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Luo T, Li J, Pu K, Yang G. Association between periodontitis and gastrointestinal cancer risk and prognosis: evidence from a nested case-control study in Southwest China. Eur J Med Res 2025; 30:225. [PMID: 40176150 PMCID: PMC11963365 DOI: 10.1186/s40001-025-02508-4] [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: 11/30/2024] [Accepted: 03/25/2025] [Indexed: 04/04/2025] Open
Abstract
BACKGROUND With low early detection rates and high incidence and mortality, Gastrointestinal cancer (GIC) imposes a significant global health burden. Emerging evidence indicates that periodontitis may be a potential risk factor for GIC development; however, epidemiological data remains inconclusive. OBJECTIVE This study aimed to examine the impact of periodontitis on the incidence, recurrence, and metastasis of GIC in Southwest China, thereby offering epidemiological evidence to support GIC prevention and management. METHODS Between September 2022 and August 2024, a case-control study was conducted at the Affiliated Hospital of North Sichuan Medical College. Five hundred GIC patients were included as the case group based on the predefined inclusion and exclusion criteria, while 1005 healthy individuals were recruited for the control group. Multivariate analyses were performed to examine the associations between periodontitis and GIC incidence, recurrence, and metastasis while controlling for potential confounding factors. RESULTS The results of this study demonstrated that periodontitis was significantly associated with the incidence of esophageal, gastric, and colorectal cancer. Even after adjusting for potential confounders, it remained a significant risk factor for esophageal cancer (OR = 2.810, 95% CI 1.032-7.649, P = 0.043), colon cancer (OR = 2.330, 95% CI 1.072-5.067, P = 0.033), and rectal cancer (OR = 2.730, 95% CI 1.247-5.379, P = 0.012). Compared to non-periodontitis subjects, periodontitis showed a significant association with distant metastasis of rectal cancer (aHR = 5.332, 95% CI 1.406-20.220, P = 0.014). Moreover, severe periodontitis was identified as an risk factor for distant metastasis in rectal cancer (aHR = 10.138, 95% CI 1.824-56.354, P = 0.008). CONCLUSION This study highlights significant associations between periodontitis and an increased risk of esophageal and colorectal cancers. Additionally, patients with rectal cancer and periodontitis exhibited an increased risk of distant metastasis compared to those without periodontitis.
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Affiliation(s)
- Ting Luo
- Department of Gastroenterology, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, China
- Jintang Hospital, West China Hospital, Sichuan University, Chengdu, 610499, China
| | - Juan Li
- Department of Gastroenterology, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, China
| | - Ke Pu
- Department of Gastroenterology, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, China.
| | - Guodong Yang
- Department of Gastroenterology, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, China.
- Department of Gastroenterology, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China.
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Ding N, Kang Y, Tan X, Tang Y, Zhang Y, He Y. Analysis of expression characteristics of ferroptosis-related lncRNAs in gastrointestinal cancer patients in Asia. Discov Oncol 2025; 16:306. [PMID: 40072763 PMCID: PMC11904047 DOI: 10.1007/s12672-024-01733-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Accepted: 12/19/2024] [Indexed: 03/14/2025] Open
Abstract
BACKGROUND Asian cancer patients have become the highest morbidity and mortality group, and gastrointestinal tumors account for the majority of them, so it is urgent to find effective targets. Therefore, ferroptosis-related lncRNAs models were established to predict the prognosis and clinical immune characteristics of GI cancer. METHODS RNA sequencing and clinical data were collected from the TCGA database (LIHC, STAD, ESCA, PAAD, COAD, CHOL, and READ) of patients with gastrointestinal cancer in Asia. Download ferrodroptosis genes from FerrDb. Through R language, differential genes were identified, prognostic related LncRNAs were screened, and risk scores were obtained by risk formula to build models. Survival analysis, risk heat map, COX regression and ROC were used to evaluate the risk model. Establish Nomogram and clinically relevant heat maps. GSEA software was used to analyze gene enrichment and immune-related characteristics in high and low risk groups. LncRNA expression was validated through paired sample differential analysis and qRT-PCR, and the drug sensitivity of genes was also analyzed. RESULTS The transcriptome data of 297 cases and clinical data of 322 cases were downloaded from TCGA, and the intersection of ferroptosis-related genes were obtaine. Cox analysis revealed 48 ferroptosis-related LncRNAs associated with prognosis. Through survival analysis, risk heatmap, COX regression and ROC, it was found that the risk model was highly accurate and efficient in predicting prognosis. KEGG-related GSEA enrichment analysis showed that 12 related pathways were significantly expressed in the low-risk group. Four immune-related functions were significantly higher in the high-risk group than in the low-risk group, and the expression of all immune checkpoints were significantly higher in the high-risk group than in the low-risk group. The three LncRNAs in the model exhibited varying expression levels across different tumors and obtained drug sensitivity data. CONCLUSIONS Our results reveal innovative and strong evidence that ferroptosis-related lncRNAs can be used as biomarkers for the treatment and prognosis of Asian GI cancer.
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Affiliation(s)
- Ning Ding
- School of Biomedical Sciences, Hunan University, No. 100, Fubu River Road, Yuelu District, Changsha, 410082, Hunan, People's Republic of China
- Department of Anorectal Surgery, The Affiliated Hospital of Hunan Academy of Traditional Chinese Medicine, 58 Lushan Rd., Yuelu District, Changsha, 410006, Hunan, People's Republic of China
| | - Ying Kang
- School of Biomedical Sciences, Hunan University, No. 100, Fubu River Road, Yuelu District, Changsha, 410082, Hunan, People's Republic of China
| | - Xiaoxiao Tan
- School of Biomedical Sciences, Hunan University, No. 100, Fubu River Road, Yuelu District, Changsha, 410082, Hunan, People's Republic of China
| | - Yanbo Tang
- Department of Anorectal Surgery, The Affiliated Hospital of Hunan Academy of Traditional Chinese Medicine, 58 Lushan Rd., Yuelu District, Changsha, 410006, Hunan, People's Republic of China
| | - Yingjie Zhang
- School of Biomedical Sciences, Hunan University, No. 100, Fubu River Road, Yuelu District, Changsha, 410082, Hunan, People's Republic of China.
| | - Yongheng He
- Department of Anorectal Surgery, The Affiliated Hospital of Hunan Academy of Traditional Chinese Medicine, 58 Lushan Rd., Yuelu District, Changsha, 410006, Hunan, People's Republic of China.
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Shi X, Zang J, Gu Q, Zhang M, Sun H, Yang L, Cheng J, Wang R, Mao H, Xu A, Wang X, Xiao Y, Cai J, Han F, Yang D, Li Y, Nie H. Comprehensive analysis of the multifaceted role of ITGAV in digestive system cancer progression and immune infiltration. Front Immunol 2025; 16:1480771. [PMID: 40018050 PMCID: PMC11864929 DOI: 10.3389/fimmu.2025.1480771] [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: 08/14/2024] [Accepted: 01/24/2025] [Indexed: 03/01/2025] Open
Abstract
Background Digestive system cancers are among the most common malignancies, exhibiting consistently high incidence and mortality rates, yet effective detection and treatment targets remain limited. Integrin αv (ITGAV, CD51) is a significant member of the integrin family, widely recognized for its role in mediating interactions between cells and the extracellular matrix, as well as intracellular signaling. In recent years, ITGAV has been found to have significantly elevated expression in multiple tumors, such as prostate cancer, breast cancer, and osteosarcoma, and was considered to be a key component in various stages of tumor progression. However, no systematic digestive system cancer analysis has been conducted to explore its function in prognosis, diagnosis, and immunology. Methods Transcriptome sequencing and clinical data of samples were obtained from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression Project (GTEx), Human Protein Atlas (HPA), cBioPortal, TIMER and TISIDB databases. Bioinformatics methods were employed to investigate the potential oncogenicity of ITGAV, focusing specifically on the analysis of its prognosis, diagnostic value, and immune infiltration level of ITGAV in digestive system cancers. In addition, GO, KEGG, and PPI network analysis revealed the biological functions and related signaling pathways related to ITGAV. Finally, the role of ITGAV in regulating cancer progression was experimentally verified using hepatocellular carcinoma and pancreatic cancer as examples. Results We found that ITGAV was highly expressed in multiple digestive system cancers. In addition, high expression of ITGAV was closely associated with poor prognosis and showed potential for early diagnosis. Enrichment of pathways related to extracellular matrix organizing processes and tumor migratory movements was identified. In vitro, results showed that the knockdown of ITGAV significantly inhibited the migratory movement ability of hepatocellular carcinoma and pancreatic cancer cells, while its overexpression significantly promoted the migration of the above cells. Finally, immunoassays showed a significant correlation between ITGAV expression and the infiltration level of various immune cells, further clarifying the critical role of ITGAV in the tumor immune microenvironment. Conclusion Our results elucidated the importance of ITGAV in the prognostic assessment, early diagnosis, and targeted immunotherapy of digestive system cancers, and revealed its multifaceted role in regulating cancer progression.
