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Recent updates on allogeneic CAR-T cells in hematological malignancies. 血液恶性肿瘤中异体 CAR-T 细胞的最新进展。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-09-03 DOI: 10.1186/s12935-024-03479-y
Shafieeh Mansoori, Ahmad Noei, Amirhosein Maali, Seyedeh Sheila Seyed-Motahari, Zahra Sharifzadeh

CAR-T cell therapy is known as an effective therapy in patients with hematological malignancies. Since 2017, several autologous CAR-T cell (auto-CAR-T) drugs have been approved by the US Food and Drug Administration (FDA) for the treatment of some kinds of relapsed/refractory hematological malignancies. However, some patients fail to respond to these drugs due to high manufacturing time, batch-to-batch variation, poor quality and insufficient quantity of primary T cells, and their insufficient expansion and function. CAR-T cells prepared from allogeneic sources (allo-CAR-Ts) can be an alternative option to overcome these obstacles. Recently, several allo-CAR-Ts have entered into the early clinical trials. Despite their promising preclinical and clinical results, there are two main barriers, including graft-versus-host disease (GvHD) and allo-rejection that may decline the safety and efficacy of allo-CAR-Ts in the clinic. The successful development of these products depends on the starter cell source, the gene editing method, and the ability to escape immune rejection and prevent GvHD. Here, we summarize the gene editing technologies and the potential of various cell sources for developing allo-CAR-Ts and highlight their advantages for the treatment of hematological malignancies. We also describe preclinical and clinical data focusing on allo-CAR-T therapy in blood malignancies and discuss challenges and future perspectives of allo-CAR-Ts for therapeutic applications.

众所周知,CAR-T细胞疗法是血液恶性肿瘤患者的一种有效疗法。自2017年以来,美国食品和药物管理局(FDA)已批准多种自体CAR-T细胞(auto-CAR-T)药物用于治疗某些复发/难治性血液恶性肿瘤。然而,由于生产时间长、批次间差异大、原代T细胞质量差、数量不足、扩增和功能不全等原因,一些患者对这些药物没有反应。异体制备的CAR-T细胞(allo-CAR-Ts)是克服这些障碍的另一种选择。最近,几种异体 CAR-T 细胞已进入早期临床试验阶段。尽管其临床前和临床结果令人鼓舞,但仍存在两个主要障碍,包括移植物抗宿主病(GvHD)和同种异体排斥反应,这可能会降低allo-CAR-Ts在临床上的安全性和有效性。这些产品的成功开发取决于起始细胞来源、基因编辑方法以及逃避免疫排斥和预防GvHD的能力。在此,我们总结了基因编辑技术和各种细胞来源在开发allo-CAR-Ts方面的潜力,并强调了它们在治疗血液恶性肿瘤方面的优势。我们还描述了allo-CAR-T治疗血液恶性肿瘤的临床前和临床数据,并讨论了allo-CAR-T在治疗应用中面临的挑战和未来前景。
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引用次数: 0
Curcumin blunts epithelial-mesenchymal transition to alleviate invasion and metastasis of prostate cancer through the JARID1D demethylation. 姜黄素通过JARID1D去甲基化作用减缓上皮-间质转化,从而减轻前列腺癌的侵袭和转移。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-09-01 DOI: 10.1186/s12935-024-03483-2
Qinghua Xie, Yaohua Hu, Chenyang Zhang, Caiqin Zhang, Jing Qin, Yong Zhao, Qingling An, Jie Zheng, Changhong Shi

Prostate cancer (PCa) is one of the most common and prevalent cancers in men worldwide. The majority of PCa-related deaths result from metastasis rather than primary tumors. Several studies have focused on the relationship between male-specific genes encoded on the Y chromosome and PCa metastasis; however, the relationship between the male specific protein encoded on the Y chromosome and tumor suppression has not been fully clarified. Here, we report a male specific protein of this type, the histone H3 lysine 4 (H3K4) demethylase JARID1D, which has the ability to inhibit the gene expression program related to cell invasion, and can thus form a phenotype that inhibits the invasion of PCa cells. However, JARID1D exhibits low expression level in advanced PCa, and which is related to rapid invasion and metastasis in patients with PCa. Curcumin, as a multi-target drug, can enhance the expression and demethylation activity of JARID1D, affect the androgen receptor (AR) and epithelial-mesenchymal transition (EMT) signaling cascade, and inhibit the metastatic potential of castration resistant cancer (CRPC). These findings suggest that using curcumin to increase the expression and demethylation activity of JARID1D may be a feasible strategy to inhibit PCa metastasis by regulating EMT and AR.

