergic populations originate from aneuploidy-prone cells of migrating neural crest or SCP origin, before lineage commitment to sympatho-adrenal cell states. Our findings expand the phenotypic spectrum of NB cell states. Considering the multipotency of SCPs in development, we suggest that the transformation of fetal SCPs may represent one possible mechanism of tumor initiation in NB with chromosome 17 aberrations as a characteristic element.

神经母细胞瘤（NB）是一种异质性胚胎性恶性肿瘤，也是婴儿期最致命的肿瘤。它是一种复杂的疾病，可导致不同的临床结果。有些患儿的肿瘤会自然消退。另一些则对现有的治疗方法反应良好。但是，对于约占所有患者 40% 的高危人群来说，尽管基础和临床研究人员通力合作，但预后仍然不容乐观。尽管其确切的细胞起源仍存在争议，但人们认为 NB 起源于神经嵴细胞系，包括多能的许旺细胞前体（SCPs），它们分化成交感肾上腺细胞状态，最终产生嗜铬细胞和交感母细胞。为了研究神经母细胞瘤细胞状态的克隆发展，我们使用单细胞多组学技术对人类肿瘤样本进行了单倍型特异性分析，包括对分选的单细胞进行DNA/RNA联合测序（DNTR-seq）。我们还利用免疫荧光染色和荧光原位杂交（FISH）对样本进行了评估。除了肾上腺素能肿瘤细胞外，我们还发现了非整倍体 SCP 样细胞亚群，其特点是克隆扩增、全染色体 17 增殖以及增殖、凋亡和非免疫调节表型的表达程序。非整倍体恶性前SCP样细胞代表了NB的一种新特征。遗传学证据和肿瘤系统发育表明，这些克隆和恶性肾上腺素能细胞群起源于易发生非整倍体的移行神经嵴细胞或SCP细胞，然后才进入交感肾上腺细胞状态。我们的发现扩大了 NB 细胞状态的表型谱。考虑到 SCP 在发育过程中的多潜能性，我们认为胎儿 SCP 的转化可能代表了以 17 号染色体畸变为特征要素的 NB 肿瘤发生的一种可能机制。

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引用次数: 0

Targeting m7G-enriched circKDM1A prevents colorectal cancer progression 靶向富含 m7G 的 circKDM1A 可预防结直肠癌进展

IF 37.3 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cancer

Pub Date : 2024-08-30 DOI: 10.1186/s12943-024-02090-z

Zhenqiang Sun, Yanxin Xu, Chaohua Si, Xiaoke Wu, Yaxin Guo, Chen Chen, Chengzeng Wang

Plenty of circRNAs have been reported to play an important role in colorectal cancer (CRC), while the reason of abnormal circRNA expression in cancer still keep elusive. Here, we found that m7G RNA modifications were enriched in some circRNAs, these m7G modifications in circRNAs were catalyzed by METTL1, and the GG motif was the main site preference for m7G modifications in circRNAs. We further confirmed that METTL1 played a cancer-promoting role in CRC. We then screened a highly expressed circRNA, called circKDM1A, and found that METTL1 prevented the degradation of circKDM1A by m7G modification. CircKDM1A was further verified to promote proliferation, invasion and migration of CRC in vivo and in vitro. Its cancer-promoting ability was weakened after the m7G site mutation. CircKDM1A was verified to activate AKT pathway by upregulating PDK1, consequently promoting CRC progression. These results suggest that m7G-modified circRNA promotes CRC progression via activating AKT pathway. Our study uncovers an essential physiological function and mechanism of METTL1-mediated m7G modification in the regulation of circRNA stability and cancer progression.

有报道称，大量的circRNA在结直肠癌（CRC）中发挥着重要作用，而癌症中circRNA异常表达的原因却仍然扑朔迷离。在这里，我们发现m7G RNA修饰在一些circRNA中富集，这些circRNA中的m7G修饰由METTL1催化，而GG基序是circRNA中m7G修饰的主要偏好位点。我们进一步证实了 METTL1 在 CRC 中的促癌作用。随后，我们筛选了一种高表达的 circRNA（名为 circKDM1A），发现 METTL1 通过 m7G 修饰阻止了 circKDM1A 的降解。经进一步验证，circKDM1A能促进体内和体外CRC的增殖、侵袭和迁移。m7G位点突变后，其促癌能力减弱。经证实，CircKDM1A 可通过上调 PDK1 激活 AKT 通路，从而促进 CRC 的进展。这些结果表明，m7G修饰的circRNA通过激活AKT通路促进CRC的进展。我们的研究揭示了 METTL1 介导的 m7G 修饰在调控 circRNA 稳定性和癌症进展中的重要生理功能和机制。

