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Zhou J, Ma W, Zhou R, Ma D, Liu C, Wang F, Yuan L, Xu L, Wang C, Li Q. Exosome-derived SLC12A2-DT promotes macrophage M2 polarization-mediated hepatocellular carcinoma progression. Int Immunopharmacol 2025; 160:114955. [PMID: 40446695 DOI: 10.1016/j.intimp.2025.114955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2025] [Revised: 05/02/2025] [Accepted: 05/21/2025] [Indexed: 06/11/2025]
Abstract
BACKGROUND Previous scholarly research highlights the indispensable roles of tumor-associated macrophages (TAMs) and exosomes in the progression of hepatocellular carcinoma (HCC). However, the nuanced molecular mechanisms by which tumor-derived exosomal lncRNAs interact with TAMs to modulate macrophage polarization and HCC proliferation remain largely obscure. METHOD Clinical specimens were subjected to sequencing and bioinformatics analysis, revealing the previously unreported SLC12A2-DT. The presence of exosomes was assessed via transmission electron microscopy and differential ultracentrifugation. In vivo and in vitro coculture experiments were employed to elucidate the functions of exosomal SLC12A2-DT. RNA pull-down assays, dual-luciferase reporter assays, and mass spectrometry were utilized to delineate the mechanisms by which exosomal SLC12A2-DT regulates the interaction between HCC cells and M2 macrophages. RESULTS Our study revealed the aberrant upregulation of SLC12A2-DT expression in HCC, particularly in advanced stages, and its association with poor prognosis in HCC patients. Notably, SLC12A2-DT-induced M2 macrophage polarization significantly induced lung metastasis in a murine HCC model. We subsequently confirmed that HCC cell-derived exosomal SLC12A2-DT induced M2 macrophage polarization by specifically binding to GSK3β/β-catenin and downregulating the degradation of ubiquitinated β-catenin, leading to Wnt signaling pathway activation. Furthermore, we revealed that KLF4 transcriptionally repressed SLC12A2-DT expression in HCC cells. CONCLUSION These findings suggest that tumor-derived exosomal SLC12A2-DT facilitates HCC progression by modulating the interplay between HCC cells and TAMs through the Wnt/GSK3β/β-catenin signaling pathway.
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Affiliation(s)
- Jingyi Zhou
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; Key Laboratory for Translational Research and Innovative Therapeutics of Gastrointestinal Oncology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Wencong Ma
- Institute of Hepatobiliary and Pancreatic Surgery, Department of Hepatobiliary and Pancreatic Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, PR China
| | - Runkai Zhou
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Di Ma
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Chuan Liu
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Fan Wang
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Lin Yuan
- Pathology center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Ling Xu
- Department of Gastroenterology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
| | - Chen Wang
- Department of Gastroenterology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; Key Laboratory for Translational Research and Innovative Therapeutics of Gastrointestinal Oncology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
| | - Qi Li
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
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Shi X, Askari Rizvi SF, Yang Y, Liu G. Emerging nanomedicines for macrophage-mediated cancer therapy. Biomaterials 2025; 316:123028. [PMID: 39693782 DOI: 10.1016/j.biomaterials.2024.123028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 11/22/2024] [Accepted: 12/13/2024] [Indexed: 12/20/2024]
Abstract
Tumor-associated macrophages (TAMs) contribute to tumor progression by promoting angiogenesis, remodeling the tumor extracellular matrix, inducing tumor invasion and metastasis, as well as immune evasion. Due to the high plasticity of TAMs, they can polarize into different phenotypes with distinct functions, which are primarily categorized as the pro-inflammatory, anti-tumor M1 type, and the anti-inflammatory, pro-tumor M2 type. Notably, anti-tumor macrophages not only directly phagocytize tumor cells, but also present tumor-specific antigens and activate adaptive immunity. Therefore, targeted regulation of TAMs to unleash their potential anti-tumor capabilities is crucial for improving the efficacy of cancer immunotherapy. Nanomedicine serves as a promising vehicle and can inherently interact with TAMs, hence, emerging as a new paradigm in cancer immunotherapy. Due to their controllable structures and properties, nanomedicines offer a plethora of advantages over conventional drugs, thus enhancing the balance between efficacy and toxicity. In this review, we provide an overview of the hallmarks of TAMs and discuss nanomedicines for targeting TAMs with a focus on inhibiting recruitment, depleting and reprogramming TAMs, enhancing phagocytosis, engineering macrophages, as well as targeting TAMs for tumor imaging. We also discuss the challenges and clinical potentials of nanomedicines for targeting TAMs, aiming to advance the exploitation of nanomedicine for cancer immunotherapy.
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Affiliation(s)
- Xueying Shi
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics Center for Molecular, Imaging and Translational Medicine, School of Public Health, Xiamen University, No. 4221 South Xiang'an Road, Xiang'an District, Xiamen, 361102, China
| | - Syed Faheem Askari Rizvi
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics Center for Molecular, Imaging and Translational Medicine, School of Public Health, Xiamen University, No. 4221 South Xiang'an Road, Xiang'an District, Xiamen, 361102, China; Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, 54000, Punjab, Pakistan
| | - Yinxian Yang
- School of Pharmaceutical Sciences, Xiamen University, No. 4221 South Xiang'an Road, Xiang'an District, Xiamen, 361102, China.
| | - Gang Liu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics Center for Molecular, Imaging and Translational Medicine, School of Public Health, Xiamen University, No. 4221 South Xiang'an Road, Xiang'an District, Xiamen, 361102, China.
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Yuan X, Zhang H, Zhu Y, Xu K, Yang Y, Xie W, Duan W, Chen Q, Chen Y. Myristoyl-CM4 Exhibits Direct Anticancer Activity and Immune Modulation in Hepatocellular Carcinoma: Evidence from In Vitro and Mouse Model Studies. Int J Mol Sci 2025; 26:3829. [PMID: 40332513 PMCID: PMC12028079 DOI: 10.3390/ijms26083829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 04/03/2025] [Accepted: 04/09/2025] [Indexed: 05/08/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a major clinical challenge due to limited treatment options, More therapy candidates with confirmed anticancer effects are urgently needed. Antimicrobial peptide myristoyl-CM4 exhibits effective anticancer activity against leukemia and breast cancer cells. However, its therapeutic potential in HCC remains unexplored. The objective of the present study was to evaluate the anticancer activity of myristoyl-CM4 against cultured HCC cells and HCC xenograft tumors in mice. Cell viability, apoptosis, proliferation, epithelial-mesenchymal transition, migration, and invasion were assessed using standard assays. Mechanistic studies focused on its effects on macrophages utilized western blotting, immunofluorescence staining, and immunohistochemistry assays in HCC/macrophage co-culture models. The study results showed that myristoyl-CM4 induced apoptosis in HCC cells by targeting mitochondria. It also inhibited HCC cell migration and invasion in both HCC monoculture and HCC/macrophage co-culture systems. Notably, myristoyl-CM4 also promoted M1 macrophage polarization and suppressed M2 polarization in co-culture models both in vitro and in vivo. It also demonstrated effective antitumor activity both in PLC-PRF-5 xenograft and PLC-PRF-5/macrophage co-xenograft mouse models. Collectively, these findings highlighted the therapeutic potential of myristoyl-CM4 in HCC treatment.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Yuqing Chen
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, Life Sciences College, Nanjing Normal University, 1# Wenyuan Rd., Nanjing 210000, China; (X.Y.); (H.Z.); (Y.Z.); (K.X.); (Y.Y.); (W.X.); (W.D.); (Q.C.)
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LIANG HAISU, YAN WEI, LIU ZHI, HE YUNBO, HU JIAO, SHU ZHIWEI, LI HUIHUANG, OTHMANE BELAYDI, REN WENBIAO, QUAN CHAO, QIU DONGXU, CHEN MINFENG, XIONG WEI, ZHANG BINGNAN, LIU PEIHUA. Immunomodulatory behavior of CircRNAs in tumor microenvironment. Oncol Res 2025; 33:1105-1119. [PMID: 40296917 PMCID: PMC12034001 DOI: 10.32604/or.2024.054623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Accepted: 11/13/2024] [Indexed: 04/30/2025] Open
Abstract
Circular RNAs (circRNAs) are a type of non coding RNA that possess unique single stranded circular structures formed through reverse splicing mechanisms. Due to the lack of a free end that is typically susceptible to degradation by nucleases, circular RNAs exhibit resistance to ribonuclease R, making them highly stable in eukaryotic cells. The complex relationship between circRNA dysregulation and various pathophysiological conditions, especially cancer. Tumor microenvironment (TME) is a collective term for various components surrounding tumors and is an important factor affecting tumor development. Simultaneous infiltration of TME by different types of immune cells; These immune cells interact with the TME, collectively forming the so-called "tumor immune microenvironment". The complex interactions between tumor cells and TME profoundly affect the behavior of malignant tumors, and circRNAs derived from tumor cells and TME cell components have become important mediators of immune response and evasion within the TME. CircRNAs can directly or indirectly regulate immune cells, thereby modulating anti-tumor immunity. This review highlights how circRNAs, especially those encapsulated in extracellular vesicles like exosomes, influence the differentiation, chemotaxis, and anti-tumor immune functions of immune cells within the TME. Metabolic reprogramming plays an important role in this process. The process of circRNAs regulating tumor immunity is affected by multiple factors, such as hypoxia and viral infection. This review emphasizes the roles of the interaction between circRNAs and the TME in tumor immune regulation and prospects the guiding significance of circRNAs in tumor immune checkpoint therapy.