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Affiliation(s)
- Xinyue Shi
- School of Life Science and Technology, Faculty of Life Sciences and Medicine, Harbin Institute of Technology, Harbin, Heilongjiang, China
| | - Jingyu Zang
- School of Life Science and Technology, Faculty of Life Sciences and Medicine, Harbin Institute of Technology, Harbin, Heilongjiang, China
| | - Qi Gu
- School of Life Science and Technology, Faculty of Life Sciences and Medicine, Harbin Institute of Technology, Harbin, Heilongjiang, China
| | - Mengmeng Zhang
- School of Life Science and Technology, Faculty of Life Sciences and Medicine, Harbin Institute of Technology, Harbin, Heilongjiang, China
| | - Handi Sun
- School of Life Science and Technology, Faculty of Life Sciences and Medicine, Harbin Institute of Technology, Harbin, Heilongjiang, China
| | - Lijun Yang
- School of Life Science and Technology, Faculty of Life Sciences and Medicine, Harbin Institute of Technology, Harbin, Heilongjiang, China
| | - Jiahui Cheng
- School of Life Science and Technology, Faculty of Life Sciences and Medicine, Harbin Institute of Technology, Harbin, Heilongjiang, China
| | - Ruonan Wang
- School of Life Science and Technology, Faculty of Life Sciences and Medicine, Harbin Institute of Technology, Harbin, Heilongjiang, China
| | - Han Mao
- School of Life Science and Technology, Faculty of Life Sciences and Medicine, Harbin Institute of Technology, Harbin, Heilongjiang, China
| | - Aitong Xu
- School of Life Science and Technology, Faculty of Life Sciences and Medicine, Harbin Institute of Technology, Harbin, Heilongjiang, China
| | - Xin Wang
- School of Life Science and Technology, Faculty of Life Sciences and Medicine, Harbin Institute of Technology, Harbin, Heilongjiang, China
| | - Yu Xiao
- School of Life Science and Technology, Faculty of Life Sciences and Medicine, Harbin Institute of Technology, Harbin, Heilongjiang, China
| | - Jialing Cai
- Department of Toxicology, College of Public Health, Harbin Medical University, Harbin, Heilongjiang, China
| | - Fang Han
- School of Life Science and Technology, Faculty of Life Sciences and Medicine, Harbin Institute of Technology, Harbin, Heilongjiang, China
| | - Depeng Yang
- School of Life Science and Technology, Faculty of Life Sciences and Medicine, Harbin Institute of Technology, Harbin, Heilongjiang, China
| | - Yu Li
- School of Life Science and Technology, Faculty of Life Sciences and Medicine, Harbin Institute of Technology, Harbin, Heilongjiang, China
| | - Huan Nie
- School of Life Science and Technology, Faculty of Life Sciences and Medicine, Harbin Institute of Technology, Harbin, Heilongjiang, China
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Zhang H, Tang H, Tu W, Peng F. Regulatory role of non-coding RNAs in 5-Fluorouracil resistance in gastrointestinal cancers. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2025; 8:4. [PMID: 39935428 PMCID: PMC11810461 DOI: 10.20517/cdr.2024.167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 12/29/2024] [Accepted: 01/07/2025] [Indexed: 02/13/2025]
Abstract
Gastrointestinal (GI) cancers are becoming a growing cause of morbidity and mortality globally, posing a significant risk to human life and health. The main treatment for this kind of cancer is chemotherapy based on 5-fluorouracil (5-FU). However, the issue of 5-FU resistance is becoming increasingly prominent, which greatly limits its effectiveness in clinical treatment. Recently, numerous studies have disclosed that some non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), exert remarkable physiological functions within cells. In addition, these ncRNAs can also serve as important information communication molecules in the tumor microenvironment and regulate tumor chemotherapy resistance. In particular, they have been shown to play multiple roles in regulating 5-FU resistance in GI cancers. Herein, we summarize the targets, pathways, and mechanisms involved in regulating 5-FU resistance by ncRNAs and briefly discuss the application potential of ncRNAs as biomarkers or therapeutic targets for 5-FU resistance in GI cancers, aiming to offer a reference to tackle issues related to 5-FU resistance.
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Affiliation(s)
- Heng Zhang
- Department of Pharmacology, West China School of Pharmacy, Sichuan University, Chengdu 610051, Sichuan, China
- Department of Nuclear Medicine, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu 610051, Sichuan, China
| | - Hailin Tang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou 510700, Guangdong, China
| | - Wenling Tu
- Department of Nuclear Medicine, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu 610051, Sichuan, China
| | - Fu Peng
- Department of Pharmacology, West China School of Pharmacy, Sichuan University, Chengdu 610051, Sichuan, China
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Sichuan University, Chengdu 610041, Sichuan, China
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Jin H, Zhao YR, Huang F, Hong Z, Jia XY, Wang H, Wang YG. Vaccinia virus-mediated oncolytic immunotherapy: Emerging strategies for gastrointestinal cancer treatment at dawn. Virology 2025; 602:110303. [PMID: 39577274 DOI: 10.1016/j.virol.2024.110303] [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: 08/17/2024] [Revised: 11/11/2024] [Accepted: 11/12/2024] [Indexed: 11/24/2024]
Abstract
Oncolytic vaccinia virus (VVs) based immunotherapy is a rapidly developing treatment for gastrointestinal (GI) cancers. Conventional treatments, such as chemotherapy, radiotherapy and surgery achieve good effects in early-stage GI cancers, but effects are limited in advanced disease. Immunotherapy has limited efficacy in GI cancers due to tumor heterogeneity and complex immunosuppressive mechanisms. Oncolytic VV immunotherapy is a novel treatment approach showing promising results in preclinical and clinical trials. Oncolytic VV's intracytoplasmic replication and assembly mechanism, diverse mature forms, and use methods make it extremely safe and versatile for drug delivery. Combining oncolytic VV with conventional therapies and immunotherapy (e.g., ICIs, CAR-T) enhances tumor regression and survival compared to monotherapies. Researchers are establishing response protocols and improvement strategies, rapidly developing VV tumor oncolytic immunotherapy. This article focuses on oncolytic vaccinia development and outlook in gastrointestinal cancer therapy, advantages when combined with other drugs to improve clinical survival, safety, and risk reduction for patients.
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Affiliation(s)
- Hao Jin
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, 310018, Zhejiang Province, China; Oncology Department, Zhejiang Sci-Tech University Shaoxing Academy of Biomedicine, Shaoxing, China
| | - Ya-Ru Zhao
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, 310018, Zhejiang Province, China; Oncology Department, Zhejiang Sci-Tech University Shaoxing Academy of Biomedicine, Shaoxing, China
| | - Fang Huang
- Department of Pathology, Zhejiang Provincial People's Hospital, Hangzhou, 310014, China
| | - Zhang Hong
- Department of Respiratory and Critical Care Medicine, Second Medical Center, Chinese PLA General Hospital, Beijing, 100089, China
| | - Xiao-Yuan Jia
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, 310018, Zhejiang Province, China
| | - Hui Wang
- Oncology Department, Zhejiang Xiaoshan Hospital, 311201, Hangzhou, China.
| | - Yi-Gang Wang
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, 310018, Zhejiang Province, China; Oncology Department, Zhejiang Sci-Tech University Shaoxing Academy of Biomedicine, Shaoxing, China.
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Zhong X, Xu Y, Yang S, Liao J, Hong Z, Zhang X, Wu Z, Tu C, Zuo Q. Molecular mechanisms of transmitted endoplasmic reticulum stress mediating immune escape of gastric cancer via PVR overexpression in TAMs. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167560. [PMID: 39486660 DOI: 10.1016/j.bbadis.2024.167560] [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: 01/21/2024] [Revised: 09/13/2024] [Accepted: 10/28/2024] [Indexed: 11/04/2024]
Abstract
Gastric cancer (GC) is the fourth leading cause of cancer death worldwide. Due to the complex tumor microenvironment (TME), the efficacy of immunotherapy in GC has not met expectations. Malignant changes in the TME induce endoplasmic reticulum stress (ERS). ERS can be transmitted between tumor cells and tumor-associated macrophages (TAMs), promoting tumor immune escape, but the specific mechanism in GC remains unclear. We established a TAM model of transmitted ERS (TERS), and iTRAQ proteomic analysis identified overexpressed proteins. The overexpression of poliovirus receptor (PVR) was screened while flow cytometry and ELISA showed that PVR mediated the immunosuppressive function of TAMs by downregulating the proliferative activity and cytotoxicity of cocultured CD8+ T lymphocytes. With EMSA and dual-luciferase reporter assays, we confirmed that erythropoietin-producing hepatocellular receptor A2 (EphA2) affected PVR expression by increasing the transcriptional activity of activator protein-1 (AP-1). MFC cells were mixed with EphA2 knockdown or control RAW264.7 cells to establish subcutaneous tumor models with or without tunicamycin treatment in vivo. The vivo experiments revealed that ERS promoted subcutaneous xenograft growth, which was reversed by EphA2 knockdown. Clinically, GC patients with high expression of PVR and EphA2 tended to have an immunosuppressive TME, which were determined by immunohistochemical and immunofluorescence analyses. In conclusion, the transcriptional activity of AP-1 is upregulated in ERS-transmitted TAMs through EphA2 to increase PVR expression, which promotes immune escape in GC. Our study provides a new perspective on the role of ERS in tumor immunity.