前列腺癌(PCa)是全球最常见、最普遍的男性癌症之一。大多数与 PCa 相关的死亡病例都是死于转移而非原发肿瘤。一些研究关注 Y 染色体上编码的男性特异性基因与 PCa 转移之间的关系;然而,Y 染色体上编码的男性特异性蛋白与肿瘤抑制之间的关系尚未完全阐明。在这里,我们报告了一种男性特异性蛋白--组蛋白 H3 赖氨酸 4(H3K4)去甲基化酶 JARID1D,它具有抑制与细胞侵袭相关的基因表达程序的能力,因此可以形成抑制 PCa 细胞侵袭的表型。然而,JARID1D在晚期PCa中的表达水平较低,这与PCa患者的快速侵袭和转移有关。姜黄素作为一种多靶点药物,可以提高JARID1D的表达和去甲基化活性,影响雄激素受体(AR)和上皮-间质转化(EMT)信号级联,抑制阉割耐药癌(CRPC)的转移潜力。这些研究结果表明,利用姜黄素增加JARID1D的表达和去甲基化活性可能是通过调节EMT和AR来抑制PCa转移的一种可行策略。
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引用次数: 0
The sEVs miR-487a/Notch2/GATA3 axis promotes osteosarcoma lung metastasis by inducing macrophage polarization toward the M2-subtype. sEVs miR-487a/Notch2/GATA3轴通过诱导巨噬细胞向M2亚型极化促进骨肉瘤肺转移。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-31 DOI: 10.1186/s12935-024-03488-x
Piaopiao Wang, Lei Yang, Jing Dong, Wenjing Liu, Fan Xie, Yan Lu, Wenyan Li

Small extracellular vesicles (sEVs) are important mediators of intercellular communication between tumor cells and their surrounding environment. Furthermore, the mechanisms by which miRNAs carried in tumor sEVs regulate macrophage polarization remain largely unknown. To concentrate sEVs, we used the traditional ultracentrifugation method. Western blot, NanoSight, and transmission electron microscopy were used to identify sEVs. To determine the function of sEVs-miR-487a, we conducted in vivo and in vitro investigations. The intercellular communication mechanism between osteosarcoma cells and M2 macrophages, mediated by sEVs carrying miR-487a, was validated using luciferase reporter assays, transwell assays, and Western blot analysis. In vitro, sEVs enriched in miR-487a and delivered miR-487a to macrophages, promoting macrophage polarization toward an M2-like type, which promotes proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of osteosarcoma cells. In vivo, sEVs enriched in miR-487a facilitate lung metastasis of osteosarcoma. Moreover, plasma miR-487a in sEVs was shown to be a potential biomarker applicable for osteosarcoma diagnosis. In summary, miR-487a derived from osteosarcoma cells can be transferred to macrophages via sEVs, then promote macrophage polarization towards an M2-like type by targeting Notch2 and activating the GATA3 pathway. In a feedback loop, the activation of macrophages accelerates epithelial-mesenchymal transition (EMT), which in turn promotes the migration, invasion, and lung metastasis of osteosarcoma cells. This reciprocal interaction between activated macrophages and osteosarcoma cells contributes to the progression of the disease. Our data demonstrate a new mechanism that osteosarcoma tumor cells derived exosomal-miR-487a which is involved in osteosarcoma development by regulating macrophage polarization in tumor microenvironment (TME).