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Affiliation(s)
- HAISU LIANG
- Department of Urology, Xiangya Hospital, Central South University, Changsha, 410000, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410000, China
| | - WEI YAN
- Department of Urology, Shimen Hospital of TCM, Changde, 415300, China
| | - ZHI LIU
- Department of Urology, Xiangya Hospital, Central South University, Changsha, 410000, China
- Department of Urology, The Second Affiliated Hospital, Guizhou Medical University, Kaili, 556000, China
| | - YUNBO HE
- Department of Urology, Xiangya Hospital, Central South University, Changsha, 410000, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410000, China
- NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
| | - JIAO HU
- Department of Urology, Xiangya Hospital, Central South University, Changsha, 410000, China
| | - ZHIWEI SHU
- Department of Urology, Xiangya Hospital, Central South University, Changsha, 410000, China
| | - HUIHUANG LI
- Department of Urology, Xiangya Hospital, Central South University, Changsha, 410000, China
| | - BELAYDI OTHMANE
- Department of Urology, Xiangya Hospital, Central South University, Changsha, 410000, China
| | - WENBIAO REN
- Department of Urology, Xiangya Hospital, Central South University, Changsha, 410000, China
- George Whipple Lab for Cancer Research, University of Rochester Medical Institute, Rochester, NY 14627, USA
| | - CHAO QUAN
- Department of Urology, Xiangya Hospital, Central South University, Changsha, 410000, China
| | - DONGXU QIU
- Department of Urology, Xiangya Hospital, Central South University, Changsha, 410000, China
| | - MINFENG CHEN
- Department of Urology, Xiangya Hospital, Central South University, Changsha, 410000, China
| | - WEI XIONG
- NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
| | - BINGNAN ZHANG
- Department of Urology, Xiangya Hospital, Central South University, Changsha, 410000, China
| | - PEIHUA LIU
- Department of Urology, Xiangya Hospital, Central South University, Changsha, 410000, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410000, China
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Yang Q, Cui M, Wang J, Zhao Y, Yin W, Liao Z, Liang Y, Jiang Z, Li Y, Guo J, Qi L, Chen J, Zhao J, Bao D, Xu ZX. Circulating mitochondrial DNA promotes M2 polarization of tumor associated macrophages and HCC resistance to sorafenib. Cell Death Dis 2025; 16:153. [PMID: 40038250 PMCID: PMC11880550 DOI: 10.1038/s41419-025-07473-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 02/07/2025] [Accepted: 02/21/2025] [Indexed: 03/06/2025]
Abstract
Mitochondrial damage-associated molecular patterns (DAMPs) including mitochondrial DNA (mtDNA), TFAM (transcription factor A, mitochondrial), and ATP, which play crucial roles in the regulation of inflammatory environment in human diseases. However, the role of mitochondrial DAMPs in regulating tumor microenvironment (TME) remains unclear. Herein, we demonstrate that infiltration of M2-type tumor-associated macrophages (TAMs) was correlated with the resistance of hepatocellular carcinoma (HCC) to sorafenib. We found that cell-free mtDNA in the plasma was significantly increased in sorafenib-resistant HCC mice. Sorafenib induced mitochondrial dysfunction and promoted the release of mtDNA into extracellular matrix of HCC. Macrophages retook the mtDNA in the TME of HCC, activated TLR9 signaling, and promoted the activation of NF-κB and the polarization of TAMs into M2. Application of DNase I to digest mtDNA or depletion of macrophages with clodronate liposomes reduced M2 macrophage infiltration, decreased the growth of HCC, and sensitized the tumors to sorafenib. Furthermore, we showed that blocking the activation of TLR9 enhanced the therapeutic effect of sorafenib in HCC. Together, we demonstrate that sorafenib treatment leads to the release of mtDNA into TME in HCC, which in turn facilitates the polarization of TAMs into M2 macrophages through TLR9 activation and aggravates the resistance of HCC to sorafenib. Our study reveals a novel mechanism underlying circulating mtDAMPs in remodeling the HCC microenvironment by reprograming the TAMs and provides a new strategy for improving the therapeutic effect of sorafenib and overcoming its resistance in HCC.
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MESH Headings
- Sorafenib/pharmacology
- Sorafenib/therapeutic use
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/blood
- Animals
- DNA, Mitochondrial/blood
- DNA, Mitochondrial/genetics
- DNA, Mitochondrial/metabolism
- Liver Neoplasms/drug therapy
- Liver Neoplasms/pathology
- Liver Neoplasms/genetics
- Liver Neoplasms/blood
- Humans
- Drug Resistance, Neoplasm/drug effects
- Mice
- Tumor-Associated Macrophages/metabolism
- Tumor-Associated Macrophages/drug effects
- Tumor-Associated Macrophages/pathology
- Tumor Microenvironment/drug effects
- Toll-Like Receptor 9/metabolism
- Male
- Mitochondria/metabolism
- Mitochondria/drug effects
- Cell Line, Tumor
- Signal Transduction/drug effects
- Mice, Inbred C57BL
- Macrophages
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Affiliation(s)
- Qi Yang
- School of Life Sciences, School of Pharmacy, Henan University, Kaifeng, Henan, 475004, China
- The Zhongzhou Laboratory for Integrative Biology, Henan University, Zhengzhou, Henan, 450000, China
- Laboratory of Cancer Biomarkers and Liquid Biopsy, School of Pharmacy, Henan University, Kaifeng, Henan, 475004, China
| | - Mengmeng Cui
- The Zhongzhou Laboratory for Integrative Biology, Henan University, Zhengzhou, Henan, 450000, China
- Laboratory of Cancer Biomarkers and Liquid Biopsy, School of Pharmacy, Henan University, Kaifeng, Henan, 475004, China
- Department of Thoracic Surgery, The First Affiliated Hospital of Henan University, Kaifeng, Henan, 475000, China
- State key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, Kaifeng, Henan, 475004, China
| | - Jiaxin Wang
- The Zhongzhou Laboratory for Integrative Biology, Henan University, Zhengzhou, Henan, 450000, China
- Laboratory of Cancer Biomarkers and Liquid Biopsy, School of Pharmacy, Henan University, Kaifeng, Henan, 475004, China
- Department of Thoracic Surgery, The First Affiliated Hospital of Henan University, Kaifeng, Henan, 475000, China
- State key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, Kaifeng, Henan, 475004, China
| | - Yuan Zhao
- School of Life Sciences, School of Pharmacy, Henan University, Kaifeng, Henan, 475004, China
| | - Weitao Yin
- School of Life Sciences, School of Pharmacy, Henan University, Kaifeng, Henan, 475004, China
| | - Ziqian Liao
- The Zhongzhou Laboratory for Integrative Biology, Henan University, Zhengzhou, Henan, 450000, China
- Laboratory of Cancer Biomarkers and Liquid Biopsy, School of Pharmacy, Henan University, Kaifeng, Henan, 475004, China
| | - Yixuan Liang
- The Zhongzhou Laboratory for Integrative Biology, Henan University, Zhengzhou, Henan, 450000, China
- Laboratory of Cancer Biomarkers and Liquid Biopsy, School of Pharmacy, Henan University, Kaifeng, Henan, 475004, China
| | - Zhixiong Jiang
- Laboratory of Cancer Biomarkers and Liquid Biopsy, School of Pharmacy, Henan University, Kaifeng, Henan, 475004, China
- Department of Thoracic Surgery, The First Affiliated Hospital of Henan University, Kaifeng, Henan, 475000, China
- State key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, Kaifeng, Henan, 475004, China
| | - Yujia Li
- School of Life Sciences, School of Pharmacy, Henan University, Kaifeng, Henan, 475004, China
| | - Jinrong Guo
- School of Life Sciences, School of Pharmacy, Henan University, Kaifeng, Henan, 475004, China
| | - Lixia Qi
- Laboratory of Cancer Biomarkers and Liquid Biopsy, School of Pharmacy, Henan University, Kaifeng, Henan, 475004, China
- Department of Thoracic Surgery, The First Affiliated Hospital of Henan University, Kaifeng, Henan, 475000, China
- State key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, Kaifeng, Henan, 475004, China
| | - Jiaxing Chen
- Laboratory of Cancer Biomarkers and Liquid Biopsy, School of Pharmacy, Henan University, Kaifeng, Henan, 475004, China
- Department of Thoracic Surgery, The First Affiliated Hospital of Henan University, Kaifeng, Henan, 475000, China
- State key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, Kaifeng, Henan, 475004, China
| | - Jing Zhao
- School of Life Sciences, School of Pharmacy, Henan University, Kaifeng, Henan, 475004, China
- The Zhongzhou Laboratory for Integrative Biology, Henan University, Zhengzhou, Henan, 450000, China
- Laboratory of Cancer Biomarkers and Liquid Biopsy, School of Pharmacy, Henan University, Kaifeng, Henan, 475004, China
| | - Dengke Bao
- School of Life Sciences, School of Pharmacy, Henan University, Kaifeng, Henan, 475004, China.
- The Zhongzhou Laboratory for Integrative Biology, Henan University, Zhengzhou, Henan, 450000, China.
- Laboratory of Cancer Biomarkers and Liquid Biopsy, School of Pharmacy, Henan University, Kaifeng, Henan, 475004, China.
- Department of Thoracic Surgery, The First Affiliated Hospital of Henan University, Kaifeng, Henan, 475000, China.
- State key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, Kaifeng, Henan, 475004, China.
| | - Zhi-Xiang Xu
- School of Life Sciences, School of Pharmacy, Henan University, Kaifeng, Henan, 475004, China.
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Zhang S, Dong H, Jin X, Sun J, Li Y. The multifaceted roles of macrophages in the transition from hepatitis to hepatocellular carcinoma: From mechanisms to therapeutic strategies. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167676. [PMID: 39828046 DOI: 10.1016/j.bbadis.2025.167676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 01/06/2025] [Accepted: 01/15/2025] [Indexed: 01/22/2025]
Abstract
Macrophages are central to the progression from hepatitis to hepatocellular carcinoma (HCC), with their remarkable plasticity and ability to adapt to the changing liver microenvironment. Chronic inflammation, fibrosis, and ultimately tumorigenesis are driven by macrophage activation, making them key regulators of liver disease progression. This review explores the diverse roles of macrophages in the transition from hepatitis to HCC. In the early stages of hepatitis, macrophages are essential for pathogen clearance and tissue repair. However, chronic activation leads to prolonged inflammation, which exacerbates liver damage and promotes fibrosis. As the disease progresses to liver fibrosis, macrophages interact with hepatic stellate cells, fostering a pro-tumorigenic microenvironment that supports HCC development. In hepatocarcinogenesis, macrophages contribute to tumor initiation, growth, metastasis, immune evasion, cancer stem cell maintenance, and angiogenesis. Their functional plasticity enables them to adapt to the tumor microenvironment, thereby promoting tumor progression and resistance to therapy. Targeting macrophages represents a promising strategy for preventing and treating HCC. Therapeutic approaches, including reprogramming macrophage phenotypes to enhance anti-tumor immunity, blocking macrophage recruitment and activation, and utilizing nanoparticle-based drug delivery systems, may provide new avenues for combating HCC by modulating macrophage functions and tumor microenvironment dynamics.
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Affiliation(s)
- Shuairan Zhang
- Department of Gastroenterology, The First Hospital of China Medical University, Shenyang, PR China
| | - Hang Dong
- Phase I Clinical Trials Center, The People's Hospital of China Medical University, Shenyang, PR China
| | - Xiuli Jin
- Department of Gastroenterology, The First Hospital of China Medical University, Shenyang, PR China
| | - Jing Sun
- Department of Gastroenterology, The First Hospital of China Medical University, Shenyang, PR China
| | - Yiling Li
- Department of Gastroenterology, The First Hospital of China Medical University, Shenyang, PR China.