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Affiliation(s)
- Xuxian Zhong
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province 510515, China
| | - Youqin Xu
- The fifth clinical school, Guangzhou Medical University, Guangzhou, Guangdong Province 511436, China; Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, China
| | - Shengnan Yang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province 510515, China
| | - Jiaqi Liao
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province 510515, China
| | - Ziyang Hong
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province 510515, China
| | - Xingyu Zhang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province 510515, China
| | - Ziqing Wu
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province 510515, China
| | - Chengshu Tu
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province 510515, China
| | - Qiang Zuo
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province 510515, China.
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Li Q, Zhao X, Yang H, Zhu X, Sui X, Feng J. Modulating Endoplasmic Reticulum Stress in Gastrointestinal Cancers: Insights from Traditional Chinese Medicine. Pharmaceuticals (Basel) 2024; 17:1599. [PMID: 39770441 PMCID: PMC11676909 DOI: 10.3390/ph17121599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 11/24/2024] [Accepted: 11/25/2024] [Indexed: 01/11/2025] Open
Abstract
Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) play critical roles in tumorigenesis, cancer progression, and drug resistance. Persistent activation of the ER stress system enhances the survival capacities of malignant tumor cells, including increased proliferation, invasion, and resistance to treatment. Dysregulation of ER function and the resultant stress is a common cellular response to cancer therapies and may lead to cancer cell death. Currently, growing evidence suggests that Traditional Chinese medicine (TCM), either as a monotherapy or in combination with other treatments, offers significant advantages in preventing cancer, inhibiting tumor growth, reducing surgical complications, improving drug sensitivity, and mitigating drug-induced damage. Some of these natural products have even entered clinical trials as primary or complementary anticancer agents. In this review, we summarize the anticancer effects of TCM monomers/natural products on the gastrointestinal (GI) tumors and explore their mechanisms through ER stress modulation. We believe that ongoing laboratory research and the clinical development of TCM-based cancer therapies hold considerable potential for advancing future cancer treatments.
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Affiliation(s)
| | | | | | | | | | - Jiao Feng
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China; (Q.L.); (X.Z.); (H.Y.); (X.Z.); (X.S.)
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Yang T, Guo L. Advancing gastric cancer treatment: nanotechnology innovations and future prospects. Cell Biol Toxicol 2024; 40:101. [PMID: 39565472 PMCID: PMC11579161 DOI: 10.1007/s10565-024-09943-9] [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: 06/24/2024] [Accepted: 11/04/2024] [Indexed: 11/21/2024]
Abstract
Gastric cancer (GC) is the fifth most common cancer worldwide, particularly prevalent in Asia, especially in China, where both its incidence and mortality rates are significantly high. Meanwhile, nanotechnology has demonstrated great potential in the treatment of GC. In particular, nanodrug delivery systems have improved therapeutic efficacy and targeting through various functional modifications, such as targeting peptides, tumor microenvironment responsiveness, and instrument-based methods. For instance, silica (SiO2) has excellent biocompatibility and can be used as a drug carrier, with its porous structure enhancing drug loading capacity. Polymer nanoparticles regulate drug release rates and mechanisms by altering material composition and preparation methods. Lipid nanoparticles efficiently encapsulate hydrophilic drugs and promote cellular uptake, while carbon-based nanoparticles can be used in biosensors and drug delivery. Targets such as integrins, HER2 receptors, and the tumor microenvironment have been used to improve drug efficacy in GC treatment. Nanodrug delivery techniques not only enhance drug efficacy and delivery capabilities but also selectively target tumor cells. Currently, there is a lack of systematic summarization and synthesis regarding the relationship between nanodrug delivery systems and GC treatment, which to some extent hinders researchers and clinicians from efficiently searching for and referencing related studies, thereby reducing work efficiency. This study aims to systematically summarize the existing research on the relationship between nanodrug delivery systems and GC treatment, making it easier for professionals to search and reference, and thereby promoting further research on the role of nanodrug delivery systems and their clinical applications in GC. This review discusses the applications of functionalized nanocarriers in the treatment of GC in recent years, including surface modifications with targeted markers, the combination of phototherapy, chemotherapy, and immunotherapy, along with their advantages and challenges. It also examines the future prospects of targeted nanomaterials in GC treatment. The review particularly focuses on the combined application of nanocarriers in multiple treatment modalities, such as phototherapy, chemotherapy, and immunotherapy, demonstrating their potential in multimodal treatments. Furthermore, it thoroughly explores the specific challenges that nanocarriers face in GC treatment, such as biocompatibility, drug release control, and clinical translation issues, while providing a systematic outlook on future developments. Additionally, this study emphasizes the potential value and feasibility of nanocarriers in clinical applications, contrasting with most reviews that focus on basic research. Through these innovations, we offer new perspectives and directions for the development of nanotechnology in the treatment of GC.
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Affiliation(s)
- Tengfei Yang
- Department of Health Management, Shengjing Hospital of China Medical University, Shenyang, 110004, P. R. China
| | - Lin Guo
- Department of General Surgery, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning Province, P. R. China.
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Zheng C, Jiang L, Gong X, Zhang W, Pu R, Zhang Y, Zhao M, Jiang C, Wang H, Zhang P, Li Y. Cabozantinib-encapsulated and maytansine-conjugated high-density lipoprotein for immunotherapy in colorectal cancer. J Control Release 2024; 376:138-148. [PMID: 39362608 DOI: 10.1016/j.jconrel.2024.09.047] [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: 06/28/2024] [Revised: 09/24/2024] [Accepted: 09/27/2024] [Indexed: 10/05/2024]
Abstract
Advanced colorectal cancer (CRC) responds poorly to current adjuvant therapies, partially due to its immunosuppressive intestinal microenvironment. We found that myeloid-derived suppressor cells (MDSCs) were enriched in orthotopic tumors due to treatment-induced succinate release, which activated tuft cells and upregulated interleukin 25 (IL-25) and interleukin 13 (IL-13). We engineered a cabozantinib (Cabo)-encapsulated and maytansine (DM1)-conjugated synthetic high-density lipoprotein (ECCD-sHDL) to modulate the tumor microenvironment. DM1 induced immunogenic cell death and promoted the maturation of dendritic cells. Meanwhile, Cabo alleviated DM1-induced succinate release, preventing tuft cell activation, downregulating IL-25 and IL-13 secretion, and reducing intratumoral MDSC infiltration. ECCD-sHDL increased the densities of active cytotoxic T lymphocytes (CTLs) and M1 macrophages in the tumors, effectively inhibiting tumor growth and metastasis, thereby prolonging survival in murine CRC models. Our study sheds light on the mechanism of treatment-induced immunosuppression in orthotopic CRC and demonstrates that this combinatorial therapy could be an effective treatment for CRC.
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Affiliation(s)
- Chao Zheng
- Department of Pharmaceutics, School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai 201203, China.; State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; National Advanced Medical Engineering Research Center, China State Institute of Pharmaceutical Industry, Shanghai 201203, China
| | - Linyang Jiang
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xiang Gong
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; National Advanced Medical Engineering Research Center, China State Institute of Pharmaceutical Industry, Shanghai 201203, China
| | - Wen Zhang
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; National Advanced Medical Engineering Research Center, China State Institute of Pharmaceutical Industry, Shanghai 201203, China
| | - Rong Pu
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yuan Zhang
- Department of Pulmonary and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China
| | - Mengmeng Zhao
- Department of Pulmonary and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China
| | - Chen Jiang
- Department of Pharmaceutics, School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai 201203, China..
| | - Hao Wang
- Department of Pharmaceutics, School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai 201203, China.; National Advanced Medical Engineering Research Center, China State Institute of Pharmaceutical Industry, Shanghai 201203, China.
| | - Pengcheng Zhang
- School of Biomedical Engineering & State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai 201210, China; Shanghai Clinical Research and Trial Center, Shanghai 201203, China.
| | - Yaping Li
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; Nanjing University of Chinese Medicine, Nanjing 210023, China; Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai 264000, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China.
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Jin X, Wang S, Luo L, Yan F, He Q. Targeting the Wnt/β-catenin signal pathway for the treatment of gastrointestinal cancer: Potential for advancement. Biochem Pharmacol 2024; 227:116463. [PMID: 39102994 DOI: 10.1016/j.bcp.2024.116463] [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: 05/07/2024] [Revised: 07/25/2024] [Accepted: 08/02/2024] [Indexed: 08/07/2024]
Abstract
Gastrointestinal cancers (GICs) are highly prevalent cancers that threaten human health worldwide. The Wnt/β-catenin signaling pathway has been reported to play a pivotal role in the carcinogenesis of GICs. Numerous interventions targeting the Wnt/β-catenin signaling in GICs are currently being tested in clinical trials with promising results. Unfortunately, there are no clinically approved drugs that effectively target this pathway. This comprehensive review aims to evaluate the impact of clinical therapies targeting the Wnt/β-catenin signaling pathway in GICs. By integrating data from bioinformatics databases and recent literature from the past five years, we examine the heterogeneous expression and regulatory mechanisms of Wnt/β-catenin pathway genes and proteins in GICs. Specifically, we focus on expression patterns, mutation frequencies, and clinical prognoses to understand their implications for treatment strategies. Additionally, we discuss recent clinical trial efforts targeting this pathway. Understanding the inhibitors currently under clinical investigation may help optimize foundational research and clinical strategies. We hope that elucidating the current status of precision therapeutic stratification for patients targeting the Wnt/β-catenin pathway will guide future innovations in precision medicine for GICs.