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引用次数: 0

Writers, readers, and erasers RNA modifications and drug resistance in cancer 作家、读者和橡皮擦癌症中的 RNA 修饰和耐药性

IF 37.3 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cancer

Pub Date : 2024-08-30 DOI: 10.1186/s12943-024-02089-6

Di Chen, Xinyu Gu, Yeltai Nurzat, Lixia Xu, Xueyuan Li, Lixin Wu, Henan Jiao, Peng Gao, Xuqiang Zhu, Dongming Yan, Shaohua Li, Chen Xue

Drug resistance in cancer cells significantly diminishes treatment efficacy, leading to recurrence and metastasis. A critical factor contributing to this resistance is the epigenetic alteration of gene expression via RNA modifications, such as N6-methyladenosine (m6A), N1-methyladenosine (m1A), 5-methylcytosine (m5C), 7-methylguanosine (m7G), pseudouridine (Ψ), and adenosine-to-inosine (A-to-I) editing. These modifications are pivotal in regulating RNA splicing, translation, transport, degradation, and stability. Governed by “writers,” “readers,” and “erasers,” RNA modifications impact numerous biological processes and cancer progression, including cell proliferation, stemness, autophagy, invasion, and apoptosis. Aberrant RNA modifications can lead to drug resistance and adverse outcomes in various cancers. Thus, targeting RNA modification regulators offers a promising strategy for overcoming drug resistance and enhancing treatment efficacy. This review consolidates recent research on the role of prevalent RNA modifications in cancer drug resistance, with a focus on m6A, m1A, m5C, m7G, Ψ, and A-to-I editing. Additionally, it examines the regulatory mechanisms of RNA modifications linked to drug resistance in cancer and underscores the existing limitations in this field.

癌细胞的耐药性会大大降低治疗效果，导致复发和转移。导致耐药性的一个关键因素是通过 RNA 修饰（如 N6-甲基腺苷（m6A）、N1-甲基腺苷（m1A）、5-甲基胞嘧啶（m5C）、7-甲基鸟苷（m7G）、假尿苷（Ψ）和腺苷-肌苷（A-I）编辑）对基因表达进行表观遗传学改变。这些修饰在调节 RNA 剪接、翻译、运输、降解和稳定性方面起着关键作用。在 "书写者"、"阅读者 "和 "擦除者 "的控制下，RNA修饰影响着许多生物过程和癌症进展，包括细胞增殖、干性、自噬、侵袭和凋亡。异常的 RNA 修饰可导致各种癌症的耐药性和不良后果。因此，靶向 RNA 修饰调节因子为克服耐药性和提高疗效提供了一种前景广阔的策略。这篇综述综述了近期关于常见 RNA 修饰在癌症耐药性中的作用的研究，重点关注 m6A、m1A、m5C、m7G、Ψ 和 A 到 I 编辑。此外，它还探讨了与癌症耐药性相关的 RNA 修饰的调控机制，并强调了该领域现有的局限性。

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引用次数: 0

Assessment of SWI/SNF chromatin remodeling complex related genes as potential biomarkers and therapeutic targets in pan-cancer. 将 SWI/SNF 染色质重塑复合体相关基因评估为泛癌症的潜在生物标记物和治疗靶点。

IF 27.7 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cancer

Pub Date : 2024-08-27 DOI: 10.1186/s12943-024-02015-w

Kai Zhuang, Lishan Wang, Chengyu Lu, Zhiping Liu, Dongli Yang, Hao Zhong, Jiami Zou, Aamir Fahira, Jiaojiao Wang, Zunnan Huang

