Glycogen metabolism-mediated intercellular communication in the tumor microenvironment influences liver cancer prognosis

Glycogen metabolism plays a key role in the development of hepatoellular carcinoma(HCC),but the function of glycogen metabolism genes in the tumor microenvironment(TME)is still to be elucidated.Single cell RNA-seq data were obtained from ten HCC tumor samples totaling 64,545 cells and 65 glycogen metabolism genes were analyzed bya nonnegative matrix factorization(NMF).The prognosis and immune response of new glycogen TME cell dusters were predicted by using HCC and immunotherapy cohorts from public databases.HOC single cell analysis was divided into fibroblasts,NT T cells,macrophages,endothelial clls,and B cells,which were separately divided into new cell clusters by glycogen metabolism gene annotation.Pseudo temporal trajectory analysis demonstrated the temporal differentiation trajectory of different glycogen subtype cell dusters.Cellular communication analysis revealed extensive interactions between endothelial cells with glycogen metabolizing TME cell.related subtypes and diferent glycogen subtype cell clusters.SCENIC analysis of transcription factors upstream of TME cell clusters with different glycogen metabolism.In addition,TME cell dusters of glycogen metabolism were found to be enriched in expression in CAF subtypes,CD8 depleted,M1,and M2 types.Bulk seq analysis showed the prognostic signifcance of glycogen metabolism.mediated TME cell dusters in HCC,while a significant immune response was found in the immunotherapy cohort in patients treated with immune checkpoint blockade(ICB),especially for CAFs,T cells,and macrophages In summary,our study reveals for the first time that glycogen metabolism mediates intercellular communication in the hepatocellular carcinoma microenvironment while elucidating the anti-tumor mechanisms and immune prognostic responses of different subtypes of cell dusters.

Exploring a new chapter in traditional Chinese medicine:The potential of Calculus bovis in liver cancer treatment

In the ongoing quest for new treatments in medicine,traditional Chinese medicine offers unique insights and potential.Recently,studies on the ability of Calculus bovis to inhibit M2-type tumour-associated macrophage polarisation by modulating the Wnt/β-catenin signalling pathway to suppress liver cancer have undoubtedly revealed new benefits and hope for this field of research.The purpose of this article is to comment on this study and explore its strengths and weaknesses,thereby providing ideas for the future treatment of liver cancer.

Calculus bovis inhibits M2 tumor-associated macrophage polarization via Wnt/β-catenin pathway modulation to suppress liver cancer

BACKGROUND Calculus bovis(CB),used in traditional Chinese medicine,exhibits anti-tumor effects in various cancer models.It also constitutes an integral component of a compound formulation known as Pien Tze Huang,which is indicated for the treatment of liver cancer.However,its impact on the liver cancer tumor microenvironment,particularly on tumor-associated macrophages(TAMs),is not well understood.AIM To elucidate the anti-liver cancer effect of CB by inhibiting M2-TAM polarization via Wnt/β-catenin pathway modulation.METHODS This study identified the active components of CB using UPLC-Q-TOF-MS,evaluated its anti-neoplastic effects in a nude mouse model,and elucidated the underlying mechanisms via network pharmacology,transcriptomics,and molecular docking.In vitro assays were used to investigate the effects of CB-containing serum on HepG2 cells and M2-TAMs,and Wnt pathway modulation was validated by real-time reverse transcriptase-polymerase chain reaction and Western blot analysis.RESULTS This study identified 22 active components in CB,11 of which were detected in the bloodstream.Preclinical investigations have demonstrated the ability of CB to effectively inhibit liver tumor growth.An integrated approach employing network pharmacology,transcriptomics,and molecular docking implicated the Wnt signaling pathway as a target of the antineoplastic activity of CB by suppressing M2-TAM polarization.In vitro and in vivo experiments further confirmed that CB significantly hinders M2-TAM polarization and suppresses Wnt/β-catenin pathway activation.The inhibitory effect of CB on M2-TAMs was reversed when treated with the Wnt agonist SKL2001,confirming its pathway specificity.CONCLUSION This study demonstrated that CB mediates inhibition of M2-TAM polarization through the Wnt/β-catenin pathway,contributing to the suppression of liver cancer growth.