细胞外小泡(sEVs)是肿瘤细胞与其周围环境进行细胞间交流的重要媒介。此外,肿瘤 sEVs 中携带的 miRNA 调节巨噬细胞极化的机制在很大程度上仍然未知。为了浓缩 sEVs,我们采用了传统的超速离心法。我们使用 Western 印迹、NanoSight 和透射电子显微镜来鉴定 sEVs。为了确定 sEVs-miR-487a 的功能,我们进行了体内和体外研究。利用荧光素酶报告实验、透孔实验和 Western 印迹分析验证了携带 miR-487a 的 sEVs 介导的骨肉瘤细胞与 M2 巨噬细胞之间的细胞间通信机制。在体外,sEV富含miR-487a并将miR-487a传递给巨噬细胞,促进巨噬细胞向M2样类型极化,从而促进骨肉瘤细胞的增殖、迁移、侵袭和上皮-间质转化(EMT)。在体内,富含 miR-487a 的 sEVs 会促进骨肉瘤的肺转移。此外,sEVs 中的血浆 miR-487a 被证明是一种潜在的生物标记物,可用于骨肉瘤诊断。综上所述,来自骨肉瘤细胞的miR-487a可通过sEVs转移到巨噬细胞,然后通过靶向Notch2和激活GATA3通路促进巨噬细胞向M2样类型极化。在一个反馈回路中,巨噬细胞的活化会加速上皮-间质转化(EMT),进而促进骨肉瘤细胞的迁移、侵袭和肺转移。活化的巨噬细胞与骨肉瘤细胞之间的这种相互影响有助于疾病的进展。我们的数据证明了一种新的机制,即骨肉瘤肿瘤细胞衍生出的外泌体-miR-487a通过调节肿瘤微环境(TME)中巨噬细胞的极化参与骨肉瘤的发展。
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引用次数: 0
Locoregional therapies combined with immune checkpoint inhibitors for liver metastases. 局部疗法联合免疫检查点抑制剂治疗肝转移。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-31 DOI: 10.1186/s12935-024-03484-1
Xing-Chen Zhang, Yu-Wen Zhou, Gui-Xia Wei, Yi-Qiao Luo, Meng Qiu

Immune checkpoint inhibitors (ICIs) have achieved remarkable success in clinical research and practice. Notably, liver metastasis is not sensitive to ICIs. Liver locoregional therapies can cause irreversible damage to tumor cells and release tumor antigens, thereby providing a rationale for immunotherapy treatments in liver metastasis. The combination therapy of ICIs with locoregional therapies is a promising option for patients with liver metastasis. Preclinical studies have demonstrated that combining ICIs with locoregional therapies produces a significantly synergistic anti-tumor effect. However, the current evidence for the efficacy of ICIs combined with locoregional therapies remains insufficient. Therefore, we review the literature on the mechanisms of locoregional therapies in treating liver metastasis and the clinical research progress of their combination with ICIs.

免疫检查点抑制剂(ICIs)在临床研究和实践中取得了令人瞩目的成就。值得注意的是,肝转移对 ICIs 并不敏感。肝脏局部治疗可对肿瘤细胞造成不可逆损伤并释放肿瘤抗原,从而为肝转移的免疫治疗提供了理论依据。ICIs 与局部治疗的联合疗法是肝转移患者的一个很有前景的选择。临床前研究表明,将 ICIs 与局部治疗相结合可产生显著的协同抗肿瘤效果。然而,目前有关 ICIs 与局部治疗相结合的疗效证据仍然不足。因此,我们回顾了有关局部区域疗法治疗肝转移的机制及其与 ICIs 联用的临床研究进展的文献。
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引用次数: 0
Capsaicin combined with cisplatin inhibits TGF-β1-induced EMT and TSCC cells migration via the Claudin-1/PI3K/AKT/mTOR signaling pathway. 辣椒素联合顺铂可通过Claudin-1/PI3K/AKT/mTOR信号通路抑制TGF-β1诱导的EMT和TSCC细胞迁移。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-28 DOI: 10.1186/s12935-024-03485-0
Zhuang Li, Qiwei Zhao, Xiayang Liu, Xinyue Zhou, Yu Wang, Min Zhao, Fenghua Wu, Gang Zhao, Xiaohong Guo