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Wan H, Zhang YX, Shan GY, Cheng JY, Qiao DR, Liu YY, Shi WN, Li HJ. Antiviral therapy for hepatitis B virus infection is beneficial for the prognosis hepatocellular carcinoma. World J Gastrointest Oncol 2025; 17:93983. [PMID: 39817121 PMCID: PMC11664622 DOI: 10.4251/wjgo.v17.i1.93983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 09/20/2024] [Accepted: 09/29/2024] [Indexed: 12/12/2024] Open
Abstract
In this editorial, we comment on the article by Mu et al, published in the recent issue of the World Journal of Gastrointestinal Oncology. We pay special attention to the immune tolerance mechanism caused by hepatitis B virus (HBV) infection, the pathogenesis of hepatocellular carcinoma (HCC), and the role of antiviral therapy in treating HCC related to HBV infection. HBV infection leads to systemic innate immune tolerance by directly inhibiting pattern recognition receptor recognition and antiviral signaling pathways, as well as by inhibiting the immune functions of macrophages, natural killer cells and dendritic cells. In addition, HBV leads to an immunosuppressive cascade by expressing inhibitory molecules to induce exhaustion of HBV-specific cluster of differentiation 8 + T cells, ultimately leading to long-term viral infection. The loss of immune cell function caused by HBV infection ultimately leads to HCC. Long-term antiviral therapy can improve the prognosis of patients with HCC and prevent tumor recurrence and metastasis.
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Affiliation(s)
- Hui Wan
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
| | - Yu-Xin Zhang
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
| | - Guan-Yue Shan
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
| | - Jun-Ya Cheng
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
- Department of Bioengineering, Pharmacy School of Jilin University, Changchun 130061, Jilin Province, China
| | - Duan-Rui Qiao
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
- Department of Bioengineering, Pharmacy School of Jilin University, Changchun 130061, Jilin Province, China
| | - Yi-Ying Liu
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
- Department of Bioengineering, Pharmacy School of Jilin University, Changchun 130061, Jilin Province, China
| | - Wen-Na Shi
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
- Department of Bioengineering, Pharmacy School of Jilin University, Changchun 130061, Jilin Province, China
| | - Hai-Jun Li
- Institute of Liver Diseases, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
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Yang L, Fang A, Zhou S, Liu H. -RAMP3 promotes hepatocellular carcinoma tumor cell-mediated CCL2 degradation by supporting membrane distribution of ACKR2. Int Immunopharmacol 2024; 143:113419. [PMID: 39437486 DOI: 10.1016/j.intimp.2024.113419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 10/12/2024] [Accepted: 10/13/2024] [Indexed: 10/25/2024]
Abstract
This study aimed to explore the potential bind of Receptor Activity-Modifying Protein 3 (RAMP3) with atypical chemokine receptor 2 (ACKR2), and their cooperative regulation on the degradation of the immunosuppressive chemokine CCL2 in the tumor microenvironment of HCC. Bioinformatic analysis was conducted using available bulk-tissue RNA-seq, single-cell RNA-seq, and protein-protein interaction datasets. Human HCC cell line Huh7 and HepG2 and mouse HCC cell line Hepa1-6 were utilized for experiments. Results showed that RAMP3 binds with ACKR2 in HCC tumor cells and promotes the membrane distribution of ACKR2 through RAB4-positive vesicles. RAMP3 promotes CCL2 scavenging through ACKR2 in HCC cells. Mouse RAMP3 inhibited the proliferation of mouse liver cancer cell line (Hepa1-6)-derived syngeneic tumors through ACKR2, reduced the intratumoral concentration of CCL2 in the tumor, and inhibited the phosphorylation of Signal Transducer and Activator of Transcription 3 (STAT3) and protein kinase B (AKT). In addition, mouse RAMP3 inhibited CD11b+/Gr-1 + myeloid cell infiltration and neovascularization in the tumors through ACKR2. In TCGA-LIHC, RAMP3low/ACKR2low group had the worst progression-free interval (PFI), while the RAMP3high/ACKR2high group had the best overall survival (OS). In summary, restoring RAMP3 expression in HCC cells may generate synergistic support for the anticancer effect of ACKR2.
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Affiliation(s)
- Lan Yang
- Department of Oncology Centre, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Aiping Fang
- West China School of Public Health and West China Fourth Hospital, Sichuan University, 610072 Chengdu, China
| | - Shijie Zhou
- Jinruijie Biotechnology Center, Chengdu 610041, China.
| | - Hao Liu
- Department of Oncology Centre, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China.
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Ye J, Lin Y, Liao Z, Gao X, Lu C, Lu L, Huang J, Huang X, Huang S, Yu H, Bai T, Chen J, Wang X, Xie M, Luo M, Zhang J, Wu F, Wu G, Ma L, Xiang B, Li L, Li Y, Luo X, Liang R. Single cell-spatial transcriptomics and bulk multi-omics analysis of heterogeneity and ecosystems in hepatocellular carcinoma. NPJ Precis Oncol 2024; 8:262. [PMID: 39548284 PMCID: PMC11568154 DOI: 10.1038/s41698-024-00752-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Accepted: 10/30/2024] [Indexed: 11/17/2024] Open
Abstract
This study profiled global single cell-spatial-bulk transcriptome landscapes of hepatocellular carcinoma (HCC) ecosystem from six HCC cases and a non-carcinoma liver control donor. We discovered that intratumoral heterogeneity mainly derived from HCC cells diversity and pervaded the genome-transcriptome-proteome-metabolome network. HCC cells are the core driving force of taming tumor-associated macrophages (TAMs) with pro-tumorigenic phenotypes for favor its dominant growth. Remarkably, M1-types TAMs had been characterized by disturbance of metabolism, poor antigen-presentation and immune-killing abilities. Besides, we found simultaneous cirrhotic and HCC lesions in an individual patient shared common origin and displayed parallel clone evolution via driving disparate immune reprograms for better environmental adaptation. Moreover, endothelial cells exhibited phenotypically conserved but executed differential functions in a space-dependent manner. Further, the spatiotemporal traits of rapid recurrence niche genes were identified and validated by immunohistochemistry. Our data unravels the great significance of HCC cells in shaping vibrant tumor ecosystems corresponding to clinical scenarios.
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Affiliation(s)
- Jiazhou Ye
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Yan Lin
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Zhiling Liao
- Department of Pathology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Xing Gao
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Cheng Lu
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Lu Lu
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Julu Huang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Xi Huang
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Shilin Huang
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Hongping Yu
- Department of Experimental Research, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Tao Bai
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Jie Chen
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Xiaobo Wang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Mingzhi Xie
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Min Luo
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Jinyan Zhang
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Feixiang Wu
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Guobin Wu
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Liang Ma
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Bangde Xiang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Lequn Li
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Yongqiang Li
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Xiaoling Luo
- Department of Experimental Research, Guangxi Medical University Cancer Hospital, Nanning, China.
| | - Rong Liang
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China.
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10
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Liang B, Li L, He C, Wang M, Mao G. MRTO4 acts as an independent prognostic and immunological biomarker and is correlated with tumor microenvironment in hepatocellular carcinoma. Braz J Med Biol Res 2024; 57:e13780. [PMID: 39504066 PMCID: PMC11540254 DOI: 10.1590/1414-431x2024e13780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 09/04/2024] [Indexed: 11/08/2024] Open
Abstract
Liver cancer is a malignant tumor found worldwide. mRNA turnover 4 homolog (MRTO4) is highly expressed in hepatocellular carcinoma (HCC) tissues, and we explored its relationship with HCC. All cancer data were downloaded from the Cancer Genome Atlas (TCGA), the Cancer Immune Atlas (TCIA), and the Human Protein Atlas (THPA). Stromal scores, immune scores, and ESTIMATE scores were calculated by "ESTIMATE" R package. Single sample gene set enrichment analysis and CIBERSORT were used to evaluate the immune status and infiltration of cancer tissues. pRRophetic R package was used to predict the half-maximal inhibitory concentration (IC50) of different drugs in each sample. MRTO4 overexpression was associated with poor prognosis in HCC, and positively correlated with the stage and grade of HCC patients. The average immunophenoscore (IPS) of the low MRTO4 group was significantly higher than that of the high MRTO4 group. Tumor microenvironment (TME) scores were significantly higher in the low MRTO4 group than in the high MRTO4 group in HCC. MRTO4 expression was positively correlated with tumor mutation burden (TMB) and was positively correlated with most immune checkpoint gene expressions in HCC. Drug sensitivity analysis showed significantly higher IC50 values for 5-fluorouracil, gemcitabine, and sorafenib in patients with low MRTO4 expression than in those with high MRTO4 expression. MRTO4 acts as an independent prognostic and immunological biomarker and is correlated with clinical stage, tumor grade, and drug sensitivity in HCC. It may serve as a putative therapeutic target and potential biomarker for prognosis of HCC.
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Affiliation(s)
- Baobao Liang
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Lan Li
- Department of Breast Surgery, Shaanxi Provincial Cancer Hospital, Xi'an, Shaanxi, China
| | - Chenyang He
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Meng Wang
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Guochao Mao
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
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11
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Shi Y, Taherifard E, Saeed A, Saeed A. MASLD-Related HCC: A Comprehensive Review of the Trends, Pathophysiology, Tumor Microenvironment, Surveillance, and Treatment Options. Curr Issues Mol Biol 2024; 46:5965-5983. [PMID: 38921027 PMCID: PMC11202630 DOI: 10.3390/cimb46060356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 06/07/2024] [Accepted: 06/11/2024] [Indexed: 06/27/2024] Open
Abstract
Hepatocellular carcinoma (HCC) represents a significant burden on global healthcare systems due to its considerable incidence and mortality rates. Recent trends indicate an increase in the worldwide incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) and a shift in the etiology of HCC, with MASLD replacing the hepatitis B virus as the primary contributor to new cases of HCC. MASLD-related HCC exhibits distinct characteristics compared to viral HCC, including unique immune cell profiles resulting in an overall more immunosuppressive or exhausted tumor microenvironment. Furthermore, MASLD-related HCC is frequently identified in older age groups and among individuals with cardiometabolic comorbidities. Additionally, a greater percentage of MASLD-related HCC cases occur in noncirrhotic patients compared to those with viral etiologies, hindering early detection. However, the current clinical practice guidelines lack specific recommendations for the screening of HCC in MASLD patients. The evolving landscape of HCC management offers a spectrum of therapeutic options, ranging from surgical interventions and locoregional therapies to systemic treatments, for patients across various stages of the disease. Despite ongoing debates, the current evidence does not support differences in optimal treatment modalities based on etiology. In this study, we aimed to provide a comprehensive overview of the current literature on the trends, characteristics, clinical implications, and treatment modalities for MASLD-related HCC.