Immunotherapy in gastric cancer with liver metastasis:Challenges and opportunities

In this editorial,we review the article by Liu et al published in the World Journal of Gastrointestinal Surgery investigating the efficacy and safety of immunotherapy in patients with gastric cancer(GC)and liver metastasis.GC,the fifth most com-monly diagnosed malignancy worldwide,presents a significant challenge due to its multifactorial etiology and a grim prognosis for unresectable or recurrent cases.The advent of immune checkpoint inhibitors(ICIs)has revolutionized oncology;yet liver metastasis has been associated with reduced response rates,progression-free survival,and overall survival in various malignancies.The Che-ckMate-649 and KEYNOTE-859 trials demonstrated promising results with ICIs in advanced GC,particularly in patients with liver metastasis.However,a meta-analysis of liver metastatic solid tumors revealed worse outcomes with ICIs,high-lighting the need for further investigation.While combined therapies,including ICIs with local treatments,show promise in improving outcomes,the nuanced landscape of ICIs in liver metastatic GC necessitates continued research for robust conclusions.The current contradictions in the literature underscore the impor-tance of cautious interpretation and the exploration of tailored approaches to enhance clinical efficacy in this challenging patient population.

Targeting the mechano-microenvironment and liver cancer stem cells:a promising therapeutic strategy for liver cancer

Over the past 2 decades,cancer stem cells(CSCs)have been identified as the root cause of cancer occurrence,progression,chemoradioresistance,recurrence,and metastasis.Targeting CSCs is a novel therapeutic strategy for cancer management and treatment.Liver cancer(LC)is a malignant disease that can endanger human health.Studies are increasingly suggesting that changes in the liver mechanical microenvironment are a primary driver triggering the occurrence and development of liver cancer.In this review,we summarize current understanding of the roles of the liver mechano-microenvironment and liver cancer stem cells(LCSCs)in liver cancer progression.We also discuss the relationship between the mechanical heterogeneity of liver cancer tissues and LCSC recruitment and metastasis.Finally,we highlight potential mechanosensitive molecules in LCSCs and mechanotherapy in liver cancer.Understanding the roles and regulatory mechanisms of the mechano-microenvironment and LCSCs may provide fundamental insights into liver cancer progression and aid in further development of novel therapeutic strategies.

Platelets in liver disease, cancer and regeneration

Although viral hepatitis treatments have evolved over the years, the resultant liver cirrhosis still does not completely heal. Platelets contain proteins required for hemostasis, as well as many growth factors required for organ development, tissue regeneration and repair. Thrombocytopenia, which is frequently observed in patients with chronic liver disease(CLD) and cirrhosis, can manifest from decreased thrombopoietin production and accelerated platelet destruction caused by hypersplenism; however, the relationship between thrombocytopenia and hepatic pathogenesis, as well as the role of platelets in CLD, is poorly understood. In this paper, experimental evidence of platelets improving liver fibrosis and accelerating liver regeneration is summarized and addressed based on studies conducted in our laboratory and current progress reports from other investigators. In addition, we describe our current perspective based on the results of these studies. Platelets improve liver fibrosis by inactivating hepatic stellate cells, which decreases collagen production. The regenerative effect of platelets in the liver involves a direct effect on hepatocytes, a cooperative effect with liver sinusoidal endothelial cells, and a collaborative effect with Kupffer cells. Based on these observations, we ascertained the direct effect of platelet transfusion on improving several indicators of liver function in patients with CLD and liver cirrhosis. However, unlike the results of our previous clinical study, the smaller incremental changes in liver function in patients with CLD who received eltrombopag for 6 mo were due to patient selection from a heterogeneous population. We highlight the current knowledge concerning the role of platelets in CLD and cancer and anticipate a novel application of platelet-based clinical therapies to treat liver disease.

Role of BMSCs in liver regeneration and metastasis after hepatectomy

Hepatocellular carcinoma(HCC),which develops from liver cirrhosis,is highly prevalent worldwide and is a malignancy that leads to liver failure and systemic metastasis.While surgery is the preferred treatment for HCC,intervention and liver transplantation are also treatment options for end-stage liver disease.However,the success of partial hepatectomy and intervention is hindered by the decompensation of liver function.Conversely,liver transplantation is difficult to carry out due to its high cost and the lack of donor organs.Fortunately,research into bone-marrow stromal cells(BMSCs)has opened a new door in this field.BMSCs are a type of stem cell with powerful proliferative and differential potential that represent an attractive tool for the establishment of successful stem cell-based therapy for liver diseases.A number of different stromal cells contribute to the therapeutic effects exerted by BMSCs because BMSCs can differentiate into functional hepatic cells and can produce a series of growth factors and cytokines capable of suppressing inflammatory responses,reducing hepatocyte apoptosis,reversing liver fibrosis and enhancing hepatocyte functionality.Additionally,it has been shown that BMSCs can increase the apoptosis rate of cancer cells and inhibit tumor metastasis in some microenvironments.This review focuses on BMSCs and their possible applications in liver regeneration and metastasis after hepatectomy.