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Affiliation(s)
- Xizhi Jin
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, PR China; Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Zhejiang University, Hangzhou, Zhejiang 310058, PR China; Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, Zhejiang 310018, PR China
| | - Sijie Wang
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, PR China
| | - Lihua Luo
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, PR China.
| | - Fangjie Yan
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Zhejiang University, Hangzhou, Zhejiang 310058, PR China; Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, Zhejiang 310018, PR China.
| | - Qiaojun He
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Zhejiang University, Hangzhou, Zhejiang 310058, PR China.
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Liu J, Wang C, Jiang Y, Zhou Y, Chen L, Qian Z, Liu L, Wu D, Zhang Y. Comprehensive characterization of B7 family members in breast cancer: B7-H5 switch reverses breast cancer from "immuno-cold" into "immuno-hot" status. Cancer Cell Int 2024; 24:205. [PMID: 38858701 PMCID: PMC11165836 DOI: 10.1186/s12935-024-03392-4] [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: 01/24/2024] [Accepted: 06/02/2024] [Indexed: 06/12/2024] Open
Abstract
The members of the classic B7 family regulate the immune microenvironment of several malignant tumors. However, the potential relationship between the B7 family and the breast cancer (BrCa) tumor immune microenvironment has remained elusive. In the present study, we provide a comprehensive explanation of the expression, clinical significance, mutation, and immune cell infiltration of B7 family molecules in BrCa. First, we recruited 10 patients with BrCa surgery from the Wuxi Maternal and Child Health Hospital and performed single-cell RNA sequencing (scRNA-seq) analysis to investigate the distribution of B7 family members in multiple immune cell subsets. We focused on B7-2, B7-H3, and B7-H5 molecules of the B7 family and constructed tumor microarrays by self-recruiting patients to perform multiple immunohistochemical (mIHC) analyses and study tumor expression of B7-2, B7-H3, B7-H5 and CD8+ immune cell infiltration. B7-H5 displayed a strong correlation with CD8+ immune cell infiltration. In summary, B7-H5 provides a new perspective for the identification of immunothermal subtypes of BrCa and could function as a switch to reverse BrCa from an "immunologically cold" state to an "immunologically hot" state.
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Affiliation(s)
- Jiayu Liu
- Department of Oncology, Wuxi Maternal and Child Health Care Hospital, Wuxi School of Medicine, Jiangnan University, No.48 Huaishu Road, Wuxi, Jiangsu, 214002, China
| | - Cenzhu Wang
- Wuxi People's Hospital, Wuxi Medical Center, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Nanjing Medical University, Jiangsu, 214000, China
- Department of Oncology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Jiangsu, 214023, China
| | - Ying Jiang
- Department of Oncology, Wuxi Maternal and Child Health Care Hospital, Wuxi School of Medicine, Jiangnan University, No.48 Huaishu Road, Wuxi, Jiangsu, 214002, China
| | - Yunxu Zhou
- Department of Oncology, Wuxi Maternal and Child Health Care Hospital, Wuxi School of Medicine, Jiangnan University, No.48 Huaishu Road, Wuxi, Jiangsu, 214002, China
| | - Lingyan Chen
- Wuxi Maternal and Child Health Hospital, Nanjing Medical University, Jiangsu, 214000, China
| | - Zhiwen Qian
- Wuxi Maternal and Child Health Hospital, Nanjing Medical University, Jiangsu, 214000, China
| | - Lu Liu
- Wuxi Maternal and Child Health Hospital, Jiangnan University, Jiangsu, 214002, China
| | - Danping Wu
- Wuxi Maternal and Child Health Hospital, Jiangnan University, Jiangsu, 214002, China
| | - Yan Zhang
- Department of Oncology, Wuxi Maternal and Child Health Care Hospital, Wuxi School of Medicine, Jiangnan University, No.48 Huaishu Road, Wuxi, Jiangsu, 214002, China.
- Wuxi Maternal and Child Health Hospital, Jiangnan University, Jiangsu, 214002, China.
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Cai H, Zhao J, Zhang Q, Wu H, Sun Y, Guo F, Zhou Y, Qin G, Xia W, Zhao Y, Liang X, Yin S, Qin Y, Li D, Wu H, Ren D. Ubiquitin ligase TRIM15 promotes the progression of pancreatic cancer via the upregulation of the IGF2BP2-TLR4 axis. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167183. [PMID: 38657551 DOI: 10.1016/j.bbadis.2024.167183] [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: 11/30/2023] [Revised: 03/17/2024] [Accepted: 04/15/2024] [Indexed: 04/26/2024]
Abstract
BACKGROUND The tripartite motif family, predominantly characterized by its E3 ubiquitin ligase activities, is involved in various cellular processes including signal transduction, apoptosis and autophagy, protein quality control, immune regulation, and carcinogenesis. Tripartite Motif Containing 15 (TRIM15) plays an important role in melanoma progression through extracellular signal-regulated kinase activation; however, data on its role in pancreatic tumors remain lacking. We previously demonstrated that TRIM15 targeted lipid synthesis and metabolism in pancreatic cancer; however, other specific regulatory mechanisms remain elusive. METHODS We used transcriptomics and proteomics, conducted a series of phenotypic experiments, and used a mouse orthotopic transplantation model to study the specific mechanism of TRIM15 in pancreatic cancer in vitro and in vivo. RESULTS TRIM15 overexpression promoted the progression of pancreatic cancer by upregulating the toll-like receptor 4. The TRIM15 binding protein, IGF2BP2, could combine with TLR4 to inhibit its mRNA degradation. Furthermore, the ubiquitin level of IGF2BP2 was positively correlated with TRIM15. CONCLUSIONS TRIM15 could ubiquitinate IGF2BP2 to enhance the function of phase separation and the maintenance of mRNA stability of TLR4. TRIM15 is a potential therapeutic target against pancreatic cancer.
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Affiliation(s)
- Hongkun Cai
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jingyuan Zhao
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Qiyue Zhang
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Heyu Wu
- Department of Operating Room, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yan Sun
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Feng Guo
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yingke Zhou
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Gengdu Qin
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Wentao Xia
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yuhan Zhao
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xueyi Liang
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Shilin Yin
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yang Qin
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Dan Li
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Heshui Wu
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Dianyun Ren
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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Gao Y, Wu R, Pei Z, Ke C, Zeng D, Li X, Zhang Y. Cell cycle associated protein 1 associates with immune infiltration and ferroptosis in gastrointestinal cancer. Heliyon 2024; 10:e28794. [PMID: 38586390 PMCID: PMC10998105 DOI: 10.1016/j.heliyon.2024.e28794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 03/23/2024] [Accepted: 03/25/2024] [Indexed: 04/09/2024] Open
Abstract
Background Cell Cycle-Associated Protein 1 (CAPRIN1) play an important role in cell proliferation, oxidative stress, and inflammatory response. Nonetheless, its role in tumor immunity and ferroptosis is largely unknown in gastrointestinal cancer patients. Methods Through comprehensive bioinformatics, we investigate CAPRIN1 expression patterns and its role in diagnosis, functional signaling pathways, tumor immune infiltration and ferroptosis of different gastrointestinal cancer subtypes. Besides, immunohistochemistry (IHC) and immune blot were used to validate our esophagus cancer clinical data. The ferroptotic features of CAPRIN1 in vitro were assessed through knockdown assays in esophagus cancer cells. Results CAPRIN1 expression was significantly upregulated, correlated with poor prognosis, and served as an independent risk factor for most gastrointestinal cancer. Moreover, CAPRIN1 overexpression positively correlated with gene markers of most infiltrating immune cells, and immune checkpoints. CAPRIN1 knockdown significantly decreased the protein level of major histocompatibility complex class I molecules. We also identified a link between CAPRIN1 and ferroptosis-related genes in gastrointestinal cancer. Knockdown of CAPRIN1 significantly increased the production of lipid reactive oxygen species and malondialdehyde. Inhibition of CAPRIN1 expression promoted ferroptotic cell death induced by RAS-selective lethal 3 and erastin in human esophagus cancer cells. Conclusion Collectively, our results demonstrate that CAPRIN1 is aberrantly expressed in gastrointestinal cancer, is associated with poor prognosis, and could potentially influence immune infiltration and ferroptosis.