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Affiliation(s)
- Yuming Shi
- Department of Medicine, Division of Hematology & Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA; (Y.S.); (E.T.)
| | - Erfan Taherifard
- Department of Medicine, Division of Hematology & Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA; (Y.S.); (E.T.)
| | - Ali Saeed
- Department of Medicine, Ochsner Lafayette General Medical Center, Lafayette, LA 70503, USA;
| | - Anwaar Saeed
- Department of Medicine, Division of Hematology & Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA; (Y.S.); (E.T.)
- UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA
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12
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Luo MY, Han Z, Wang J, Zhong C, Chen J. TARDBP is a candidate diagnostic biomarker promoting tumor progression via impacting tumor immunity and tumor microenvironment. J Cancer 2024; 15:4113-4127. [PMID: 38947395 PMCID: PMC11212099 DOI: 10.7150/jca.96800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Accepted: 05/23/2024] [Indexed: 07/02/2024] Open
Abstract
In the realm of cancer research, particularly hepatocellular carcinoma (HCC), TAR DNA-binding protein (TARDBP) has transitioned from being associated with neurodegenerative diseases to emerging as a significant molecule in oncology due to its aberrant expression in HCC and other malignancies. This shift underlines the versatility of TARDBP and its critical role in tumorigenesis. Our study illuminates TARDBP's universal upregulation across various cancers, indicating its involvement in fundamental oncogenic processes and potential impact on genomic instability. The relationship between TARDBP expression and tumor mutational burden (TMB) across several cancers highlights its influence on a key hallmark of cancer progression. Additionally, TARDBP's interaction with immune and inflammatory factors within the tumor microenvironment, including its association with immune-stimulatory factors and inverse relationship with immune inhibitors, suggests its role in modulating immune evasion. Clinically, TARDBP's aberrant expression correlates with adverse patient outcomes in HCC, making it a promising candidate for therapeutic targeting. The study concludes that TARDBP holds significant potential as a novel therapeutic target in HCC and possibly other malignancies, meriting further exploration to integrate TARDBP-targeted therapies into cancer treatment protocols, thereby advancing the field of precision medicine.
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Affiliation(s)
- Min-Yi Luo
- Department of Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, 510080, Guangzhou, Guangdong, China
- Department of Coloproctology, The Sixth Affiliated Hospital, Sun Yat-sen University, 510080, Guangzhou, Guangdong, China
| | - Zhe Han
- Department of Neurology, The First Bethune Hospital of Jilin University, 130000, Changchun, Jilin, China
| | - Jiaqi Wang
- Department of Neonatology, Jiangmen People's Hospital, 52900, Jiangmen, Guangdong, China
| | - Cheng Zhong
- Department of Orthopedics, Jiangmen Hospital of Traditional Chinese Medicine Affiliated to Jinan University, 52900, Jiangmen, Guangdong, China
| | - Jiancong Chen
- Department of Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, 510080, Guangzhou, Guangdong, China
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13
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Xu K, Dong M, Wu Z, Luo L, Xie F, Li F, Huang H, Wang F, Xiong X, Wen Z. Single-Cell RNA Sequencing Identifies Crucial Genes Influencing the Polarization of Tumor-Associated Macrophages in Liver Cancer. Int J Genomics 2024; 2024:7263358. [PMID: 38938448 PMCID: PMC11208785 DOI: 10.1155/2024/7263358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 04/15/2024] [Accepted: 05/06/2024] [Indexed: 06/29/2024] Open
Abstract
Background In the context of hepatocellular carcinoma (HCC), tumor-associated macrophages (TAMs) are pivotal for the immunosuppressive nature of the tumor microenvironment (TME). This investigation delves into the functional transformations of TAMs within the TME by leveraging single-cell transcriptomics to pinpoint critical genes influencing TAM subset polarization. Methods We procured single-cell and bulk transcriptomic data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA), implementing quality assurance, dimensional reduction, clustering, and annotation on the single-cell sequencing data. To examine cellular interactions, CellChat was utilized, while single-cell regulatory network inference and clustering (SCENIC) was applied to deduce transcription factors (TFs) and their associated targets. Through gene enrichment, survival, and immune infiltration correlation analyses, we sought to pinpoint and validate influential genes. A TAM model under HCC conditions was then established to confirm the expression levels of these key genes. Results Our analysis encompassed 74,742 cells and 23,110 genes. Through postdimensional reduction and clustering, we identified seven distinct cell types and nine TAM subtypes. Analysis via CellChat highlighted a predominance of M2-phenotype-inclined TAM subsets within the tumor's core. SCENIC pinpointed the transcription factor PRDM1 and its target genes as pivotal in this region. Further analysis indicated these genes' involvement in macrophage polarization. Employing trajectory analysis, survival analysis, and immune infiltration correlation, we scrutinized and validated genes likely directing M2 polarization. Experimental validation confirmed PRDM1's heightened expression in TAMs conditioned by HCC. Conclusions Our findings suggest the PRDM1 gene is a key regulator of M2 macrophage polarization, contributing to the immunosuppressive TME in HCC.
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Affiliation(s)
- Kedong Xu
- Department of GastroenterologyThe Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Mingyi Dong
- Department of GastroenterologyThe Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Zhengqiang Wu
- Department of GastroenterologyThe Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Linfei Luo
- Department of GastroenterologyThe Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Fei Xie
- Department of GastroenterologyThe Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Fan Li
- Department of GastroenterologyThe Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Hongyan Huang
- Department of GastroenterologyThe Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Fenfen Wang
- Department of GastroenterologyThe Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Xiaofeng Xiong
- Department of GastroenterologyThe Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Zhili Wen
- Department of GastroenterologyThe Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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14
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Yang S, Wang M, Hua Y, Li J, Zheng H, Cui M, Huang N, Liu Q, Liao Q. Advanced insights on tumor-associated macrophages revealed by single-cell RNA sequencing: The intratumor heterogeneity, functional phenotypes, and cellular interactions. Cancer Lett 2024; 584:216610. [PMID: 38244910 DOI: 10.1016/j.canlet.2024.216610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 11/28/2023] [Accepted: 12/18/2023] [Indexed: 01/22/2024]
Abstract
Single-cell RNA sequencing (scRNA-seq) is an emerging technology used for cellular transcriptome analysis. The application of scRNA-seq has led to profoundly advanced oncology research, continuously optimizing novel therapeutic strategies. Intratumor heterogeneity extensively consists of all tumor components, contributing to different tumor behaviors and treatment responses. Tumor-associated macrophages (TAMs), the core immune cells linking innate and adaptive immunity, play significant roles in tumor progression and resistance to therapies. Moreover, dynamic changes occur in TAM phenotypes and functions subject to the regulation of the tumor microenvironment. The heterogeneity of TAMs corresponding to the state of the tumor microenvironment has been comprehensively recognized using scRNA-seq. Herein, we reviewed recent research and summarized variations in TAM phenotypes and functions from a developmental perspective to better understand the significance of TAMs in the tumor microenvironment.
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Affiliation(s)
- Sen Yang
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science, and Peking Union Medical College, Beijing, 100730, China
| | - Mengyi Wang
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science, and Peking Union Medical College, Beijing, 100730, China
| | - Yuze Hua
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science, and Peking Union Medical College, Beijing, 100730, China
| | - Jiayi Li
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science, and Peking Union Medical College, Beijing, 100730, China
| | - Huaijin Zheng
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science, and Peking Union Medical College, Beijing, 100730, China
| | - Ming Cui
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science, and Peking Union Medical College, Beijing, 100730, China
| | - Nan Huang
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science, and Peking Union Medical College, Beijing, 100730, China
| | - Qiaofei Liu
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science, and Peking Union Medical College, Beijing, 100730, China.
| | - Quan Liao
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science, and Peking Union Medical College, Beijing, 100730, China.
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15
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Hu M, Fan JX, He ZY, Zeng J. The regulatory role of autophagy between TAMs and tumor cells. Cell Biochem Funct 2024; 42:e3984. [PMID: 38494666 DOI: 10.1002/cbf.3984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 03/05/2024] [Accepted: 03/06/2024] [Indexed: 03/19/2024]
Abstract
Cancer has become a global public health problem and its harmful effects have received widespread attention. Conventional treatments such as surgical resection, radiotherapy and other techniques are applicable to clinical practice, but new drugs are constantly being developed and other therapeutic approaches, such as immunotherapy are being applied. In addition to studying the effects on individual tumor cells, it is important to explore the role of tumor microenvironment on tumor cell development since tumor cells do not exist alone but in the tumor microenvironment. In the tumor microenvironment, tumor cells are interconnected with other stromal cells and influence each other, among which tumor-associated macrophages (TAMs) are the most numerous immune cells. At the same time, it was found that cancer cells have different levels of autophagy from normal cells. In cancer therapy, the occurrence of autophagy plays an important role in promoting tumor cell death or inhibiting tumor cell death, and is closely related to the environment. Therefore, elucidating the regulatory role of autophagy between TAMs and tumor cells may be an important breakthrough, providing new perspectives for further research on antitumor immune mechanisms and improving the efficacy of cancer immunotherapy.