Tongue squamous cell carcinoma (TSCC) is one of the most common malignant tumors among oral cancers, and its treatment is based on radio-chemotherapy and surgery, which always produces more serious side effects and sequelae. Traditional medicine can compensate for the shortcomings of modern medical treatments and play a better therapeutic role. Currently, active ingredients derived from plants are attracting the attention of researchers and clinical professionals. We examined capsaicin (CAP), an active ingredient isolated from Capsicum annuum (family Solanaceae), and explored the effect of CAP combined with cisplatin (DDP) on epithelial-mesenchymal transition (EMT) and TSCC cells migration. Our results demonstrated that Transforming growth factor-β1(TGF-β1) induced EMT and promoted cell migration in TSCC cells. CAP combined with DDP inhibits non-TGF-β1-induced or TGF-β1-induced EMT and migration. Mechanistically, the inhibition of non-TGF-β1-induced EMT and migration by CAP combined with DDP was mediated by the AMPK/mTOR pathway, whereas TGF-β1-induced EMT and migration were regulated by the Claudin-1/PI3K/AKT/mTOR pathway. A nude lung metastasis mouse model was established for in vivo validation. These results support our hypothesis that the combination of CAP and DDP inhibits TSCC metastasis. These data set the stage for further studies aimed at validating CAP as an effective active ingredient for enhancing chemotherapy efficacy and reducing the dosage and toxicity of chemotherapeutic drugs, ultimately paving the way for translational research and clinical trials for TSCC eradication.

舌鳞状细胞癌(TSCC)是口腔癌中最常见的恶性肿瘤之一,其治疗方法以放射化疗和手术为主,但总是会产生较严重的副作用和后遗症。传统医学可以弥补现代医学治疗的不足,发挥更好的治疗作用。目前,从植物中提取的活性成分正受到研究人员和临床专业人员的关注。我们研究了从茄科植物辣椒(Capsicum annuum)中分离出的有效成分辣椒素(CAP),并探讨了 CAP 与顺铂(DDP)联合使用对上皮细胞-间质转化(EMT)和 TSCC 细胞迁移的影响。结果表明,转化生长因子-β1(TGF-β1)可诱导上皮-间质转化并促进 TSCC 细胞迁移。CAP 联合 DDP 可抑制非 TGF-β1 诱导或 TGF-β1 诱导的 EMT 和迁移。从机理上讲,CAP联合DDP抑制非TGF-β1诱导的EMT和迁移是由AMPK/mTOR途径介导的,而TGF-β1诱导的EMT和迁移是由Claudin-1/PI3K/AKT/mTOR途径调控的。我们建立了一个裸肺转移小鼠模型进行体内验证。这些结果支持了我们的假设,即 CAP 和 DDP 联合使用可抑制 TSCC 转移。这些数据为进一步的研究奠定了基础,这些研究旨在验证 CAP 是一种有效的活性成分,可增强化疗效果并减少化疗药物的剂量和毒性,最终为根除 TSCC 的转化研究和临床试验铺平道路。
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引用次数: 0
Complicated role of ALKBH5 in gastrointestinal cancer: an updated review. ALKBH5 在胃肠癌中的复杂作用:最新综述。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-24 DOI: 10.1186/s12935-024-03480-5
Weitong Shu, Qianying Huang, Rui Chen, Huatao Lan, Luxin Yu, Kai Cui, Wanjun He, Songshan Zhu, Mei Chen, Li Li, Dan Jiang, Guangxian Xu

Gastrointestinal cancer is the most common malignancy in humans, often accompanied by poor prognosis. N6-methyladenosine (m6A) modification is widely present in eukaryotic cells as the most abundant RNA modification. It plays a crucial role in RNA splicing and processing, nuclear export, translation, and stability. Human AlkB homolog 5 (ALKBH5) is a type of RNA demethylase exhibiting abnormal expression in various gastrointestinal cancers.It is closely related to the tumorigenesis, proliferation, migration, and other biological functions of gastrointestinal cancer. However, recent studies indicated that the role and mechanism of ALKBH5 in gastrointestinal cancer are complicated and even controversial. Thus, this review summarizes recent advances in elucidating the role of ALKBH5 as a tumor suppressor or promoter in gastrointestinal cancer. It examines the biological functions of ALKBH5 and its potential as a therapeutic target, providing new perspectives and insights for gastrointestinal cancer research.