Effect of liver regeneration on malignant hepatic tumors

Liver regeneration after major surgery may activate occult micrometastases and facilitate tumor growth,leading to liver tumor recurrence.Molecular changes during liver regeneration can provide a microenvironment that stimulates intrahepatic tumor propagation through alterations in cellular signaling pathways,where activation and proliferation of mature hepatocytes,hepatic progenitor cells,non-parenchymal liver cells might favor both liver regeneration and tumor growth.This review highlights recent advances of tumor growth and development in the regenerating liver,possible mechanisms and clinical implications.

Tumor microenvironment in primary liver tumors: A challenging role of natural killer cells

In the last years,several studies have been focused on elucidate the role of tumor microenvironment(TME)in cancer development and progression.Within TME,cells from adaptive and innate immune system are one of the main abundant components.The dynamic interactions between immune and cancer cells lead to the activation of complex molecular mechanisms that sustain tumor growth.This important cross-talk has been elucidate for several kind of tumors and occurs also in patients with liver cancer,such as hepatocellular carcinoma(HCC)and intrahepatic cholangiocarcinoma(iCCA).Liver is well-known to be an important immunological organ with unique microenvironment.Here,in normal conditions,the rich immune-infiltrating cells cooperate with non-parenchymal cells,such as liver sinusoidal endothelial cells and Kupffer cells,favoring self-tolerance against gut antigens.The presence of underling liver immunosuppressive microenvironment highlights the importance to dissect the interaction between HCC and iCCA cells with immune infiltrating cells,in order to understand how this cross-talk promotes tumor growth.Deeper attention is,in fact,focused on immune-based therapy for these tumors,as promising approach to counteract the intrinsic anti-tumor activity of this microenvironment.In this review,we will examine the key pathways underlying TME cell-cell communications,with deeper focus on the role of natural killer cells in primary liver tumors,such as HCC and iCCA,as new opportunities for immune-based therapeutic strategies.

Advances in Research on Immunological Checkpoint Inhibitors in Immunotherapy of Liver Cancer

The current treatments of liver cancer in China are mainly comprehensive treatment and systematic treatment, with poor therapeutic effect and high recurrence rate and metastasis rate. The existence of immunosuppressive microenvironment is an important reason for liver tumor cells to escape from the host immune system, and also an important basis for the occurrence and development of liver cancer. With the recent transformation of the target of tumor therapy from tumor cells to tumor cell immune microenvironment, immunotherapy has emerged quietly. It is a new strategy for the treatment of hepatocellular carcinoma to improve the immune attack on tumor cells by changing the immunosuppressive environment of hepatocellular carcinoma cells. Immune checkpoint is the main mechanism by which liver cancer cells escape the host immune system. PD-1/PDL-1 and CTLA-4 are targeted immunocheckpoint inhibitors, which have shown good therapeutic effects and application prospects in the clinical treatment of HCC. This article reviews the latest advances in immunocheckpoint inhibitors in the immunotherapy of hepatocellular carcinoma.

Use of traditional Chinese medicine bezoars and bezoar-containing preparations in hepatocarcinoma

This manuscript used network pharmacology and experimental verification to analyze the anti-hepatocarcinoma mechanism of action of bezoars in traditional Chinese medicine(TCM),discovering that it can affect the immune cells within the tumor microenvironment and related pathways to produce inhibitory effects in liver cancer.In TCM,bezoars have a unique therapeutic advantage in the prevention and treatment of tumors.They play an anti-tumorigenic role by regulating the immune microenvironment through multi-component,multi-target and multi-pathway mechanisms.With the application of nanotechnology,bezoars and their compound preparations have been developed into anti-cancer drugs with unique therapeutic advantages,providing novel treatment options for tumor patients.

From traditional Chinese medicine formulations to effective anticancer agents:Insights from Calculus bovis

This editorial examines the therapeutic potential of traditional Chinese medicine(TCM)for aggressive cancers,particularly liver cancer.It highlights the study by Huang et al,which shows how Calculus bovis,a component of the TCM Pien Tze Huang,suppresses liver cancer by inhibiting M2 macrophage polarization via the Wnt/β-catenin pathway.This research emphasizes the importance of transitioning from effective TCM formulations to isolating active components and understanding their mechanisms.While the study provides valuable insights,it primarily focuses on the Wnt/β-catenin pathway and does not delve deeply into the mechanisms of individual components.Future research should aim to comprehensively study these components,explore their interactions,and validate findings through clinical trials.This approach will integrate traditional wisdom with modern scientific validation,advancing the development of innovative cancer treatments based on TCM formulations.