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Affiliation(s)
- Yan Gao
- Department of Pharmacy, Taihe Hospital, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, P.R. China
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China
| | - Ruimin Wu
- Department of Pharmacy, Taihe Hospital, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Zhijun Pei
- Department of Pharmacy, Taihe Hospital, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Changbin Ke
- Department of Pharmacy, Taihe Hospital, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Daobing Zeng
- Department of Pharmacy, Taihe Hospital, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Xiaohui Li
- Department of Pharmacy, Taihe Hospital, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Yanmin Zhang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, P.R. China
- State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi'an Jiaotong University, Xi'an, 710061, China
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Wang T, Jin Y, Wang M, Chen B, Sun J, Zhang J, Yang H, Deng X, Cao X, Wang L, Tang Y. SALL4 in gastrointestinal tract cancers: upstream and downstream regulatory mechanisms. Mol Med 2024; 30:46. [PMID: 38584262 PMCID: PMC11000312 DOI: 10.1186/s10020-024-00812-z] [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: 07/18/2023] [Accepted: 03/20/2024] [Indexed: 04/09/2024] Open
Abstract
Effective therapeutic targets and early diagnosis are major challenges in the treatment of gastrointestinal tract (GIT) cancers. SALL4 is a well-known transcription factor that is involved in organogenesis during embryonic development. Previous studies have revealed that SALL4 regulates cell proliferation, survival, and migration and maintains stem cell function in mature cells. Additionally, SALL4 overexpression is associated with tumorigenesis. Despite its characterization as a biomarker in various cancers, the role of SALL4 in GIT cancers and the underlying mechanisms are unclear. We describe the functions of SALL4 in GIT cancers and discuss its upstream/downstream genes and pathways associated with each cancer. We also consider the possibility of targeting these genes or pathways as potential therapeutic options for GIT cancers.
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Affiliation(s)
- Tairan Wang
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453003, China
| | - Yan Jin
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453003, China
| | - Mengyao Wang
- First Clinical Medical College, Xinxiang Medical University, Xinxiang, 453003, China
| | - Boya Chen
- First Clinical Medical College, Xinxiang Medical University, Xinxiang, 453003, China
| | - Jinyu Sun
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453003, China
| | - Jiaying Zhang
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453003, China
| | - Hui Yang
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453003, China
| | - Xinyao Deng
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453003, China
| | - Xingyue Cao
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453003, China
| | - Lidong Wang
- State Key Laboratory of Esophageal Cancer Prevention & Treatment and Henan Key, Laboratory for Esophageal Cancer Research of The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China.
| | - Yuanyuan Tang
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453003, China.
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15
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Peng C, Xiong F, Pu X, Hu Z, Yang Y, Qiao X, Jiang Y, Han M, Wang D, Li X. m 6A methylation modification and immune cell infiltration: implications for targeting the catalytic subunit m 6A-METTL complex in gastrointestinal cancer immunotherapy. Front Immunol 2023; 14:1326031. [PMID: 38187373 PMCID: PMC10768557 DOI: 10.3389/fimmu.2023.1326031] [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: 10/22/2023] [Accepted: 12/04/2023] [Indexed: 01/09/2024] Open
Abstract
N6-methyladenosine (m6A) methylation modification is a ubiquitous RNA modification involved in the regulation of various cellular processes, including regulation of RNA stability, metabolism, splicing and translation. Gastrointestinal (GI) cancers are some of the world's most common and fatal cancers. Emerging evidence has shown that m6A modification is dynamically regulated by a complex network of enzymes and that the catalytic subunit m6A-METTL complex (MAC)-METTL3/14, a core component of m6A methyltransferases, participates in the development and progression of GI cancers. Furthermore, it has been shown that METTL3/14 modulates immune cell infiltration in an m6A-dependent manner in TIME (Tumor immune microenvironment), thereby altering the response of cancer cells to ICIs (Immune checkpoint inhibitors). Immunotherapy has emerged as a promising approach for treating GI cancers. Moreover, targeting the expression of METTL3/14 and its downstream genes may improve patient response to immunotherapy. Therefore, understanding the role of MAC in the pathogenesis of GI cancers and its impact on immune cell infiltration may provide new insights into the development of effective therapeutic strategies for GI cancers.
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Affiliation(s)
- Chen Peng
- Department of Medical Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Fen Xiong
- Department of Medical Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Xi Pu
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Zhangmin Hu
- Department of Medical Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Yufei Yang
- Department of Medical Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Xuehan Qiao
- Department of Medical Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Yuchun Jiang
- Department of Medical Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Miao Han
- Department of Medical Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Deqiang Wang
- Institute of Digestive Diseases, Jiangsu University, Zhenjiang, China
| | - Xiaoqin Li
- Department of Medical Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
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16
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Guo F, Yang X, Hu C, Li W, Han W. Network Pharmacology Combined with Machine Learning to Reveal the Action Mechanism of Licochalcone Intervention in Liver Cancer. Int J Mol Sci 2023; 24:15935. [PMID: 37958916 PMCID: PMC10649909 DOI: 10.3390/ijms242115935] [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: 09/22/2023] [Revised: 10/30/2023] [Accepted: 11/01/2023] [Indexed: 11/15/2023] Open
Abstract
There are reports indicating that licochalcones can inhibit the proliferation, migration, and invasion of cancer cells by promoting the expression of autophagy-related proteins, inhibiting the expression of cell cycle proteins and angiogenic factors, and regulating autophagy and apoptosis. This study aims to reveal the potential mechanisms of licochalcone A (LCA), licochalcone B (LCB), licochalcone C (LCC), licochalcone D (LCD), licochalcone E (LCE), licochalcone F (LCF), and licochalcone G (LCG) inhibition in liver cancer through computer-aided screening strategies. By using machine learning clustering analysis to search for other structurally similar components in licorice, quantitative calculations were conducted to collect the structural commonalities of these components related to liver cancer and to identify key residues involved in the interactions between small molecules and key target proteins. Our research results show that the seven licochalcones molecules interfere with the cancer signaling pathway via the NF-κB signaling pathway, PDL1 expression and PD1 checkpoint pathway in cancer, and others. Glypallichalcone, Echinatin, and 3,4,3',4'-Tetrahydroxy-2-methoxychalcone in licorice also have similar structures to the seven licochalcones, which may indicate their similar effects. We also identified the key residues (including ASN364, GLY365, TRP366, and TYR485) involved in the interactions between ten flavonoids and the key target protein (nitric oxide synthase 2). In summary, we provide valuable insights into the molecular mechanisms of the anticancer effects of licorice flavonoids, providing new ideas for the design of small molecules for liver cancer drugs.
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Affiliation(s)
| | | | | | - Wannan Li
- Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Science, Jilin University, 2699 Qianjin Street, Changchun 130012, China; (F.G.); (X.Y.); (C.H.)
| | - Weiwei Han
- Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Science, Jilin University, 2699 Qianjin Street, Changchun 130012, China; (F.G.); (X.Y.); (C.H.)
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17
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Ren X, Tang X, Huang T, Hu Z, Wang Y, Zhou Y. FTO plays a crucial role in gastrointestinal cancer and may be a target for immunotherapy: an updated review. Front Oncol 2023; 13:1241357. [PMID: 37916161 PMCID: PMC10616962 DOI: 10.3389/fonc.2023.1241357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 09/22/2023] [Indexed: 11/03/2023] Open
Abstract
Gastrointestinal cancer is a common malignancy with high mortality and poor prognosis. Therefore, developing novel effective markers and therapeutic targets for gastrointestinal cancer is currently a challenging and popular topic in oncology research. Accumulating studies have reported that N6-methyladenosine is the most abundant epigenetic modification in eukaryotes. N6-methyladenosine plays an essential role in regulating RNA expression and metabolism, including splicing, translation, stability, decay, and transport. FTO, the earliest demethylase discovered to maintain the balance of N6-adenosine methylation, is abnormally expressed in many tumors. In this review, we discuss the molecular structure and substrate selectivity of FTO. we focus on the role of FTO in gastrointestinal tumor proliferation, migration, invasion, apoptosis, autophagy, immune microenvironment, and its molecular mechanisms. We also discuss its potential in the treatment of gastrointestinal cancers.
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Affiliation(s)
- Xiangqing Ren
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, China
| | - Xiaolong Tang
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Tian Huang
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, China
| | - Zenan Hu
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, China
| | - Yuping Wang
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, China
| | - Yongning Zhou
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, China
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Di Y, Ding L, Gao L, Huang H. Association of meat consumption with the risk of gastrointestinal cancers: a systematic review and meta-analysis. BMC Cancer 2023; 23:782. [PMID: 37612616 PMCID: PMC10463360 DOI: 10.1186/s12885-023-11218-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 07/24/2023] [Indexed: 08/25/2023] Open
Abstract
BACKGROUND The association between gastrointestinal cancer and types of meat consumption, including red meat, processed meat, or a combination of both, remains disputable. Therefore, we performed a systematic review and meta-analysis of prospective cohort studies to estimate the association between meat consumption and gastrointestinal cancer risk. METHODS PubMed, EmBase, and the Cochrane library databases were searched systematically for eligible studies that investigated the relation between meat consumption and the risk of developing gastrointestinal cancers, including esophageal cancer (EC), gastric cancer (GC), colorectal cancer (CRC), colon cancer (CC), rectal cancer (RC), pancreatic cancer (PC), and hepatocellular carcinoma (HCC) throughout February, 2023. The pooled relative risk (RR) with 95% confidence interval (CI) was assigned as an effect estimate and calculated using a random-effects model with inverse variance weighting. RESULTS Forty cohorts comprising 3,780,590 individuals were selected for the final quantitative analysis. The summary results indicated that a higher red meat consumption was associated with an increased risk of CRC (RR: 1.09; 95% CI: 1.02-1.16; P = 0.007) and CC (RR: 1.13; 95% CI: 1.03-1.25; P = 0.011). Moreover, a higher processed meat consumption was associated with an increased risk of CRC (RR: 1.19; 95% CI: 1.13-1.26; P < 0.001), CC (RR: 1.24; 95% CI: 1.13-1.26; P < 0.001), and RC (RR: 1.24; 95% CI: 1.08-1.42; P = 0.002). Furthermore, a higher total consumption of red and processed meat was associated with an increased risk of CRC (RR: 1.13; 95% CI: 1.06-1.20; P < 0.001), CC (RR: 1.17; 95% CI: 1.04-1.33; P = 0.012), and RC (RR: 1.20; 95% CI: 1.04-1.39; P = 0.016). Finally, the strength of higher consumption of total red and processed meat with the risk of GC, and higher consumption of red meat with the risk of RC in subgroup of high adjusted level was lower than subgroup of moderate adjusted level, while the strength of higher consumption of processed meat with the risk of RC and HCC in subgroup of follow-up ≥ 10.0 years was higher than subgroup of follow-up < 10.0 years. CONCLUSIONS This study found that meat consumption was associated with an increased risk of CRC, CC, and RC, and dietary intervention could be considered an effective strategy in preventing CRC.