胃肠癌是人类最常见的恶性肿瘤,通常预后不良。N6-甲基腺苷(m6A)修饰作为最丰富的 RNA 修饰广泛存在于真核细胞中。它在 RNA 剪接和加工、核输出、翻译和稳定性方面起着至关重要的作用。人类 AlkB 同源物 5(ALKBH5)是一种 RNA 去甲基化酶,在多种胃肠道癌症中表现出异常表达,与胃肠道癌症的肿瘤发生、增殖、迁移等生物学功能密切相关。然而,近年来的研究表明,ALKBH5 在胃肠癌中的作用和机制十分复杂,甚至存在争议。因此,本综述总结了阐明 ALKBH5 在胃肠癌中作为肿瘤抑制因子或促进因子的作用的最新进展。它探讨了 ALKBH5 的生物学功能及其作为治疗靶点的潜力,为胃肠癌研究提供了新的视角和见解。
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引用次数: 0
Characterization of the stem cell landscape and identification of a stemness-associated prognostic signature in bladder cancer. 膀胱癌干细胞图谱的特征和干细胞相关预后特征的鉴定。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-24 DOI: 10.1186/s12935-024-03465-4
Gaoteng Lin, Jiamei Lin, Hao Wang, Liucheng Wang, Fangfang Zhan, Liqian Wu, Liang Xue, Yang Dong, Wanqing Wei, Lin Liu

It is accepted that cancer stem cells (CSCs) are key to the occurrence, progression, drug resistance, and recurrence of bladder cancer (BLCA). Here, we aimed to characterize the landscapes of CSCs and investigate the biological and clinical signatures based on a prognostic model constructed by genes associated with CSCs. The malignant epithelial cells were discovered and sorted into six clusters through single cell analysis. C2 was identified as the CSCs. The signaling involved in the interactions between C2, cancer-associated fibroblasts (CAFs), and immune cells mainly consisted of MK, THBS, ANGPTL, VISFATIN, JAM, and ncWNT pathways. The CSC-like prognostic index (CSCLPI) constructed by the random survival forest was a reliable risk factor for BLCA and had a stable and powerful effect on predicting the overall survival of patients with BLCA. The level of CAFs was higher among patients with higher CSCLPI scores, suggesting that CAFs play a significant role in regulating biological characteristics. The CSCLPI-developed survival prediction nomogram has the potential to be applied clinically to predict the 1-, 2-, 3-, and 5-year overall survival of patients with BLCA. The CSCLPI can be used for prognostic prediction and drug treatment evaluation in the clinic.

癌症干细胞(CSCs)是膀胱癌(BLCA)发生、发展、耐药和复发的关键,这一点已得到公认。在此,我们旨在描述癌干细胞的分布,并根据与癌干细胞相关的基因构建的预后模型研究其生物学和临床特征。我们发现了恶性上皮细胞,并通过单细胞分析将其分为六个集群。C2被确定为CSCs。C2、癌相关成纤维细胞(CAF)和免疫细胞之间的信号转导主要包括MK、THBS、ANGPTL、VISFATIN、JAM和ncWNT通路。随机生存森林构建的类干细胞预后指数(CSCLPI)是BLCA的可靠危险因素,对预测BLCA患者的总生存期具有稳定而强大的作用。在CSCLPI得分较高的患者中,CAFs的水平较高,这表明CAFs在调控生物学特征方面发挥着重要作用。CSCLPI开发的生存预测提名图有望应用于临床,预测BLCA患者的1年、2年、3年和5年总生存率。CSCLPI 可用于临床预后预测和药物治疗评估。
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引用次数: 0
Prognostic and immunological implications of heterogeneous cell death patterns in prostate cancer. 前列腺癌异质性细胞死亡模式的预后和免疫学意义。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-24 DOI: 10.1186/s12935-024-03462-7
Ming Wang, Bangshun Dai, Qiushi Liu, Xiansheng Zhang

Background: Prostate cancer is one of the most common cancers in men with a significant proportion of patients developing biochemical recurrence (BCR) after treatment. Programmed cell death (PCD) mechanisms are known to play critical roles in tumor progression and can potentially serve as prognostic and therapeutic biomarkers in PCa. This study aimed to develop a prognostic signature for BCR in PCa using PCD-related genes.