Immune Regulatory Networks and Therapy of yδT Cells in Liver Cancer:Recent Trends and Advancements

The roles of γδ T cells in liver cancer,especially in the poten-tial function of immunotherapy due to their direct cytotoxic effects on tumor cells and secretion of important cytokines and chemokines,have aroused research interest.This re-view briefly describes the basic characteristics of γδ T cells,focusing on their diverse effects on liver cancer.In particular,different subtypes of γδ T cells have diverse or even opposite effects on liver cancer.We provide a detailed description of the immune regulatory network of γδ T cells in liver can-cer from two aspects:immune components and nonimmune components.The interactions between various components in this immune regulatory network are dynamic and pluralis-tic,ultimately determining the biological effects of γδ T cells in liver cancer.We also integrate the current knowledge of γδ T-cell immunotherapy for liver cancer treatment,emphasiz-ing the potential of these cells in liver cancer immunotherapy.

Microcirculation of Liver Cancer,Microenvironment of Liver Regeneration,and the Strategy of Chinese Medicine

Microcirculation of liver cancer is the micro-vascular system which comes from the tissue of liver cancer. It can offer the nutritional requirement for accelerating the cancer cell proliferation and metastasis. The intrinsic mechanism of angiogenesis is the key link in the formation of liver cancer microcirculation system. Liver regeneration microenvironment also plays an important role in the construction of liver cancer microcirculation, through the improvement of liver regeneration microenvironment affecting tumor microcirculation is the new strategy of prevention and treatment of liver cancer. In recent years, it is found that many kinds of Chinese medicine can inhibit angiogenesis, decrease the microvessel density, and delay or prevent the development of liver cancer.

Microenvironment of Liver Regeneration in Liver Cancer

The occurrence and development of liver cancer are essentially the most serious outcomes of uncontrolled liver regeneration. The progression of liver cancer is inevitably related to the abnormal microenvironment of liver regeneration. The deterioration observed in the microenvironment of liver regeneration is a necessary condition for the occurrence, development and metastasis of cancer. Therefore, the use of a technique to prevent and treat liver cancer via changes in the microenvironment of liver regeneration is a novel strategy. This strategy would be an effective way to delay, prevent or even reverse cancer occurrence, development and metastasis through an improvement in the liver regeneration microenvironment along with the integrated regulation of multiple components, targets, levels, channels and time sequences. In addition, the treatment of ＂tonifying Shen（Kidney） to regulate liver regeneration and repair by affecting stem cells and their microenvironment＂ can regulate ＂the dynamic imbalance between the normal liver regeneration and the abnormal liver regeneration＂; this would improve the microenvironment of liver regeneration, which is also a mechanism by which liver cancer may be prevented or treated.

从“虚瘀劫肝”论原发性肝癌中医药防治思路

理论创新是中医药发展的源泉,在新理论指导下形成的新方药或新诊治方案是中医药临床防治重大疑难疾病的新突破口。正邪交争,正不胜邪是慢性疾病持续进展的内在驱力和一般特性,慢性肝病持续恶性进展囊括了:肝纤维、肝硬化、肝癌等逐步恶化的病理进程。其在遵循中医“正不胜邪”基本病机的基础也必须有其特殊性和指向性,也可理解为在慢性肝病持续进展的病理状态下将一般性的病机进行指向性和特征性的阐发。肝正虚主要是指维持正常肝再生修复的相关机制和途径异常或紊乱,肝邪胜则是指肝损伤因素持续存在及其下游触发的恶性肝再生状态进行性亢进;而“瘀”作为正邪交争过程中产生的最主要病理产物也在不断推动疾病的恶性发展。在此基础上,从“虚瘀劫肝”论肝癌的病理新认识及补虚(补肾生髓、健脾)祛瘀(疏肝、柔肝、化肝)阻断慢性肝病持续恶性进展以防治肝癌的基本思路,期望有益于疑难肝脏病症的临床防治。