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Affiliation(s)
- Yan Di
- Department of Medical Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Lei Ding
- Department of Oncology Surgery/ Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Luying Gao
- Department of Ultrasond/Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hongyan Huang
- Department of Medical Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
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19
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Shen X, Du J. Editorial: The role of immune checkpoints in gastrointestinal diseases. Front Physiol 2023; 14:1251966. [PMID: 37588850 PMCID: PMC10425598 DOI: 10.3389/fphys.2023.1251966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 07/25/2023] [Indexed: 08/18/2023] Open
Affiliation(s)
- Xiaofei Shen
- Division of Gastric Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Junfeng Du
- Department of General Surgery, The 7th Medical Center, Chinese PLA General Hospital, Beijing, China
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20
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Zhang NZ, Zhao LF, Zhang Q, Fang H, Song WL, Li WZ, Ge YS, Gao P. Core fucosylation and its roles in gastrointestinal glycoimmunology. World J Gastrointest Oncol 2023; 15:1119-1134. [PMID: 37546555 PMCID: PMC10401475 DOI: 10.4251/wjgo.v15.i7.1119] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 02/28/2023] [Accepted: 05/08/2023] [Indexed: 07/12/2023] Open
Abstract
Glycosylation is a common post-translational modification in eukaryotic cells. It is involved in the production of many biologically active glycoproteins and the regulation of protein structure and function. Core fucosylation plays a vital role in the immune response. Most immune system molecules are core fucosylated glycoproteins such as complements, cluster differentiation antigens, immunoglobulins, cytokines, major histocompatibility complex molecules, adhesion molecules, and immune molecule synthesis-related transcription factors. These core fucosylated glycoproteins play important roles in antigen recognition and clearance, cell adhesion, lymphocyte activation, apoptosis, signal transduction, and endocytosis. Core fucosylation is dominated by fucosyltransferase 8 (Fut8), which catalyzes the addition of α-1,6-fucose to the innermost GlcNAc residue of N-glycans. Fut8 is involved in humoral, cellular, and mucosal immunity. Tumor immunology is associated with aberrant core fucosylation. Here, we summarize the roles and potential modulatory mechanisms of Fut8 in various immune processes of the gastrointestinal system.
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Affiliation(s)
- Nian-Zhu Zhang
- Clinical Laboratory, The Second Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| | - Li-Fen Zhao
- Clinical Laboratory, The Second Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| | - Qian Zhang
- Department of Cell Therapy, Shanghai Tianze Yuntai Biomedical Co., Ltd., Shanghai 200100, China
| | - Hui Fang
- Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba 305-0005, Ibaraki, Japan
| | - Wan-Li Song
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Wen-Zhe Li
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yu-Song Ge
- Department of Neurology, The Second Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| | - Peng Gao
- Clinical Laboratory, The Second Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
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21
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Wang J, Zhang X, Ni Z, Elam E, Thakur K, Li K, Wang C, Zhang J, Wei Z. The anti-cancerous mechanism of licochalcone A on human hepatoma cell HepG2 based on the miRNA omics. FOOD SCIENCE AND HUMAN WELLNESS 2023. [DOI: 10.1016/j.fshw.2022.10.039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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22
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Anu RI, Shiu KK, Khan KH. The immunomodulatory role of IDO1-Kynurenine-NAD + pathway in switching cold tumor microenvironment in PDAC. Front Oncol 2023; 13:1142838. [PMID: 37456260 PMCID: PMC10348419 DOI: 10.3389/fonc.2023.1142838] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 06/01/2023] [Indexed: 07/18/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common exocrine tumor of the pancreas characterized by late diagnosis, adverse overall 5-year survival, a higher propensity for metastatic disease, and lack of efficacy of systemic therapy options. These adverse outcomes can be partly attributed to complex tumor microenvironment (TME). Over the past decade, immunotherapy has revolutionized the management of certain cancers; thus far, the immunologically 'non-inflamed' tumor microenvironment in PDACs has proven to be challenging. Indolamine 2,3-dioxygenase 1 (IDO1) is the rate-limiting enzyme in the catabolic pathway of L-Tryptophan, an essential amino acid, that gives rise to the immunosuppressive metabolite Kynurenine. IDO1, Indolamine 2,3-dioxygenase 2 (IDO2), and Tryptophan 2,3-dioxygenase (TDO) are the key enzymes in the tryptophan catabolic pathway but we focus on the role of the predominant enzyme form IDO1 in this review. Nicotinamide phosphoribosyl transferase (iNAMPT) regulates the intracellular concentration of NAD and is upregulated in the tumor. In light of the potential role of IDO1 as a driver of hostile TME in PDAC and NAD+ as a key coenzyme in anti-tumor immune response, this review urges focus on extensive research and initiation of clinical trials using IDO1 and NAMPT inhibitors in pancreatic cancer in the future.
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Affiliation(s)
- R. I. Anu
- Department of Cancer Biology and Therapeutics, Precision Oncology and Multi-Omics Clinic, Genetic Counseling Clinic, Department of Clinical Biochemistry, MVR Cancer Centre and Research Institute, Calicut, Kerala, India
| | - Kai-Keen Shiu
- Gastrointestinal Oncology Service, University College London Hospitals National Health Services (NHS) Foundation Trust, London, United Kingdom
- Universtiy College London (UCL) Cancer Institute, University College London Hospitals National Health Services (NHS) Foundation Trust, London, United Kingdom
| | - Khurum Hayat Khan
- Gastrointestinal Oncology Service, University College London Hospitals National Health Services (NHS) Foundation Trust, London, United Kingdom
- Universtiy College London (UCL) Cancer Institute, University College London Hospitals National Health Services (NHS) Foundation Trust, London, United Kingdom
- Whittington Health, National Health Services (NHS), London, United Kingdom
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23
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Shi T, Wang H, Wei J, Wang J, Fan Y, Zheng C, Che X. Editorial: Gastrointestinal cancer immunotherapy: from drug resistance mechanisms to overcoming strategies. Front Immunol 2023; 14:1230591. [PMID: 37350965 PMCID: PMC10283005 DOI: 10.3389/fimmu.2023.1230591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 06/01/2023] [Indexed: 06/24/2023] Open
Affiliation(s)
- Tao Shi
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Hanbing Wang
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Jia Wei
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Jinyan Wang
- Department of Immunology, Basic School of Medicine, China Medical University, Shenyang, China
| | - Yibo Fan
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Chunlei Zheng
- Department of Oncology, Shanghai Electric Power Hospital, Shanghai, China
| | - Xiaofang Che
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
- Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China
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24
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Li C, Zhu M, Wang J, Wu H, Liu Y, Huang D. Role of m6A modification in immune microenvironment of digestive system tumors. Biomed Pharmacother 2023; 164:114953. [PMID: 37269812 DOI: 10.1016/j.biopha.2023.114953] [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: 04/11/2023] [Revised: 05/21/2023] [Accepted: 05/27/2023] [Indexed: 06/05/2023] Open
Abstract
Digestive system tumors are huge health problem worldwide, largely attributable to poor dietary choices. The role of RNA modifications in cancer development is an emerging field of research. RNA modifications are associated with the growth and development of various immune cells, which, in turn, regulate the immune response. The majority of RNA modifications are methylation modifications, and the most common type is the N6-methyladenosine (m6A) modification. Here, we reviewed the molecular mechanism of m6A in the immune cells and the role of m6A in the digestive system tumors. However, further studies are required to better understand the role of RNA methylation in human cancers for designing diagnostic and treatment strategies and predicting the prognosis of patients.
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Affiliation(s)
- Chao Li
- Department of Child Health Care, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan, China
| | - Mengqi Zhu
- Department of Child Health Care, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan, China
| | - Jiajia Wang
- Department of Health Management, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan, China
| | - Hengshuang Wu
- Department of Gynecological Pelvis Floor Reconstruction Ward, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan, China
| | - Yameng Liu
- Department of Child Health Care, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan, China
| | - Di Huang
- Department of Child Health Care, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan, China.