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Affiliation(s)
- Min Hu
- College of Life Sciences, Chongqing Normal University, Chongqing, 401331, China
| | - Jiao-Xiu Fan
- College of Life Sciences, Chongqing Normal University, Chongqing, 401331, China
| | - Zi-Yue He
- College of Life Sciences, Chongqing Normal University, Chongqing, 401331, China
| | - Jun Zeng
- College of Life Sciences, Chongqing Normal University, Chongqing, 401331, China
- Animal Biology Key Laboratory of Chongqing Education Commission of China
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16
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Qiu Y, Lu G, Li N, Hu Y, Tan H, Jiang C. Exosome-mediated communication between gastric cancer cells and macrophages: implications for tumor microenvironment. Front Immunol 2024; 15:1327281. [PMID: 38455041 PMCID: PMC10917936 DOI: 10.3389/fimmu.2024.1327281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Accepted: 01/25/2024] [Indexed: 03/09/2024] Open
Abstract
Gastric cancer (GC) is a malignant neoplasm originating from the epithelial cells of the gastric mucosa. The pathogenesis of GC is intricately linked to the tumor microenvironment within which the cancer cells reside. Tumor-associated macrophages (TAMs) primarily differentiate from peripheral blood monocytes and can be broadly categorized into M1 and M2 subtypes. M2-type TAMs have been shown to promote tumor growth, tissue remodeling, and angiogenesis. Furthermore, they can actively suppress acquired immunity, leading to a poorer prognosis and reduced tolerance to chemotherapy. Exosomes, which contain a myriad of biologically active molecules including lipids, proteins, mRNA, and noncoding RNAs, have emerged as key mediators of communication between tumor cells and TAMs. The exchange of these molecules via exosomes can markedly influence the tumor microenvironment and consequently impact tumor progression. Recent studies have elucidated a correlation between TAMs and various clinicopathological parameters of GC, such as tumor size, differentiation, infiltration depth, lymph node metastasis, and TNM staging, highlighting the pivotal role of TAMs in GC development and metastasis. In this review, we aim to comprehensively examine the bidirectional communication between GC cells and TAMs, the implications of alterations in the tumor microenvironment on immune escape, invasion, and metastasis in GC, targeted therapeutic approaches for GC, and the efficacy of potential GC drug resistance strategies.
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Affiliation(s)
- Yue Qiu
- Medical Oncology Department of Gastrointestinal Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, China
| | - Guimei Lu
- Department of Laboratory, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, China
| | - Na Li
- Medical Oncology Department of Gastrointestinal Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, China
| | - Yanyan Hu
- Medical Oncology Department of Gastrointestinal Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, China
| | - Hao Tan
- Thoracic Esophageal Radiotherapy Department, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, China
| | - Chengyao Jiang
- Department of Gastric Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, China
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17
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Lee YR. A multidisciplinary approach with immunotherapies for advanced hepatocellular carcinoma. JOURNAL OF LIVER CANCER 2023; 23:316-329. [PMID: 37743048 PMCID: PMC10565553 DOI: 10.17998/jlc.2023.09.04] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 08/30/2023] [Accepted: 09/04/2023] [Indexed: 09/26/2023]
Abstract
Hepatocellular carcinoma (HCC) is a highly aggressive disease that is usually diagnosed at an advanced stage. Advanced HCC has limited treatment options and often has a poor prognosis. For the past decade, tyrosine kinase inhibitors have been the only treatments approved for advanced HCC that have shown overall survival (OS) benefits; however, but their clinical efficacy has been limited. Recent trials have demonstrated promising advancements in survival outcomes through immunotherapy-based treatments, such as combinations of immune checkpoint inhibitors (ICIs) with other ICIs, antiangiogenic drugs, and locoregional therapies. The atezolizumab-bevacizumab and durvalumab-tremelimumab (STRIDE) regimen has significantly improved survival rates as a first-line treatment and has become the new standard of care. Therefore, combined treatments for advanced HCC can result in better treatment outcomes owing to their synergistic effects, which requires a multidisciplinary approach. Ongoing studies are examining other therapeutic innovations that can improve disease control and OS rates. Despite improvements in the treatment of advanced HCC, further studies on the optimal treatment selection and sequences, biomarker identification, combination approaches with other therapies, and development of novel immunotherapy agents are required. This review presents the current treatment options and clinical data of the ICI-based combination immunotherapies for advanced HCC from a multidisciplinary perspective.
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Affiliation(s)
- Yu Rim Lee
- Department of Internal Medicine, Kyungpook National University Chilgok Hospital, School of Medicine, Kyungpook National University, Daegu, Korea
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18
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Wang Q, Lin Y, Yu W, Chen X, He Q, Ye Z. The core role of macrophages in hepatocellular carcinoma: the definition of molecular subtypes and the prognostic risk system. Front Pharmacol 2023; 14:1228052. [PMID: 37693905 PMCID: PMC10491020 DOI: 10.3389/fphar.2023.1228052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 08/11/2023] [Indexed: 09/12/2023] Open
Abstract
Background: In patients with hepatocellular carcinoma (HCC), the tumor microenvironment (TME) is resistant to immunotherapy because of its specificity. It is meaningful to explore the role of macrophage, which is one of the most abundant immune cells in the TME, in cellular communication and its effect on the prognosis and immunotherapy of HCC. Methods: Dimensionality reduction and clustering of the single-cell RNA-seq data from the GSE149614 dataset were carried out to identify the cellular composition of HCC. CellChat was used to analyze the communication between different cells. The specifically highly expressed genes of macrophages were extracted for univariate Cox regression analysis to obtain prognostic genes for HCC cluster analysis, and the risk system of macrophage-specifically highly expressed genes was developed by random forest analysis and multivariate Cox regression analysis. Prognosis, TME infiltration, potential responses to immunotherapy, and antineoplastic drugs were compared among molecular subtypes and between risk groups. Results: We found that HCC included nine identifiable cell types, of which macrophages had the highest communication intensity with each of the other eight cell types. Of the 179 specifically highly expressed genes of macrophage, 56 were significantly correlated with the prognosis of HCC, which classified HCC into three subtypes, which were reproducible and produced different survival outcomes, TME infiltration, and immunotherapy responses among the subtypes. In the integration of four macrophage-specifically highly expressed genes for the development of a risk system, the risk score was significantly involved in higher immune cell infiltration, poor prognosis, immunotherapy response rate, and sensitivity of six drugs. Conclusion: In this study, through single-cell RNA-seq data, we identified nine cell types, among which macrophage had the highest communication intensity with the rest of the cell types. Based on specifically highly expressed genes of macrophage, we successfully divided HCC patients into three clusters with distinct prognosis, TME, and therapeutic response. Additionally, a risk system was constructed, which provided a potential reference index for the prognostic target and preclinical individualized treatment of HCC.
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Affiliation(s)
- Qiaona Wang
- Department of Breast Surgery, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Yunshou Lin
- Department of Hernia and Hepatobiliary Surgery, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Wenguan Yu
- Department of Hernia and Hepatobiliary Surgery, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Xiaogang Chen
- Department of Hernia and Hepatobiliary Surgery, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Qingqing He
- Department of Breast Surgery, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Zhiyu Ye
- Department of Hernia and Hepatobiliary Surgery, The First Affiliated Hospital of Ningbo University, Ningbo, China
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19
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Shen C, Li M, Duan Y, Jiang X, Hou X, Xue F, Zhang Y, Luo Y. HDAC inhibitors enhance the anti-tumor effect of immunotherapies in hepatocellular carcinoma. Front Immunol 2023; 14:1170207. [PMID: 37304265 PMCID: PMC10250615 DOI: 10.3389/fimmu.2023.1170207] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 05/18/2023] [Indexed: 06/13/2023] Open
Abstract
Hepatocellular carcinoma (HCC), the most common liver malignancy with a poor prognosis and increasing incidence, remains a serious health problem worldwide. Immunotherapy has been described as one of the ideal ways to treat HCC and is transforming patient management. However, the occurrence of immunotherapy resistance still prevents some patients from benefiting from current immunotherapies. Recent studies have shown that histone deacetylase inhibitors (HDACis) can enhance the efficacy of immunotherapy in a variety of tumors, including HCC. In this review, we present current knowledge and recent advances in immunotherapy-based and HDACi-based therapies for HCC. We highlight the fundamental dynamics of synergies between immunotherapies and HDACis, further detailing current efforts to translate this knowledge into clinical benefits. In addition, we explored the possibility of nano-based drug delivery system (NDDS) as a novel strategy to enhance HCC treatment.
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Affiliation(s)
- Chen Shen
- Department of Laboratory Medicine, Medical Equipment Innovation Research Center/Medical Device Regulatory Research and Evaluation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Mei Li
- Department of Laboratory Medicine, Medical Equipment Innovation Research Center/Medical Device Regulatory Research and Evaluation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yujuan Duan
- School of Chemical Science and Engineering, Tongji University, Shanghai, China
- School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Xin Jiang
- Department of Laboratory Medicine, Medical Equipment Innovation Research Center/Medical Device Regulatory Research and Evaluation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoming Hou
- Department of Laboratory Medicine, Medical Equipment Innovation Research Center/Medical Device Regulatory Research and Evaluation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Fulai Xue
- Department of Laboratory Medicine, Medical Equipment Innovation Research Center/Medical Device Regulatory Research and Evaluation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yinan Zhang
- School of Chemical Science and Engineering, Tongji University, Shanghai, China
| | - Yao Luo
- Department of Laboratory Medicine, Medical Equipment Innovation Research Center/Medical Device Regulatory Research and Evaluation Center, West China Hospital, Sichuan University, Chengdu, China
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Ren H, Kang N, Yin S, Xu C, Qu T, Dai D. Characteristic of molecular subtypes based on PANoptosis-related genes and experimental verification of hepatocellular carcinoma. Aging (Albany NY) 2023; 15:204720. [PMID: 37171396 DOI: 10.18632/aging.204720] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 05/03/2023] [Indexed: 05/13/2023]
Abstract
Hepatocellular carcinoma (HCC) is a type of liver cancer that originates from liver cells. It is one of the most common types of liver cancer and a leading cause of cancer-related death worldwide. Early detection and treatment can improve the HCC prognosis. Therefore, it is necessary to further improve HCC markers and risk stratification. PANoptosome is a cytoplasmic polymer protein complex that regulates a proinflammatory programmed cell death pathway called "PANoptosis". The role of PANoptosis in HCC remains unclear. In this study, the molecular changes of PANoptosis related genes (PAN-RGs) in HCC were systematically evaluated. We characterized the heterogeneity of HCC by using consensus clustering to identify two distinct subtypes. The two subtypes showed different survival rate, biological function, chemotherapy drug sensitivity and immune microenvironment. After identification of PAN-RG differential expression genes (DEGs), a prognostic model was established by Cox regression analysis using minimum absolute contraction and selection operator (LASSO), and its prognostic value was verified by Cox regression analysis, Kaplan-Meier curve and receiver operating characteristic (ROC) curve. Our own specimens were also used to further validate the prognostic significance and possible clinical value of the selected targets. Subsequently, we conducted a preliminary discussion on the reasons for the influence of the model on the prognosis through TME analysis, drug resistance analysis, TMB analysis and other studies. This study provides a new idea for individualized and precise treatment of HCC.