聚焦超声在多模式协同治疗肝癌方面的最新研究进展

声动力疗法(Sonodynamic Therapy,SDT)是一种利用聚焦超声非入侵性治疗癌症的手段,基于SDT的协同策略治疗肝癌,具有较高的研究意义和临床转化价值。总结了SDT的治疗机理和常见声敏剂,分析了基于单模态声动力疗法很难满足现阶段治疗肝癌肿瘤原因,重点阐述声动力疗法和化疗、光动力治疗、光热治疗等双重协同治疗模式以及基于声动力的多模式协同治疗的研究进展,旨在为今后SDT协同模式治疗肝癌及其它类型癌症提供参考和借鉴,同时提出SDT协同治疗在研究过程中仍面临的单一治疗效果不显著和多模态联合治疗研究较少等问题,最后提出了开发新型声敏剂、探究联合治疗机理以及实现实时诊疗等应用等发展前景。

Exosomal microRNAs in hepatocellular carcinoma,expanding research field

In this editorial we comment on the review by Wang et al published in the recent issue of the World Journal of Gastroenterology in 2023.Small extracellular vesicles(exosomes)play important roles in the tumor microenvironment.In this review,the authors introduce the following points:(1)The composition and function of exosomal microRNAs(miRNAs)of different cell origins in hepatocellular carcinoma(HCC);(2)the crosstalk between exosomal miRNAs from stromal cells and immune cells in the tumor microenvironment and the progression of HCC;and(3)the potential applicability of exosomal miRNAs derived from mesenchymal stem cells in the treatment of HCC.In addition,the potential applicability of exosomal miRNAs derived from mesenchymal stem cells in the treatment of HCC was introduced.In this review,the authors give us an overview of the exosomal RNA and summarize the function of exosomal RNA in HCC,which provides a deeper understanding of exosomal miRNAs to the readers.

LOXL3对肝癌免疫微环境、化学治疗耐药和免疫治疗预测影响的研究

目的运用生物信息学方法研究赖氨酸氧化酶3(LOXL3)基因在肝癌组织中的表达和对患者生存情况的影响,分析LOXL3基因对肝癌免疫微环境的影响,并对肝癌的化学治疗耐药和免疫治疗疗效进行预测。方法通过TCGA数据库和ICGC数据库分析LOXL3基因在肝癌细胞中的表达情况;采用GSEA富集分析LOXL3可能富集的相关通路;通过TIMER数据库和TISIDB分析肝癌患者中LOXL3基因表达情况与免疫细胞浸润的关系;通过GDSC数据库分析LOXL3基因与治疗中肝癌对化疗药物耐药的关系。并通过TIDE数据库对肝癌患者免疫治疗的疗效进行预测,使用Kaplan-Meier分析LOXL3基因对患者生存情况的影响。结果对于TCGA和ICGC数据库,两个数据库的结果均显示在肝癌组织中LOXL3的表达高于正常组织(P<0.05)。LOXL3对TGF-β、Wnt-β-Cantenin、Hypoxia和PI3K/AKT等通路有一定的激活作用。免疫细胞浸润水平发现,LOXL3在肝癌组织中的表达水平与B细胞(r=0.463,P<0.05)、CD8+T细胞(r=0.469,P<0.05)、CD4+T细胞(r=0.557,P<0.05)、巨噬细胞(r=0.71,P<0.05)、中性粒细胞(r=0.528,P<0.05)和树突状细胞(r=0.654,P<0.05)均呈一定的正相关。化疗敏感性分析表示在肝癌组织中,对于阿昔替尼、紫杉醇、顺铂、阿糖胞苷、喜树碱、长春碱等化疗药物,低表达LOXL3基因人群对其耐药。但在免疫治疗预测中,低表达LOXL3人群能从免疫治疗中有一定的获益。生存分析显示,高表达LOXL3的患者预后较差。结论LOXL3在肝癌组织中高表达,能激活免疫相关通路,对一些化疗药物敏感,同时免疫治疗能获益,因此可作为肝癌新型分子标志物。

外泌体参与结直肠癌肝转移发病机制的研究进展

结直肠癌是全世界最常见的第三大癌症,60%的患者在未经过有效治疗的情况下会发生肝转移。其发病率和死亡率均很高。尽管诊断和治疗技术取得了很大进展,但结直肠癌肝转移(colorectal cancer liver metastasis,CRLM)患者的生存率仍然很低。外泌体作为细胞间通讯中的重要介质被广泛研究,在CRLM发病过程中的每一步都有非常重要的影响。本文归纳了不同来源、不同内含物外泌体通过包括:促进上皮-间充质转化(epithelial-mesenchymal transition,EMT)、调节细胞外基质(extracellular matrix,ECM)、增加血管生成和血管通透性、促进转移前生态位(pre-metastatic niche,PMN)形成、参与免疫抑制等途径来影响CRLM发病的机制,以期为未来CRLM提供潜在诊断及治疗靶点。