Materials and methods: We conducted an analysis of 19 different modes of PCD to develop a comprehensive model. Bulk transcriptomic, single-cell transcriptomic, genomic, and clinical data were collected from multiple cohorts, including TCGA-PRAD, GSE58812, METABRIC, GSE21653, and GSE193337. We analyzed the expression and mutations of the 19 PCD modes and constructed, evaluated, and validated the model.

Results: Ten PCD modes were found to be associated with BCR in PCa, with specific PCD patterns exhibited by various cell components within the tumor microenvironment. Through Lasso Cox regression analysis, we established a Programmed Cell Death Index (PCDI) utilizing an 11-gene signature. High PCDI values were validated in five independent datasets and were found to be associated with an increased risk of BCR in PCa patients. Notably, older age and advanced T and N staging were associated with higher PCDI values. By combining PCDI with T staging, we constructed a nomogram with enhanced predictive performance. Additionally, high PCDI values were significantly correlated with decreased drug sensitivity, including drugs such as Docetaxel and Methotrexate. Patients with lower PCDI values demonstrated higher immunophenoscores (IPS), suggesting a potentially higher response rate to immune therapy. Furthermore, PCDI was associated with immune checkpoint genes and key components of the tumor microenvironment, including macrophages, T cells, and NK cells. Finally, clinical specimens validated the differential expression of PCDI-related PCDRGs at both the gene and protein levels.

Conclusion: In conclusion, we developed a novel PCD-based prognostic feature that successfully predicted BCR in PCa patients and provided insights into drug sensitivity and potential response to immune therapy. These findings have significant clinical implications for the treatment of PCa.

背景:前列腺癌是男性最常见的癌症之一,相当一部分患者在治疗后会出现生化复发(BCR)。众所周知,程序性细胞死亡(PCD)机制在肿瘤进展中起着关键作用,有可能成为 PCa 的预后和治疗生物标志物。本研究旨在利用 PCD 相关基因建立 PCa BCR 的预后特征:我们对 19 种不同的 PCD 模式进行了分析,以建立一个综合模型。我们从TCGA-PRAD、GSE58812、METABRIC、GSE21653和GSE193337等多个队列中收集了大量转录组、单细胞转录组、基因组和临床数据。我们分析了19种PCD模式的表达和突变,并构建、评估和验证了该模型:结果:发现10种PCD模式与PCa中的BCR相关,肿瘤微环境中的各种细胞成分表现出特定的PCD模式。通过Lasso Cox回归分析,我们利用11个基因特征建立了程序性细胞死亡指数(PCDI)。高 PCDI 值在五个独立数据集中得到了验证,发现它与 PCa 患者 BCR 风险的增加有关。值得注意的是,年龄较大、T 和 N 分期较晚与 PCDI 值较高有关。通过将 PCDI 与 T 分期相结合,我们构建了一个具有更强预测能力的提名图。此外,高 PCDI 值与药物敏感性下降(包括多西他赛和甲氨蝶呤等药物)显著相关。PCDI 值较低的患者免疫评分(IPS)较高,表明其对免疫疗法的反应率可能较高。此外,PCDI 还与免疫检查点基因和肿瘤微环境的关键成分有关,包括巨噬细胞、T 细胞和 NK 细胞。最后,临床标本验证了 PCDI 相关 PCDRGs 在基因和蛋白质水平上的差异表达:总之,我们开发出了一种基于 PCD 的新型预后特征,它能成功预测 PCa 患者的 BCR,并能深入了解药物敏感性和对免疫疗法的潜在反应。这些发现对 PCa 的治疗具有重要的临床意义。
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引用次数: 0
Extracellular vesicle-bound VEGF in oral squamous cell carcinoma and its role in resistance to Bevacizumab Therapy. 口腔鳞状细胞癌中与细胞外囊泡结合的血管内皮生长因子及其在贝伐珠单抗疗法耐药性中的作用。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-23 DOI: 10.1186/s12935-024-03476-1
Jiasheng Zhou, Xue Liu, Qi Dong, Jiao Li, Weidong Niu, Tingjiao Liu

Background: Vascular endothelial growth factor (VEGF) is an important proangiogenic factor and has been considered as a key target of antiangiogenetic therapy in oral squamous cell carcinoma (OSCC). However, clinical application of bevacizumab, a specific VEGF antibody, didn't improve the survival rate of OSCC patients. One possible explanation is that VEGF gene expresses diverse isoforms, which associate with extracellular vesicles (EVs), and EVs potentially contribute to VEGF resistance to bevacizumab. However, clear solution is lacking in addressing this issue.