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25
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Silva-Pilipich N, Covo-Vergara Á, Smerdou C. Local Delivery of Immunomodulatory Antibodies for Gastrointestinal Tumors. Cancers (Basel) 2023; 15:cancers15082352. [PMID: 37190279 DOI: 10.3390/cancers15082352] [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: 03/17/2023] [Revised: 04/12/2023] [Accepted: 04/13/2023] [Indexed: 05/17/2023] Open
Abstract
Cancer therapy has experienced a breakthrough with the use of immune checkpoint inhibitors (ICIs) based on monoclonal antibodies (mAbs), which are able to unleash immune responses against tumors refractory to other therapies. Despite the great advancement that ICIs represent, most patients with gastrointestinal tumors have not benefited from this therapy. In addition, ICIs often induce adverse effects that are related to their systemic use. Local administration of ICIs in tumors could concentrate their effect in the malignant tissue and provide a higher safety profile. A new and attractive approach for local delivery of ICIs is the use of gene therapy vectors to express these blocking antibodies in tumor cells. Several vectors have been evaluated in preclinical models of gastrointestinal tumors to express ICIs against PD-1, PD-L1, and CTLA-4, among other immune checkpoints, with promising results. Vectors used in these settings include oncolytic viruses, self-replicating RNA vectors, and non-replicative viral and non-viral vectors. The use of viral vectors, especially when they have replication capacity, provides an additional adjuvant effect that has been shown to enhance antitumor responses. This review covers the most recent studies involving the use of gene therapy vectors to deliver ICIs to gastrointestinal tumors.
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Affiliation(s)
- Noelia Silva-Pilipich
- Division of Gene Therapy and Regulation of Gene Expression, Cima Universidad de Navarra, 31008 Pamplona, Spain
- Instituto de Investigación Sanitaria de Navarra (IdISNA), Cancer Center Clínica Universidad de Navarra (CCUN), 31008 Pamplona, Spain
| | - Ángela Covo-Vergara
- Division of Gene Therapy and Regulation of Gene Expression, Cima Universidad de Navarra, 31008 Pamplona, Spain
- Instituto de Investigación Sanitaria de Navarra (IdISNA), Cancer Center Clínica Universidad de Navarra (CCUN), 31008 Pamplona, Spain
| | - Cristian Smerdou
- Division of Gene Therapy and Regulation of Gene Expression, Cima Universidad de Navarra, 31008 Pamplona, Spain
- Instituto de Investigación Sanitaria de Navarra (IdISNA), Cancer Center Clínica Universidad de Navarra (CCUN), 31008 Pamplona, Spain
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26
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Xie F, Huang Y, Zhan Y, Bao L. Exosomes as drug delivery system in gastrointestinal cancer. Front Oncol 2023; 12:1101823. [PMID: 36761427 PMCID: PMC9905849 DOI: 10.3389/fonc.2022.1101823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 12/29/2022] [Indexed: 01/26/2023] Open
Abstract
Gastrointestinal cancer is one of the most common malignancies with relatively high morbidity and mortality. Exosomes are nanosized extracellular vesicles derived from most cells and widely distributed in body fluids. They are natural endogenous nanocarriers with low immunogenicity, high biocompatibility, and natural targeting, and can transport lipids, proteins, DNA, and RNA. Exosomes contain DNA, RNA, proteins, lipids, and other bioactive components, which can play a role in information transmission and regulation of cellular physiological and pathological processes during the progression of gastrointestinal cancer. In this paper, the role of exosomes in gastrointestinal cancers is briefly reviewed, with emphasis on the application of exosomes as drug delivery systems for gastrointestinal cancers. Finally, the challenges faced by exosome-based drug delivery systems are discussed.
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27
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Frederico SC, Darling C, Bielanin JP, Dubinsky AC, Zhang X, Hadjipanayis CG, Kohanbash G. Neoadjuvant immune checkpoint inhibition in the management of glioblastoma: Exploring a new frontier. Front Immunol 2023; 14:1057567. [PMID: 36875096 PMCID: PMC9981631 DOI: 10.3389/fimmu.2023.1057567] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 02/03/2023] [Indexed: 02/19/2023] Open
Abstract
Brain tumors are one of the leading causes of cancer related death in both the adult and pediatric patient population. Gliomas represent a cohort of brain tumors derived from glial cell lineages which include astrocytomas, oligodendrogliomas and glioblastomas (GBMs). These tumors are known to grow aggressively and have a high lethality with GBM being the most aggressive tumor in this group. Currently, few treatment options exist for GBM outside of surgical resection, radiation therapy and chemotherapy. While these measures have been shown to marginally improve patient survival, patients, especially those diagnosed with GBM, often experience a recurrence of their disease. Following disease recurrence, treatment options become more limited as additional surgical resections can pose life threatening risk to the patient, patients may be ineligible for additional radiation, and the recurrent tumor may be resistant to chemotherapy. Immune checkpoint inhibitors (ICIs) have revolutionized the field of cancer immunotherapy as many patients with cancers residing outside the central nervous system (CNS) have experienced a survival benefit from this treatment modality. It has often been observed that this survival benefit is increased following neoadjuvant administration of immune checkpoint inhibitors as tumor antigen is still present in the patient which enables a more robust anti-tumor immune response. Interestingly, results for ICI-based studies for patients with GBM have been largely disappointing which is a stark contrast from the success this treatment modality has had in non-central nervous system cancers. In this review, we will discuss the various benefits of neoadjuvant immune checkpoint inhibition such as how this approach reduces tumor burden and allows for a greater induction of an anti-tumor immune response. Additionally, we will discuss several non-CNS cancers where neoadjuvant immune checkpoint inhibition has been successful and discuss why we believe this approach may provide a survival benefit for GBM patients. We hope this manuscript will foster future studies aimed at exploring whether this approach may be beneficial for patients diagnosed with GBM.
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Affiliation(s)
- Stephen C Frederico
- University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.,Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, United States
| | - Corbin Darling
- University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.,Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, United States
| | - John P Bielanin
- University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | | | - Xiaoran Zhang
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, United States
| | | | - Gary Kohanbash
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, United States
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Muacevic A, Adler JR. Physiological Role of Orexin/Hypocretin in the Human Body in Motivated Behavior: A Comprehensive Review. Cureus 2023; 15:e34009. [PMID: 36814741 PMCID: PMC9939734 DOI: 10.7759/cureus.34009] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 01/20/2023] [Indexed: 01/22/2023] Open
Abstract
Neurohormones are neurosecretory materials released by neurosecretory cells that serve both as neuromodulators in the brain and spinal cord and as circulating regulatory hormones. They serve a wide range of functions, including homeostasis, development, and modulation of neuronal and muscle activity. In the hypothalamus, neurohormones called hypocretins are created that were discovered in the late nineties. Orexin receptors (OXRs) have been shown to enhance synaptic signaling in the central nervous system at the cellular level. The orexins improve stimulated neural activity in the hippocampus, which, in turn, aids with spatial memory, learning, and mood. They present themselves as mediators for the hypothalamic functions. They have been shown to regulate sleep-wake cycles, arousal mechanisms, addiction, sympathetic nerve activity (SNA), blood pressure, and thermogenesis. Its role in storing brown adipose tissue has implications for thermal homeostasis. The significant role of orexins is seen in tumorigenesis when orexin A (OrxA) and orexin B (OrxB) induce apoptosis in fast-growing tumor cells. Orexin-null subjects show clinical narcolepsy, indicating that orexins were responsible for keeping them awake. Orexin microinjections in mice brains stimulated increased physical activity, thus possibly countering diet-induced obesity. Physical activity significantly increased plasma orexin-A levels, which facilitated the process of energy homeostasis. The amount of adrenocorticotropic hormone (ACTH) increases in stress conditions, which further facilitates the release of the stress hormone cortisol. No increase in the ACTH hormone is seen in stressed mice administered with orexin receptor 2 (OX2R) antagonists thus showing orexin's role in stress reaction. As a result of linking hypocretin/orexin to various physiological procedures, increased research into the medicinal potential of drugs targeting these receptors is emerging. We summed up in this review the recent advances in our understanding of how orexin and its receptor system play an essential role in clinical and pathological functions. This research summarizes a new area for research in human medicine, providing the possibility of controlling a vast array of physiological functions through intra-cerebroventricular injections of a single neuropeptide.