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Affiliation(s)
- Haitao Ren
- Department of Interventional Medicine, The Affiliated Hospital of Qingdao University, Qingdao, Shangdong 266071, China
| | - Na Kang
- Operating Room, The Affiliated Hospital of Qingdao University, Qingdao, Shangdong 266071, China
| | - Shuan Yin
- Department of Pediatrics, The Affiliated Hospital of Qingdao University, Qingdao, Shangdong 266071, China
| | - Chen Xu
- Department of Infectious Disease, The Affiliated Hospital of Qingdao University, Qingdao, Shangdong 266071, China
| | - Tengfei Qu
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shangdong 266071, China
| | - Dongdong Dai
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shangdong 266071, China
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21
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Ebrahimi N, Far NP, Fakhr SS, Faghihkhorasani F, Miraghel SA, Chaleshtori SR, Rezaei-Tazangi F, Beiranvand S, Baziyar P, Manavi MS, Zarrabi A, Nabavi N, Ren J, Aref AR. The endocannabinoid system, a new gatekeeper in the pharmacology of human hepatocellular carcinoma. ENVIRONMENTAL RESEARCH 2023; 228:115914. [PMID: 37062475 DOI: 10.1016/j.envres.2023.115914] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 04/01/2023] [Accepted: 04/13/2023] [Indexed: 05/06/2023]
Abstract
Despite numerous prevention methodologies and treatment options, hepatocellular carcinoma (HCC) still remains as the third leading life-threatening cancer. It is thus pertinent to develop new treatment modality to fight this devastating carcinoma. Ample recent studies have shown the anti-inflammatory and antitumor roles of the endocannabinoid system in various forms of cancers. Preclinical studies have also confirmed that cannabinoid therapy can be an optimal regimen for cancer treatments. The endocannabinoid system is involved in many cancer-related processes, including induction of endoplasmic reticulum (ER) stress-dependent apoptosis, autophagy, PITRK and ERK signaling pathways, cell invasion, epithelial-mesenchymal transition (EMT), and cancer stem cell (CSC) phenotypes. Moreover, changes in signaling transduction of the endocannabinoid system can be a potential diagnostic and prognostic biomarker for HCC. Due to its pivotal role in lipid metabolism, the endocannabinoid system affects metabolic reprogramming as well as lipid content of exosomes. In addition, due to the importance of non-coding RNAs (ncRNAs), several studies have examined the relationship between microRNAs and the endocannabinoid system in HCC. However, HCC is a pathological condition with high heterogeneity, and therefore using the endocannabinoid system for treatment has faced many controversies. While some studies favored a role of the endocannabinoid system in carcinogenesis and tumor induction, others exhibited the anticancer potential of endocannabinoids in HCC. In this review, specific studies delineating the relationship between endocannabinoids and HCC are examined. Based on collected findings, detailed studies of the molecular mechanism of endocannabinoids as well as preclinical studies for investigating therapeutic or carcinogenic impacts in HCC cancer are strongly suggested.
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Affiliation(s)
- Nasim Ebrahimi
- Genetics Division, Department of Cell and Molecular Biology and Microbiology, Faculty of Science and Technology, University of Isfahan, Iran
| | - Nazanin Pazhouhesh Far
- Department of Microbiology,Faculty of Advanced Science and Technology, Tehran Medical Science, Islamic Azad University, Tehran, Iran
| | - Siavash Seifollahy Fakhr
- Division of Biotechnology, Faculty of Applied Ecology, Agricultural Sciences and Biotechnology, Campus, Hamar, Norway
| | | | - Seyed Ali Miraghel
- Nocivelli Institute for Molecular Medicine, Department of Molecular and Translational Medicine, University of Brescia, Italy
| | | | - Fatemeh Rezaei-Tazangi
- Department of Anatomy, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Sheida Beiranvand
- Department of Biotechnology, School of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Payam Baziyar
- Department of Molecular and Cell Biology, Faculty of Basic Science, Uinversity of Mazandaran, Babolsar, Iran
| | | | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul, 34396, Turkey
| | - Noushin Nabavi
- Department of Urological Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, V6H3Z6, Canada
| | - Jun Ren
- Department of Cardiology, Zhongshan Hospital Fudan University, Shanghai, 200032, China; Department of Laboratory Medicine and Pathology, University of Washington, WA, 98195, USA
| | - Amir Reza Aref
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA; Xsphera Biosciences, Translational Medicine Group, 6 Tide Street, Boston, MA, 02210, USA.
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Yin Z, Ma T, Chen S, Yu M. Identification of therapeutic targets and prognostic biomarkers among CXC chemokines in hepatocellular carcinoma microenvironment. Cancer Biomark 2023; 36:231-250. [PMID: 36938723 DOI: 10.3233/cbm-210300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/15/2023]
Abstract
BACKGROUD Hepatocellular carcinoma (HCC) is characterized by occult onset, rapid progression and poor prognosis. CXC chemokines play an important role in tumor microenvironment and development. OBJECTIVE The potential mechanistic values of CXC chemokines as clinical biomarkers and therapeutic targets in HCC have not been fully clarified. METHODS ONCOMINE, UALCAN, GEPIA, cBioPortal, SurvExpress, MethSurv, SurvivalMeth, String, GeneMANIA, DAVID, Metascape, TRRUST, LinkedOmics, and Timer were applied in this study. RESULTS The transcriptional levels of CXCL9/16/17 in HCC tissues were significantly elevated while CXCL1/2/5/6/7/12/14 were significantly reduced. significant correlation was found between the expression of CXC3/5 and the pathological stage of HCC patients. High level of CXCL4 was associated with a longer disease-free survival. For overall survival, lower expressions of CXCL1/3/5/8 and higher expressions of CXCL2 were associated with a better outcome. In addition, the prognostic values of CXC chemokines signature in HCC were explored in four independent cohorts, the high-risk group displayed unfavorable survival outcome compared with the low-risk group. And for the prognostic value of the DNA methylation of CXC chemokines, we identified the CpGs which were significantly associated with prognosis in HCC patients. DNA methylation signature analysis also showed a statistically significant association between the high- and low-risk group. For potential mechanism, the neighbor gene networks, interaction analyses, functional enrichment analyses of CC chemokine receptors in HCC were performed, the transcription factor targets, kinase targets, and miRNA targets of CXC chemokines were also identified in HCC. We also found significant correlations among CXC chemokines expression and the infiltration of immune cells, the tumor infiltration levels among HCC with different somatic copy number alterations of these chemokine receptors were also assessed. Moreover, the Cox proportional hazard model showed that CCR2/6/8/12, B_cell, macrophage and dendritic _cell were significantly related to the clinical outcome of HCC patients. CONCLUSION CXC chemokines might serve as therapeutic targets and prognostic biomarkers in HCC.
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Affiliation(s)
- Zi Yin
- General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
| | - Tingting Ma
- Obstetrics and Gynecology Department, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Sheng Chen
- General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
| | - Min Yu
- General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
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Huang H, Yao H, Wei Y, Chen M, Sun J. Cellular senescence-related long noncoding ribonucleic acids: Predicting prognosis in hepatocellular carcinoma. Cancer Rep (Hoboken) 2023; 6:e1791. [PMID: 36726348 PMCID: PMC10075286 DOI: 10.1002/cnr2.1791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 01/10/2023] [Accepted: 01/21/2023] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Due to their inherent role in cell function, long non-coding ribonucleic acids (lncRNAs) mediate changes in the microenvironment, and thereby participate in the development of cellular senescence. AIMS This study aimed to identify cellular senescence-related lncRNAs that could predict the prognosis of liver cancer. METHODS AND RESULTS Gene expression and clinical data were downloaded from the UCSC Xena platform, ICGC, and TCGA databases. Cox regression and LASSO regression were used to establish a cellular senescence-related lncRNA model. ROC curves and Kaplan-Meier survival curves were then constructed to predict patient prognosis. Cox regression analysis and clinical characteristics were used to evaluate the capability of the model. Tumor mutational burden and tumor-infiltrating immune cell analyses were subsequently performed in the risk subgroups and the samples in the entire cohort were reclustered. Finally, potential small molecule immune-targeted drugs were identified based on the model. The cellular senescence-related prognostic model that was constructed based on AGAP11 and FAM182B. Along with the results of Cox regression and Lasso regression, the risk score was found to be an independent factor for predicting overall survival in cohorts. In the subgroup analysis, the prognosis of the low-risk group in each cohort was significantly higher than that of the high-risk group; the area under temporal ROC curves and clinical ROC curves were all greater than 0.65, respectively. C-index shows that the risk scores are greater than 0.6, showing the stability of the model. The high-risk group demonstrated lower tumor microenvironment and higher tumor mutational burden scores, further verifying the reliability of the model grouping results. Analysis of tumor-infiltrating immune cells indicated that CD8+ and γδ T cells were more abundant among patients in the low-risk group; cluster reorganization indicated that the two groups had different prognoses and proportions of immune cells. The p value of potential drugs predicted based on the expression of model lncRNAs were all less than .05, demonstrating the potential of model lncRNAs as therapeutic targets to some extent. CONCLUSION A prognostic model based on cellular senescence-associated lncRNAs was established and this may be used as a potential biomarker for the prognosis assessment of liver cancer patients.
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Affiliation(s)
- Hao Huang
- Department of Hepatopancreatobiliary Surgery, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Hao Yao
- Department of Hepatopancreatobiliary Surgery, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Yaqing Wei
- Department of Hepatopancreatobiliary Surgery, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Ming Chen
- Department of Hepatopancreatobiliary Surgery, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Jinjin Sun
- Department of Hepatopancreatobiliary Surgery, The Second Hospital of Tianjin Medical University, Tianjin, China
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Wang K, Hou H, Zhang Y, Ao M, Luo H, Li B. Ovarian cancer-associated immune exhaustion involves SPP1+ T cell and NKT cell, symbolizing more malignant progression. Front Endocrinol (Lausanne) 2023; 14:1168245. [PMID: 37143732 PMCID: PMC10151681 DOI: 10.3389/fendo.2023.1168245] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 04/04/2023] [Indexed: 05/06/2023] Open
Abstract
Background Ovarian cancer (OC) is highly heterogeneous and has a poor prognosis. A better understanding of OC biology could provide more effective therapeutic paradigms for different OC subtypes. Methods To reveal the heterogeneity of T cell-associated subclusters in OC, we performed an in-depth analysis of single-cell transcriptional profiles and clinical information of patients with OC. Then, the above analysis results were verified by qPCR and flow cytometry examine. Results After screening by threshold, a total of 85,699 cells in 16 ovarian cancer tissue samples were clustered into 25 major cell groups. By performing further clustering of T cell-associated clusters, we annotated a total of 14 T cell subclusters. Then, four distinct single-cell landscapes of exhausted T (Tex) cells were screened, and SPP1 + Tex significantly correlated with NKT cell strength. A large amount of RNA sequencing expression data combining the CIBERSORTx tool were labeled with cell types from our single-cell data. Calculating the relative abundance of cell types revealed that a greater proportion of SPP1 + Tex cells was associated with poor prognosis in a cohort of 371 patients with OC. In addition, we showed that the poor prognosis of patients in the high SPP1 + Tex expression group might be related to the suppression of immune checkpoints. Finally, we verified in vitro that SPP1 expression was significantly higher in ovarian cancer cells than in normal ovarian cells. By flow cytometry, knockdown of SPP1 in ovarian cancer cells could promote tumorigenic apoptosis. Conclusion This is the first study to provide a more comprehensive understanding of the heterogeneity and clinical significance of Tex cells in OC, which will contribute to the development of more precise and effective therapies.