Methods: Expression of VEGF isoforms in OSCC cells was confirmed by reverse transcription and polymerase chain reaction (RT-PCR) and western blot. EVs isolated from OSCC cell's conditioned medium (CM) were characterized by western blot, transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Flow cytometry, immunogold labeling and western blot were applied to study the VEGF on EVs. Tube formation assay and Matrigel plug angiogenesis assay were used for analyzing the angiogenesis capacity of EV-VEGF.

Results: The most popular isoforms expressed by VEGF gene are VEGF121, VEGF165 and VEGF189. In this study, we demonstrated that all three isoforms of mRNA could be detected at varying levels in OSCC cells, while only VEGF165 and VEGF189 proteins were found. CM derived from OSCC cells, both soluble and non-soluble forms of VEGF could be detected. We further confirmed the presence of VGEF189 bound to EVs as a non-soluble form. EV-bound VEGF189 presented angiogenic activity, which could not be neutralized by bevacizumab. It was found that VEGF189 bound to EVs by heparan sulfate proteoglycans (HSPG). In addition, the angiogenic effect of EV-VEGF could be reversed by surfen, a kind of HSPG antagonist both in vitro and in vivo.

Conclusion: Antagonists targeting HSPG might potentially overcome the resistance of EV-VEGF to bevacizumab and serve as an alternative for anti-VEGF therapy in OSCC.

背景:血管内皮生长因子(VEGF)是一种重要的促血管生成因子,一直被认为是口腔鳞状细胞癌(OSCC)抗血管生成治疗的关键靶点。然而,贝伐单抗(一种特异性血管内皮生长因子抗体)的临床应用并没有提高 OSCC 患者的生存率。一种可能的解释是血管内皮生长因子(VEGF)基因表达不同的异构体,这些异构体与细胞外囊泡(EVs)相关联,而EVs可能导致血管内皮生长因子对贝伐单抗产生耐药性。然而,在解决这一问题方面还缺乏明确的方案:方法:通过反转录聚合酶链式反应(RT-PCR)和免疫印迹证实了VEGF同工酶在OSCC细胞中的表达。从 OSCC 细胞的条件培养基(CM)中分离出的 EVs 通过 Western 印迹、透射电子显微镜(TEM)和纳米粒子追踪分析(NTA)进行表征。应用流式细胞术、免疫金标记和 Western 印迹法研究了 EVs 上的 VEGF。结果表明,EV-VEGF表达的最多的异构体是EV-VEGF,而EV-VEGF表达的最多的异构体是EV-VEGF:结果:VEGF 基因最常表达的同工型是 VEGF121、VEGF165 和 VEGF189。本研究表明,在 OSCC 细胞中可检测到不同水平的三种同工酶 mRNA,但只发现了 VEGF165 和 VEGF189 蛋白。从 OSCC 细胞中提取的 CM 可以检测到可溶性和非可溶性形式的 VEGF。我们进一步证实,与 EV 结合的 VGEF189 以非可溶性形式存在。与 EV 结合的 VEGF189 具有血管生成活性,贝伐珠单抗无法中和这种活性。研究发现,VEGF189 是通过硫酸肝素蛋白多糖(HSPG)与 EV 结合的。此外,一种 HSPG 拮抗剂 surfen 可以在体外和体内逆转 EV-VEGF 的血管生成效应:结论:靶向 HSPG 的拮抗剂有可能克服 EV-VEGF 对贝伐单抗的耐药性,成为 OSCC 抗血管内皮生长因子疗法的替代疗法。
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引用次数: 0
Lipid metabolism associated crosstalk: the bidirectional interaction between cancer cells and immune/stromal cells within the tumor microenvironment for prognostic insight. 与脂质代谢相关的串扰:肿瘤微环境中癌细胞与免疫/基质细胞之间的双向互动,有助于洞察预后。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-22 DOI: 10.1186/s12935-024-03481-4
Zhongshu Lin, Guanxiang Hua, Xiaojuan Hu