Recent research has uncovered a surprisingly high occurrence of aberrant expression and mutations in the genes that encode subunits of the SWI/SNF chromatin-remodeling complexes (SCRC). Nevertheless, the carcinogenic effects of aberrant expression and mutations in SWI/SNF genes have only been acknowledged in recent times, resulting in a comparatively limited understanding of these modifications. In this study, we comprehensively analyzed the expression difference, somatic mutation, potential biological pathways, stromal or immune cell infiltration, and drug sensitivity of SCRC-related genes (SCRGs) in pan-cancer. Furthermore, the evolutionary trend, prognostic signature, and immunotherapy response of SCRGs in kidney renal clear cell carcinoma (KIRC) were also evaluated. The expression of SCRGs was changed in 13 out of 14 tumor types, strongly linked to prognosis, and mutated in 30.9% of tumor patients. SCRGs were also closely associated with immune-related pathways and tumor metastasis pathways. The expression of SCRGs was positively associated with the immune score or stromal score but negatively correlated with Tumor purity. Three potential drugs (FK866, Ispinesib mesylate, and WZ3105) were identified to target the SCRGs. In KIRC, scRNA-seq analysis showed that the enrichment of SCRC and the communication frequency with immune cells were significantly declined during tumor cell progression. A prognostic signature was constructed in KIRC and was effective in predicting the prognosis for KIRC. Aberrant expression of eleven prognostic genes identified from the KIRC prognostic signature and the cytotoxicity of FK866 and Ispinesib mesylate to KIRC were verified by qRT-PCR and CCK-8 assay, respectively. Our study identified SCRGs as potential biomarker and therapeutic targets, providing new insights into SCRC for tumor-targeted therapy.

最近的研究发现，SWI/SNF 染色质重塑复合体（SCRC）亚基编码基因的异常表达和突变发生率之高令人惊讶。然而，SWI/SNF 基因的异常表达和突变的致癌效应直到近代才得到承认，因此人们对这些修饰的了解相对有限。在本研究中，我们全面分析了泛癌症中 SCRC 相关基因（SCRGs）的表达差异、体细胞突变、潜在生物学途径、基质或免疫细胞浸润以及药物敏感性。此外，研究还评估了肾透明细胞癌（KIRC）中SCRGs的演变趋势、预后特征和免疫治疗反应。在14种肿瘤类型中，有13种的SCRGs表达发生了变化，与预后密切相关，30.9%的肿瘤患者的SCRGs发生了突变。SCRGs还与免疫相关通路和肿瘤转移通路密切相关。SCRGs的表达与免疫评分或基质评分呈正相关，但与肿瘤纯度呈负相关。研究发现了三种针对 SCRGs 的潜在药物（FK866、甲磺酸伊斯平尼布和 WZ3105）。在 KIRC 中，scRNA-seq 分析表明 SCRC 的富集度和与免疫细胞的通讯频率在肿瘤细胞进展过程中显著下降。在KIRC中构建的预后特征能有效预测KIRC的预后。通过qRT-PCR和CCK-8检测分别验证了从KIRC预后特征中发现的11个预后基因的异常表达，以及FK866和甲磺酸伊斯平昔尼对KIRC的细胞毒性。我们的研究发现了SCRGs作为潜在的生物标记物和治疗靶点，为SCRC的肿瘤靶向治疗提供了新的见解。

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引用次数: 0

Epigenetic modification of ferroptosis by non-coding RNAs in cancer drug resistance. 非编码 RNA 在癌症耐药性中对铁突变的表观遗传修饰

IF 27.7 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cancer

Pub Date : 2024-08-27 DOI: 10.1186/s12943-024-02088-7

Hongquan Wang, Joshua S Fleishman, Sihang Cheng, Weixue Wang, Fan Wu, Yumin Wang, Yu Wang

The development of drug resistance remains a major challenge in cancer treatment. Ferroptosis, a unique type of regulated cell death, plays a pivotal role in inhibiting tumour growth, presenting new opportunities in treating chemotherapeutic resistance. Accumulating studies indicate that epigenetic modifications by non-coding RNAs (ncRNA) can determine cancer cell vulnerability to ferroptosis. In this review, we first summarize the role of chemotherapeutic resistance in cancer growth/development. Then, we summarize the core molecular mechanisms of ferroptosis, its upstream epigenetic regulation, and its downstream effects on chemotherapeutic resistance. Finally, we review recent advances in understanding how ncRNAs regulate ferroptosis and from such modulate chemotherapeutic resistance. This review aims to enhance general understanding of the ncRNA-mediated epigenetic regulatory mechanisms which modulate ferroptosis, highlighting the ncRNA-ferroptosis axis as a key druggable target in overcoming chemotherapeutic resistance.