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25
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Zhang Q, Ma L, Zhou H, Zhou Y, Liu S, Li Q. A prognostic signature of cuproptosis and TCA-related genes for hepatocellular carcinoma. Front Oncol 2022; 12:1040736. [PMID: 36324575 PMCID: PMC9619237 DOI: 10.3389/fonc.2022.1040736] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 10/03/2022] [Indexed: 11/26/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is the most common malignant tumor of the liver. Cuproptosis is a newly defined form of cell death. Copper ion induces cell death by binding to the tricarboxylic acid cycle (TCA). The effect of cuproptosis-related and TCA-related genes on the clinical prognosis of HCC is still unclear. In this study, we explores the genetic changes of cuproptosis-related genes that affect the TCA process and their potential therapeutic value in HCC patients. Methods The cuproptosis and TCA-related genes were obtained from cuproptosis-related articles and the molecular signatures database. The prognosis signatures of eight related genes were constructed using the last absolute shrinkage and selection operator (LASSO), and Receiver Operating Characteristic (ROC) curves were used to evaluate the signature. In addition, we analyzed downstream functional enrichment and immune infiltration to explore cuproptosis-inducing drugs and immunotherapeutic responses. All these analyses were validated using multiple datasets of the International Cancer Genome Consortium (ICGC). Results TCA and copper malnutrition-related genes (CDKN2A, IDH1, OGDHL, IDH3G, IDH3B, GLS, DLAT, LIPT1) were finally included. According to the risk score, they were divided into high-risk and low-risk groups. Survival analysis showed that the overall survival (OS) of the high-risk group was significantly lower than that of the low-risk group. We established a risk prognostic feature to predict the OS of patients with HCC. Based on this feature and the clinical stage, we constructed a nomogram. Functional enrichment analysis revealed pathways related to organelle division and the cell cycle. Different risk scores had different immune abundances in immune cells (including macrophages and regulatory T-cells) and immune pathways (including antigen-presenting cells co-stimulation). Moreover, the drug sensitivity of eleschomol and PD-L1 in the high-risk group was better than that in the low-risk group. The status of TP53 somatic mutation was also closely related to the risk score. Conclusion In this study, we established a new prediction signature of eight genes related to cuproptosis and the TCA process, which can effectively predict the prognosis of HCC patients.
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26
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Sukowati C, Cabral LKD, Tiribelli C. Immune checkpoint and angiogenic inhibitors for the treatment of hepatocellular carcinoma: It takes two to tangle. Ann Hepatol 2022; 27:100740. [PMID: 35809835 DOI: 10.1016/j.aohep.2022.100740] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 06/27/2022] [Indexed: 02/04/2023]
Abstract
Immunotherapy represents an effective and promising option in various cancers, including in hepatocellular carcinoma (HCC). The immune checkpoint inhibitors (ICIs) have shown a remarkable breakthrough in the last decade, in addition to molecular targeted therapy of angiogenesis such as tyrosine kinases inhibitors. ICIs provide new regimen that can be applied in different stages of the disease. In parallel, HCC progression is related to the tumor microenvironment (TME), involving the cross-talk between various cellular and non-cellular components within the TME niche. It appears logical to synergistically target several HCC components to increase the efficacy of the treatment. In this paper, we summarize evidence that the combination therapy of ICIs and angiogenesis inhibitors would be a potentially better strategy for HCC treatment.
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Affiliation(s)
- Caecilia Sukowati
- Fondazione Italiana Fegato ONLUS, AREA Science Park Campus Basovizza, SS14 km 163.5, Trieste 34149, Italy; Eijkman Research Center for Molecular Biology, National Research and Innovation Agency of Indonesia (BRIN), B.J. Habibie Building, Jl. M.H. Thamrin No. 8, Jakarta Pusat 10340, Indonesia.
| | - Loraine Kay D Cabral
- Fondazione Italiana Fegato ONLUS, AREA Science Park Campus Basovizza, SS14 km 163.5, Trieste 34149, Italy; Doctoral School in Molecular Biomedicine, University of Trieste, Piazzale Europa, 1, Trieste 34127, Italy
| | - Claudio Tiribelli
- Fondazione Italiana Fegato ONLUS, AREA Science Park Campus Basovizza, SS14 km 163.5, Trieste 34149, Italy
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27
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Kang SM, Khalil L, El-Rayes BF, Akce M. Rapidly Evolving Landscape and Future Horizons in Hepatocellular Carcinoma in the Era of Immuno-Oncology. Front Oncol 2022; 12:821903. [PMID: 35433430 PMCID: PMC9008732 DOI: 10.3389/fonc.2022.821903] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 03/08/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a serious global health problem as one of the leading causes of cancer-related death worldwide. Systemic therapy for advanced HCC has progressed with the development of molecular targeted agents, however survival benefits remain modest. More recently, immune checkpoint inhibitors (ICI) have emerged and exhibited promising therapeutic benefits in a subset of patients. Physiologically, the intrinsic microenvironment in the liver is immunosuppressive, which represents a major obstacle for effective immune therapies in primary and secondary liver malignancies. For this reason, combination therapies that can overcome immune inhibitory mechanisms and enhance the immune response are a rationale approach for drug development in HCC. A recent example is the combination of the anti-PD-L1 antibody (atezolizumab) and anti-VEGF-A antibody (bevacizumab), which has shown significant improvement in survival as compared to standard of care in the first-line treatment for HCC. Other immunotherapy approaches including cancer vaccines and adoptive cell therapy are also under investigation. This review summarizes the key trials leading to our current HCC treatment options and provides an overview of future immune-based strategies in development.
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Affiliation(s)
| | | | | | - Mehmet Akce
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, United States
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28
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Tumor Microenvironment of Hepatocellular Carcinoma: Challenges and Opportunities for New Treatment Options. Int J Mol Sci 2022; 23:ijms23073778. [PMID: 35409139 PMCID: PMC8998420 DOI: 10.3390/ijms23073778] [Citation(s) in RCA: 106] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/25/2022] [Accepted: 03/26/2022] [Indexed: 02/06/2023] Open
Abstract
The prevalence of liver cancer is constantly rising, with increasing incidence and mortality in Europe and the USA in recent decades. Among the different subtypes of liver cancers, hepatocellular carcinoma (HCC) is the most commonly diagnosed liver cancer. Besides advances in diagnosis and promising results of pre-clinical studies, HCC remains a highly lethal disease. In many cases, HCC is an effect of chronic liver inflammation, which leads to the formation of a complex tumor microenvironment (TME) composed of immune and stromal cells. The TME of HCC patients is a challenge for therapies, as it is involved in metastasis and the development of resistance. However, given that the TME is an intricate system of immune and stromal cells interacting with cancer cells, new immune-based therapies are being developed to target the TME of HCC. Therefore, understanding the complexity of the TME in HCC will provide new possibilities to design novel and more effective immunotherapeutics and combinatorial therapies to overcome resistance to treatment. In this review, we describe the role of inflammation during the development and progression of HCC by focusing on TME. We also describe the most recent therapeutic advances for HCC and possible combinatorial treatment options.
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Xing R, Gao J, Cui Q, Wang Q. Strategies to Improve the Antitumor Effect of Immunotherapy for Hepatocellular Carcinoma. Front Immunol 2021; 12:783236. [PMID: 34899747 PMCID: PMC8660685 DOI: 10.3389/fimmu.2021.783236] [Citation(s) in RCA: 112] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Accepted: 11/09/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC), one of the most fatal malignancies in the world, is usually diagnosed in advanced stages due to late symptom manifestation with very limited therapeutic options, which leads to ineffective intervention and dismal prognosis. For a decade, tyrosine kinase inhibitors (TKIs) have offered an overall survival (OS) benefit when used in a first-line (sorafenib and lenvatinib) and second-line setting (regorafenib and cabozantinib) in advanced HCC, while long-term response remains unsatisfactory due to the onset of primary or acquired resistance. Recently, immunotherapy has emerged as a promising therapy in the treatment of several solid tumors, such as melanoma and non-small cell lung cancer. Moreover, as the occurrence of HCC is associated with immune tolerance and immunosurveillance escape, there is a potent rationale for employing immunotherapy in HCC. However, immunotherapy monotherapy, mainly including immune checkpoint inhibitors (ICIs) that target checkpoints programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and the cytotoxic T lymphocyte antigen-4 (CTLA-4), has a relatively low response rate. Thus, the multi-ICIs or the combination of immunotherapy with other therapies, like antiangiogenic drugs and locoregional therapies, has become a novel strategy to treat HCC. Combining different ICIs may have a synergistical effect attributed to the complementary effects of the two immune checkpoint pathways (CTLA-4 and PD-1/PD-L1 pathways). The incorporation of antiangiogenic drugs in ICIs can enhance antitumor immune responses via synergistically regulating the vasculature and the immune microenvironment of tumor. In addition, locoregional treatments can improve antitumor immunity by releasing the neoplasm antigens from killed tumor cells; in turn, this antitumor immune response can be intensified by immunotherapy. Therefore, the combination of locoregional treatments and immunotherapy may achieve greater efficacy through further synergistic effects for advanced HCC. This review aims to summarize the currently reported results and ongoing trials of the ICIs-based combination therapies for HCC to explore the rational combination strategies and further improve the survival of patients with HCC.