Cancer is closely related to lipid metabolism, with the tumor microenvironment (TME) containing numerous lipid metabolic interactions. Cancer cells can bidirectionally interact with immune and stromal cells, the major components of the TME. This interaction is primarily mediated by fatty acids (FAs), cholesterol, and phospholipids. These interactions can lead to various physiological changes, including immune suppression, cancer cell proliferation, dissemination, and anti-apoptotic effects on cancer cells. The physiological modulation resulting from this lipid metabolism-associated crosstalk between cancer cells and immune/stromal cells provides valuable insights into cancer prognosis. A comprehensive literature review was conducted to examine the function of the bidirectional lipid metabolism interactions between cancer cells and immune/stromal cells within the TME, particularly how these interactions influence cancer prognosis. A novel autophagy-extracellular vesicle (EV) pathway has been proposed as a mediator of lipid metabolism interactions between cancer cells and immune cells/stromal cells, impacting cancer prognosis. As a result, different forms of lipid metabolism interactions have been described as being linked to cancer prognosis, including those mediated by the autophagy-EV pathway. In conclusion, understanding the bidirectional lipid metabolism interactions between cancer cells and stromal/immune cells in the TME can help develop more advanced prognostic approaches for cancer patients.

癌症与脂质代谢密切相关,肿瘤微环境(TME)中包含许多脂质代谢相互作用。癌细胞可与肿瘤微环境的主要组成部分--免疫细胞和基质细胞发生双向相互作用。这种相互作用主要由脂肪酸(FA)、胆固醇和磷脂介导。这些相互作用可导致各种生理变化,包括免疫抑制、癌细胞增殖、扩散以及对癌细胞的抗凋亡作用。癌细胞与免疫/间质细胞之间的这种脂质代谢相关串扰所导致的生理调节为癌症预后提供了宝贵的见解。为了研究癌细胞与免疫/间质细胞在肿瘤组织、器官和组织内的双向脂质代谢相互作用的功能,特别是这些相互作用如何影响癌症预后,我们进行了全面的文献综述。一种新的自噬-细胞外囊(EV)途径被认为是癌细胞与免疫细胞/间质细胞之间脂质代谢相互作用的介质,对癌症预后产生影响。因此,不同形式的脂质代谢相互作用被描述为与癌症预后有关,包括由自噬-EV途径介导的相互作用。总之,了解癌细胞与基质/免疫细胞在肿瘤组织间质中的双向脂质代谢相互作用有助于为癌症患者开发更先进的预后方法。
{"title":"Lipid metabolism associated crosstalk: the bidirectional interaction between cancer cells and immune/stromal cells within the tumor microenvironment for prognostic insight.","authors":"Zhongshu Lin, Guanxiang Hua, Xiaojuan Hu","doi":"10.1186/s12935-024-03481-4","DOIUrl":"10.1186/s12935-024-03481-4","url":null,"abstract":"<p><p>Cancer is closely related to lipid metabolism, with the tumor microenvironment (TME) containing numerous lipid metabolic interactions. Cancer cells can bidirectionally interact with immune and stromal cells, the major components of the TME. This interaction is primarily mediated by fatty acids (FAs), cholesterol, and phospholipids. These interactions can lead to various physiological changes, including immune suppression, cancer cell proliferation, dissemination, and anti-apoptotic effects on cancer cells. The physiological modulation resulting from this lipid metabolism-associated crosstalk between cancer cells and immune/stromal cells provides valuable insights into cancer prognosis. A comprehensive literature review was conducted to examine the function of the bidirectional lipid metabolism interactions between cancer cells and immune/stromal cells within the TME, particularly how these interactions influence cancer prognosis. A novel autophagy-extracellular vesicle (EV) pathway has been proposed as a mediator of lipid metabolism interactions between cancer cells and immune cells/stromal cells, impacting cancer prognosis. As a result, different forms of lipid metabolism interactions have been described as being linked to cancer prognosis, including those mediated by the autophagy-EV pathway. In conclusion, understanding the bidirectional lipid metabolism interactions between cancer cells and stromal/immune cells in the TME can help develop more advanced prognostic approaches for cancer patients.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11342506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035330","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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