耐药性的产生仍然是癌症治疗的一大挑战。铁突变是一种独特的调节性细胞死亡类型，在抑制肿瘤生长方面发挥着关键作用，为治疗化疗耐药性提供了新的机遇。越来越多的研究表明，非编码 RNA（ncRNA）的表观遗传修饰可决定癌细胞是否易受铁突变的影响。在这篇综述中，我们首先总结了化疗耐药性在癌症生长/发展中的作用。然后，我们总结了铁凋亡的核心分子机制、其上游表观遗传调控及其下游对化疗耐药性的影响。最后，我们回顾了在理解 ncRNA 如何调控铁凋亡以及由此调节化疗耐药性方面的最新进展。这篇综述旨在加深人们对 ncRNA 介导的表观遗传调控机制的总体认识，并强调 ncRNA-ferroptosis 轴是克服化疗耐药性的关键药物靶点。

引用次数: 0

Reshaping the tumor immune microenvironment to improve CAR-T cell-based cancer immunotherapy. 重塑肿瘤免疫微环境，改善基于 CAR-T 细胞的癌症免疫疗法。

IF 27.7 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cancer

Pub Date : 2024-08-26 DOI: 10.1186/s12943-024-02079-8

Xueting Xia, Zongxin Yang, Qisi Lu, Zhenyun Liu, Lei Wang, Jinwen Du, Yuhua Li, Dong-Hua Yang, Shaojie Wu

In many hematologic malignancies, the adoptive transfer of chimeric antigen receptor (CAR) T cells has demonstrated notable success; nevertheless, further improvements are necessary to optimize treatment efficacy. Current CAR-T therapies are particularly discouraging for solid tumor treatment. The immunosuppressive microenvironment of tumors affects CAR-T cells, limiting the treatment's effectiveness and safety. Therefore, enhancing CAR-T cell infiltration capacity and resolving the immunosuppressive responses within the tumor microenvironment could boost the anti-tumor effect. Specific strategies include structurally altering CAR-T cells combined with targeted therapy, radiotherapy, or chemotherapy. Overall, monitoring the tumor microenvironment and the status of CAR-T cells is beneficial in further investigating the viability of such strategies and advancing CAR-T cell therapy.

在许多血液系统恶性肿瘤中，嵌合抗原受体（CAR）T 细胞的采用性转移已经取得了显著的成功；然而，要优化治疗效果，还需要进一步的改进。目前的 CAR-T 疗法在实体瘤治疗方面尤其令人沮丧。肿瘤的免疫抑制微环境会影响 CAR-T 细胞，从而限制治疗的有效性和安全性。因此，提高 CAR-T 细胞的浸润能力，解决肿瘤微环境中的免疫抑制反应，可以增强抗肿瘤效果。具体策略包括改变 CAR-T 细胞的结构，并结合靶向治疗、放疗或化疗。总之，监测肿瘤微环境和CAR-T细胞的状态有利于进一步研究这些策略的可行性和推进CAR-T细胞疗法。

引用次数: 0

Induction of circulating ABCB1 transcripts under platinum-based chemotherapy indicates poor prognosis and a bone micrometastatic phenotype in ovarian cancer patients 铂类化疗诱导循环 ABCB1 转录物表明卵巢癌患者预后不佳并具有骨微小转移表型

IF 37.3 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cancer

Pub Date : 2024-08-23 DOI: 10.1186/s12943-024-02087-8

Franziska Maria Schwarz, Jan Dominik Kuhlmann, Jorrin Kämpfer, Anna Klimova, Daniel Martin Klotz, Lisa Freitag, Pia Herrmann, Viktoria Zinnow, Janice Smith, Theresia Scheller, Wolfgang Walther, Pauline Wimberger, Ulrike Stein

The drug efflux transporter P-glycoprotein, encoded by the ABCB1 gene, promotes acquired chemoresistance. We explored the presence and clinical relevance of circulating cell-free ABCB1 transcripts (cfABCB1tx) in ovarian cancer patients (173 longitudinal serum samples from 79 cancer patients) using digital droplet PCR. cfABCB1tx were readily detectable at primary diagnosis (median 354 mRNA copies/20 µl serum), paralleled FIGO-stage and predicted surgical outcome (p = 0.023, p=0.022, respectively). Increased cfABCB1tx levels at primary diagnosis indicated poor PFS (HR = 2.329, 95%CI:1.374–3.947, p = 0.0017) and OS (HR = 2.074, 95%CI:1.194–3.601, p = 0.0096). cfABCB1tx induction under platinum-based chemotherapy was an independent predictor for poor OS (HR = 2.597, 95%CI: 1.218–5.538, p = 0.013) and paralelled a micrometastatic phenotype, shaped by the presence of disseminated tumor cells in the bone marrow. A strong correlation was observed between cfABCB1tx and circulating transcripts of the metastasis-inducer MACC1, which is the transcriptional activator of ABCB1. Combined assessment of cfABCB1tx and circulating cell-free MACC1 transcripts (cfMACC1tx) resulted in an improved prognostic prediction, with the cfABCB1tx-high/cfMACC1tx-high phenotype bearing the highest risk for relapse and death. Conclusively, we provide proof of principle, that ABCB1 transcripts are readily traceable in the liquid-biopsy of ovarian cancer patients, advancing a new dimension for systemic monitoring of ABCB1/P-glycoprotein expression dynamics.