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Affiliation(s)
- Rui Xing
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jinping Gao
- Department of Oncology, North War Zone General Hospital, Shenyang, China
| | - Qi Cui
- Department of Cold Environmental Medicine, College of High Altitude Military Medicine, Third Military Medical University (Army Medical University), Chongqing, China
| | - Qian Wang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
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Japir AAWMM, Ke W, Li J, Mukerabigwi JF, Ibrahim A, Wang Y, Li X, Zhou Q, Mohammed F, Ge Z. Tumor-dilated polymersome nanofactories for enhanced enzyme prodrug chemo-immunotherapy. J Control Release 2021; 339:418-429. [PMID: 34662586 DOI: 10.1016/j.jconrel.2021.10.015] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 09/30/2021] [Accepted: 10/12/2021] [Indexed: 12/18/2022]
Abstract
Combination chemo-immunotherapy of cancers has attracted great attention due to its significant synergistic antitumor effect. The response rates and therapeutic efficacy of immunotherapy can be enhanced significantly after proper combination with chemotherapy. However, chemo-immunotherapy is frequently limited by severe immune-related adverse events and systemic side toxicity. In this report, efficient nanofactory-directed enzyme prodrug chemo-immunotherapy is demonstrated based on enzyme-loaded tumor-dilatable polymersomes with optimized membrane cross-linking density. Upon intravenous injection of the nanofactories, they can passively accumulate at the tumor site. The tumor pH-responsive nanofactories can swell from ~100 nm to ~200 nm under the trigger of tumor acidity, leading to prolonged retention of up to one week inside tumor tissues. Simultaneously, the membrane permeability of the nanofactories has improved significantly, which allows hydrophilic small molecules to pass across the membranes while keeping the enzymes in the inner cavities. Subsequently, the non-toxic prodrug mixtures of chemo-immunotherapy are administrated three times within 6 days, which are in situ activated by the nanofactories selectively at tumor sites. Activated chemotherapeutic drugs kill cancer cells and generate tumor-associated antigens to promote the maturation of dendritic cells. Activated indoleamine 2, 3-dioxygenase 1 inhibitors reverse the immunosuppressive tumor microenvironment. Finally, primary tumors can be effectively suppressed while causing minimal systemic toxicity. The distant tumors that are established after treatment can also be inhibited completely via activation of antitumor immunity in mice. Thus, the tumor-dilatable polymersome nanofactories with long-term intratumoral retention offer a promising paradigm for enhanced enzyme prodrug chemo-immunotherapy.
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Affiliation(s)
- Abd Al-Wali Mohammed M Japir
- CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei 230026, Anhui, China
| | - Wendong Ke
- CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei 230026, Anhui, China
| | - Junjie Li
- Innovation Center of Nanomedicine, Kawasaki Institute of Industrial Promotion, 3-25-14, Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan
| | - Jean Felix Mukerabigwi
- CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei 230026, Anhui, China
| | - Alhadi Ibrahim
- CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei 230026, Anhui, China
| | - Yuheng Wang
- CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei 230026, Anhui, China
| | - Xiang Li
- CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei 230026, Anhui, China
| | - Qinghao Zhou
- CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei 230026, Anhui, China
| | - Fathelrahman Mohammed
- CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei 230026, Anhui, China
| | - Zhishen Ge
- CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei 230026, Anhui, China.
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31
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Zhang Y, Zhang T, Yin Q, Luo H. Development and validation of genomic and epigenomic signatures associated with tumor immune microenvironment in hepatoblastoma. BMC Cancer 2021; 21:1156. [PMID: 34711185 PMCID: PMC8555350 DOI: 10.1186/s12885-021-08893-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Accepted: 10/14/2021] [Indexed: 02/07/2023] Open
Abstract
Background This study aimed to probe and verify aberrantly methylated and expressed genes in hepatoblastoma and to analyze their interactions with tumor immune microenvironment. Methods Aberrantly methylated and expressed genes were obtained by comprehensively analyzing gene expression and DNA methylation profiles from GSE81928, GSE75271 and GSE78732 datasets. Their biological functions were predicted by the STRING and Metascape databases. CIBERSORT was utilized for inferring the compositions of tumor-infiltrating immune cells (TIICs) in each sample. Correlation between hub genes and immune cells was then analyzed. Hub genes were validated in hepatoblastoma tissues via western blot or immunohistochemistry. After transfection with sh-NOTUM, migration and invasion of HuH-6 and HepG2 cells were investigated. The nude mouse tumorigenesis model was constructed. Results Totally, 83 aberrantly methylated and expressed genes were determined in hepatoblastoma, which were mainly involved in metabolic and cancer-related pathways. Moreover, their expression was liver-specific. 13 hub genes were screened, which were closely related to immune cells in hepatoblastoma tissues. Among them, it was confirmed that AXIN2, LAMB1 and NOTUM were up-regulated and SERPINC1 was down-regulated in hepatoblastoma than normal tissues. NOTUM knockdown distinctly weakened migration and invasion of HuH-6 and HepG2 cells and tumor growth in vivo. Conclusions This study identified aberrantly methylated and expressed signatures that were in relation to immune microenvironment in hepatoblastoma. Targeting NOTUM hub gene could suppress migration and invasion of hepatoblastoma cells. Thus, these aberrantly methylated and expressed genes might act as therapeutic agents in hepatoblastoma therapy. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08893-3.
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Affiliation(s)
- Yanbing Zhang
- Department of General Surgery, Hunan Children's Hospital, No.86 Ziyuan Road, Changsha, 410007, Hunan, China
| | - Tian Zhang
- Department of General Surgery, Hunan Children's Hospital, No.86 Ziyuan Road, Changsha, 410007, Hunan, China
| | - Qiang Yin
- Department of General Surgery, Hunan Children's Hospital, No.86 Ziyuan Road, Changsha, 410007, Hunan, China.
| | - Haiyan Luo
- Department of Emergency, Hunan Children's Hospital, No.86 Ziyuan Road, Changsha, 410007, Hunan, China.
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32
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Lam M, Reales-Calderon JA, Ow JR, Adriani G, Pavesi A. In vitro 3D liver tumor microenvironment models for immune cell therapy optimization. APL Bioeng 2021; 5:041502. [PMID: 34632251 PMCID: PMC8492081 DOI: 10.1063/5.0057773] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 08/03/2021] [Indexed: 12/24/2022] Open
Abstract
Despite diagnostic and therapeutic advances, liver cancer kills more than 18 million people every year worldwide, urging new strategies to model the disease and to improve the current therapeutic options. In vitro tumor models of human cancer continue to evolve, and they represent an important screening tool. However, there is a tremendous need to improve the physiological relevance and reliability of these in vitro models to fulfill today's research requirements for better understanding of cancer progression and treatment options at different stages of the disease. This review describes the hepatocellular carcinoma microenvironmental characteristics and illustrates the current immunotherapy strategy to fight the disease. Moreover, we present a recent collection of 2D and 3D in vitro liver cancer models and address the next generation of in vitro systems recapitulating the tumor microenvironment complexity in more detail.
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Affiliation(s)
- Maxine Lam
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research (ASTAR), Singapore, Singapore
| | - Jose Antonio Reales-Calderon
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research (ASTAR), Singapore, Singapore
| | - Jin Rong Ow
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research (ASTAR), Singapore, Singapore
| | - Giulia Adriani
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (ASTAR), Singapore, Singapore
| | - Andrea Pavesi
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research (ASTAR), Singapore, Singapore
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33
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Davuluri GVN, Chen CC, Chiu YC, Tsai HW, Chiu HC, Chen YL, Tsai PJ, Kuo WT, Tsao N, Lin YS, Chang CP. Autophagy Drives Galectin-1 Secretion From Tumor-Associated Macrophages Facilitating Hepatocellular Carcinoma Progression. Front Cell Dev Biol 2021; 9:741820. [PMID: 34552935 PMCID: PMC8450461 DOI: 10.3389/fcell.2021.741820] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 08/19/2021] [Indexed: 12/12/2022] Open
Abstract
Galectin-1 (Gal-1) is a secretory lectin with pro-tumor activities and is associated strongly with hepatocellular carcinoma (HCC) development. Although Gal-1 is a well-known soluble pro-tumor factor in the tumor microenvironment (TME), the secretion mode of Gal-1 is not clearly defined. On the other hand, in addition to cancer cells, Gal-1 is widely expressed in tumor stromal cells, including tumor-associated macrophages (TAMs). TAMs are a significant component of stromal cells in TME; however, their contributions in producing Gal-1 to TME are still not explored. Here we reveal that TAMs can actively secrete Gal-1 in response to stimuli of HCC cells. Gal-1 produced by TAMs leads to an increase of the systemic level of Gal-1 and HCC tumor growth in mice. Mechanistically, TLR2-dependent secretory autophagy is found to be responsible for Gal-1 secretion from TAMs. Gal-1 acts as a cargo of autophagosomes to fuse with multivesicular bodies via Rab11 and VAMP7-mediated vesicle trafficking before being secreted. This autophagy-regulated Gal-1 secretion in TAMs correlates to poor overall survival and progression-free survival rates of HCC patients. Our findings uncover the secretion mode of Gal-1 via secretory autophagy and highlight the pathological role of TAM-produced Gal-1 in HCC progression.
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Affiliation(s)
| | - Chien-Chin Chen
- Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi City, Taiwan.,Department of Cosmetic Science, Chia Nan University of Pharmacy and Science, Tainan, Taiwan
| | - Yen-Cheng Chiu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Hung-Wen Tsai
- Department of Pathology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Hung-Chih Chiu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yuh-Ling Chen
- Institute of Oral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Pei-Jane Tsai
- Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, Tainan, Taiwan
| | - Wan-Ting Kuo
- The Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Nina Tsao
- Department of Medical Laboratory Science, College of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - Yee-Shin Lin
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chih-Peng Chang
- The Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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34
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Miao L, Zhang Z, Ren Z, Li Y. Application of Immunotherapy in Hepatocellular Carcinoma. Front Oncol 2021; 11:699060. [PMID: 34513678 PMCID: PMC8426571 DOI: 10.3389/fonc.2021.699060] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 08/09/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma is one of the most common malignancies globally. It not only has a hidden onset but also progresses rapidly. Most HCC patients are already in the advanced stage of cancer when they are diagnosed, and have even lost the opportunity for surgical treatment. As an inflammation-related tumor, the immunosuppressive microenvironment of HCC can promote immune tolerance through a variety of mechanisms. Immunotherapy can activate tumor-specific immune responses, which brings a new hope for the treatment of HCC. At the present time, main immunotherapy strategies of HCC include immune checkpoint inhibitors, tumor vaccines, adoptive cell therapy, and so on. This article reviews the application and research progress of immune checkpoint inhibitors, tumor vaccines, and adoptive cell therapy in the treatment of HCC.
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Affiliation(s)
- Lele Miao
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China.,Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
| | - Zhengchao Zhang
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China.,Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
| | - Zhijian Ren
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China.,Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
| | - Yumin Li
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China.,Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
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