由 ABCB1 基因编码的药物外排转运体 P 糖蛋白会促进获得性化疗耐药性。我们使用数字液滴 PCR 技术探讨了卵巢癌患者（来自 79 名癌症患者的 173 份纵向血清样本）体内循环游离细胞 ABCB1 转录物（cfABCB1tx）的存在及其临床意义。cfABCB1tx 在初诊时很容易检测到（中位数为 354 mRNA 拷贝/20 µl 血清），与 FIGO 分期和手术预后相关（分别为 p = 0.023 和 p=0.022）。初诊时 cfABCB1tx 水平升高表明 PFS（HR = 2.329，95%CI:1.374-3.947，p = 0.0017）和 OS（HR = 2.074，95%CI:1.194-3.601，p = 0.0096）较差。铂类化疗诱导的cfABCB1tx是不良OS的独立预测因子（HR = 2.597，95%CI：1.218-5.538，p = 0.013），并通过骨髓中存在播散的肿瘤细胞形成微转移表型。在 cfABCB1tx 和转移诱导剂 MACC1（ABCB1 的转录激活剂）的循环转录物之间观察到了很强的相关性。联合评估 cfABCB1tx 和循环细胞游离 MACC1 转录物（cfMACC1tx）可改善预后预测，cfABCB1tx-高/cfMACC1tx-高的表型具有最高的复发和死亡风险。最后，我们证明了卵巢癌患者的液体活检中很容易追踪到 ABCB1 转录物，为系统监测 ABCB1/P 糖蛋白表达动态提供了一个新的维度。

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引用次数: 0

The molecular conversations of sarcomas: exosomal non-coding RNAs in tumor’s biology and their translational prospects 肉瘤的分子对话：肿瘤生物学中的外泌体非编码 RNA 及其转化前景

IF 37.3 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cancer

Pub Date : 2024-08-22 DOI: 10.1186/s12943-024-02083-y

Margherita Luongo, Pasqualina Laurenziello, Giuseppe Cesta, Anna Maria Bochicchio, Ludmila Carmen Omer, Geppino Falco, Maria Rita Milone, Francesca Cibarelli, Sabino Russi, Simona Laurino

Exosomes mediate cell-to-cell crosstalk involving a variety of biomolecules through an intricate signaling network. In recent years, the pivotal role of exosomes and their non-coding RNAs cargo in the development and progression of several cancer types clearly emerged. In particular, tumor bulk and its microenvironment co-evolve through cellular communications where these nanosized extracellular vesicles are among the most relevant actors. Knowledge about the cellular, and molecular mechanisms involved in these communications will pave the way for novel exosome-based delivery of therapeutic RNAs as well as innovative prognostic/diagnostic tools. Despite the valuable therapeutic potential and clinical relevance of exosomes, their role on sarcoma has been vaguely reported because the rarity and high heterogeneity of this type of cancer. Here, we dissected the scientific literature to unravel the multifaceted role of exosomal non-coding RNAs as mediator of cell-to-cell communications in the sarcoma subtypes.

外泌体通过错综复杂的信号网络介导细胞间的串联，其中涉及多种生物分子。近年来，外泌体及其所携带的非编码 RNAs 在几种癌症类型的发生和发展过程中的关键作用已清楚地显现出来。特别是，肿瘤体积及其微环境通过细胞通讯共同演化，而这些纳米级细胞外囊泡是其中最重要的参与者。了解这些沟通所涉及的细胞和分子机制将为基于外泌体的新型治疗 RNA 递送以及创新预后/诊断工具铺平道路。尽管外泌体具有宝贵的治疗潜力和临床相关性，但由于肉瘤的罕见性和高度异质性，其在肉瘤中的作用一直鲜有报道。在此，我们对科学文献进行了剖析，以揭示外泌体非编码RNA作为细胞间通讯介质在肉瘤亚型中的多方面作用。

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引用次数: 0