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29
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Cui Z, Du L, Wang J, Li Z, Xu J, Ou S, Li D, Li S, Hu H, Chen G, Wu Z. Overexpression of CENPL mRNA potentially regulated by miR-340-3p predicts the prognosis of pancreatic cancer patients. BMC Cancer 2022; 22:1354. [PMID: 36572856 PMCID: PMC9793567 DOI: 10.1186/s12885-022-10450-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Accepted: 12/14/2022] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND In our previous study it was found that CENPL was overexpressed in hepatocellular carcinoma and significantly predicted patient's prognosis. However, the expression and prognostic value of CENPL in other gastrointestinal tumors remain unknown. Therefore, we investigated the expression and prognostic value of CENPL in esophageal carcinoma (ESCA), stomach adenocarcinoma (STAD), pancreatic adenocarcinoma (PAAD), colon adenocarcinoma (COAD) and rectum adenocarcinoma (READ). METHODS In this study, Oncomine, GEPIA, OncoLnc, TIMER, cBioPortal, miRWalk and ENCORI databases were used to analyze the level of CENPL mRNA, prognostic value and potential regulatory mechanism of CENPL mRNA in tumors. The CENPL expression and clinicopathological data regarding PAAD were from the UCSC Xena database and univariate and multivariate Cox regression analyses were performed using R (Version 3.6.3). Immunohistochemical staining was used to verify the expression of CENPL protein in clinical specimens. Cytoscape (Version: 3.7.2) was used to visualize microRNA (miRNA) that potentially regulates CENPL. RESULTS Gene differential expression analysis showed that CENPL mRNA was significantly overexpressed in ESCA, STAD, PAAD, COAD and READ (p < 0.01). The overexpression of CENPL mRNA was significantly correlated with the poor prognosis of PAAD patients (p < 0.05). However, there was no significant correlation between the level of CENPL mRNA and the prognosis of ESCA, STAD, COAD and READ patients (p > 0.05). Univariate and multivariate Cox regression analyses suggested that CENPL was a prognostic risk factor for PAAD. The mutation rate of CENPL in PAAD was 2.2% (17/850). There was no significant correlation between the CENPL expression and the infiltration levels of immune cells in PAAD (|Cor|< 0.5). Immunohistochemical staining showed that CENPL was overexpressed in 42% (11/26) of PAAD specimens, which was significantly higher compared with that in the normal tissues. The expression of miR-340-3p and miR-484 in PAAD were significantly lower than in the normal tissues (p < 0.05) and PAAD patients with lower expression of miR-340-3p had poorer prognosis (p < 0.05). CONCLUSION CENPL potentially regulated by miR-340-3p, is overexpressed in PAAD and predicts patient's prognosis, suggestive of a diagnostic and prognostic value in PAAD patients.
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Affiliation(s)
- Zhongyuan Cui
- grid.12955.3a0000 0001 2264 7233Department of Hepatobiliary Disease, 900th Hospital of the Joint Logistics Support Force (Dongfang Hospital), Xiamen University, Fuzhou, 350025 Fujian China
| | - Ling Du
- grid.256607.00000 0004 1798 2653Department of Gastroenterology, the Fourth Affiliated Hospital (Liuzhou Workers’ Hospital), Guangxi Medical University, Liuzhou, 545000 Guangxi China
| | - Jielong Wang
- grid.12955.3a0000 0001 2264 7233Department of Hepatobiliary Disease, 900th Hospital of the Joint Logistics Support Force (Dongfang Hospital), Xiamen University, Fuzhou, 350025 Fujian China ,grid.256112.30000 0004 1797 9307Department of Hepatobiliary Disease, 900th Hospital of the Joint Logistics Support Force, Fujian Medical University, Fuzhou, 350025 Fujian China
| | - Zhongzhuan Li
- grid.256607.00000 0004 1798 2653Department of Gastroenterology, the Fourth Affiliated Hospital (Liuzhou Workers’ Hospital), Guangxi Medical University, Liuzhou, 545000 Guangxi China
| | - Jiehong Xu
- grid.256607.00000 0004 1798 2653Department of Gastroenterology, the Fourth Affiliated Hospital (Liuzhou Workers’ Hospital), Guangxi Medical University, Liuzhou, 545000 Guangxi China
| | - Shiyu Ou
- grid.256607.00000 0004 1798 2653Department of Gastroenterology, the Fourth Affiliated Hospital (Liuzhou Workers’ Hospital), Guangxi Medical University, Liuzhou, 545000 Guangxi China
| | - Dongliang Li
- grid.12955.3a0000 0001 2264 7233Department of Hepatobiliary Disease, 900th Hospital of the Joint Logistics Support Force (Dongfang Hospital), Xiamen University, Fuzhou, 350025 Fujian China ,grid.256112.30000 0004 1797 9307Department of Hepatobiliary Disease, 900th Hospital of the Joint Logistics Support Force, Fujian Medical University, Fuzhou, 350025 Fujian China
| | - Shasha Li
- grid.12955.3a0000 0001 2264 7233Department of Hepatobiliary Disease, 900th Hospital of the Joint Logistics Support Force (Dongfang Hospital), Xiamen University, Fuzhou, 350025 Fujian China ,grid.256112.30000 0004 1797 9307Department of Hepatobiliary Disease, 900th Hospital of the Joint Logistics Support Force, Fujian Medical University, Fuzhou, 350025 Fujian China
| | - Hanfang Hu
- grid.256607.00000 0004 1798 2653Department of Gastroenterology, the Fourth Affiliated Hospital (Liuzhou Workers’ Hospital), Guangxi Medical University, Liuzhou, 545000 Guangxi China
| | - Gang Chen
- grid.256607.00000 0004 1798 2653Department of Gastroenterology, the Fourth Affiliated Hospital (Liuzhou Workers’ Hospital), Guangxi Medical University, Liuzhou, 545000 Guangxi China
| | - Zhixian Wu
- grid.12955.3a0000 0001 2264 7233Department of Hepatobiliary Disease, 900th Hospital of the Joint Logistics Support Force (Dongfang Hospital), Xiamen University, Fuzhou, 350025 Fujian China ,grid.256607.00000 0004 1798 2653Department of Gastroenterology, the Fourth Affiliated Hospital (Liuzhou Workers’ Hospital), Guangxi Medical University, Liuzhou, 545000 Guangxi China
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Wang Y, Yang T, Liang H, Deng M. Cell atlas of the immune microenvironment in gastrointestinal cancers: Dendritic cells and beyond. Front Immunol 2022; 13:1007823. [PMID: 36505406 PMCID: PMC9729272 DOI: 10.3389/fimmu.2022.1007823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Accepted: 10/25/2022] [Indexed: 11/25/2022] Open
Abstract
Gastrointestinal (GI) cancers occur in the alimentary tract and accessory organs. They exert a global burden with high morbidity and mortality. Inside the tumor microenvironment, dendritic cells (DCs) are the most efficient antigen-presenting cells and are necessary for adaptive immune responses such as T and B-cell maturation. However, the subsets of DCs revealed before were mostly based on flow cytometry and bulk sequencing. With the development of single-cell RNA sequencing (scRNA-seq), the tumor and microenvironment heterogeneity of GI cancer has been illustrated. In this review, we summarize the classification and development trajectory of dendritic cells at the single-cell level in GI cancer. Additionally, we focused on the interaction of DCs with T cells and their effect on the response to immunotherapy. Specifically, we focused on the newly identified tumor-infiltrating dendritic cells and discuss their potential function in antitumor immunity.
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Affiliation(s)
- Yinuo Wang
- Peking University International Cancer Institute, Peking University Health Science Center, Peking University, Beijing, China,School of Basic Medical Sciences, Peking University Health Science Center, Peking University, Beijing, China
| | - Ting Yang
- Peking University International Cancer Institute, Peking University Health Science Center, Peking University, Beijing, China,School of Basic Medical Sciences, Peking University Health Science Center, Peking University, Beijing, China
| | - Huan Liang
- School of Basic Medical Sciences, Peking University Health Science Center, Peking University, Beijing, China
| | - Mi Deng
- Peking University International Cancer Institute, Peking University Health Science Center, Peking University, Beijing, China,School of Basic Medical Sciences, Peking University Health Science Center, Peking University, Beijing, China,Peking University Cancer Hospital and Institute, Peking University Health Science Center, Peking University, Beijing, China,*Correspondence: Mi Deng,
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Sun Y, Li B, Cao Q, Liu T, Li J. Targeting cancer stem cells with polymer nanoparticles for gastrointestinal cancer treatment. Stem Cell Res Ther 2022; 13:489. [PMID: 36182897 PMCID: PMC9526954 DOI: 10.1186/s13287-022-03180-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 09/24/2022] [Indexed: 11/10/2022] Open
Abstract
Nanomaterials are developing rapidly in the medical field, bringing new hope for treating various refractory diseases. Among them, polymer nanomaterials, with their excellent properties, have been used to treat various diseases, such as malignant tumors, diabetes, and nervous system diseases. Gastrointestinal cancer is among the cancers with the highest morbidity and mortality worldwide. Cancer stem cells are believed to play an important role in the occurrence and development of tumors. This article summarizes the characteristics of gastrointestinal cancer stem cells and reviews the latest research progress in treating gastrointestinal malignant tumors using polymer nanoparticles to target cancer stem cells. In addition, the review article highlights the potential of polymer nanoparticles in targeting gastrointestinal cancer stem cells.
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Affiliation(s)
- Yao Sun
- Department of General Surgery, The Second Hospital of Jilin University, No. 218 Ziqiang Street, Changchun, 130041, China
| | - Bo Li
- Department of Rehabilitation Medicine, China-Japan Union Hospital of Jilin University, Changchun, 130000, China
| | - Qian Cao
- Department of Education, The Second Hospital of Jilin University, Changchun, 130041, China
| | - Tongjun Liu
- Department of General Surgery, The Second Hospital of Jilin University, No. 218 Ziqiang Street, Changchun, 130041, China
| | - Jiannan Li
- Department of General Surgery, The Second Hospital of Jilin University, No. 218 Ziqiang Street, Changchun, 130041, China.
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32
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Chen Y, Bai B, Ying K, Pan H, Xie B. Anti-PD-1 combined with targeted therapy: Theory and practice in gastric and colorectal cancer. Biochim Biophys Acta Rev Cancer 2022; 1877:188775. [DOI: 10.1016/j.bbcan.2022.188775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 07/31/2022] [Accepted: 08/01/2022] [Indexed: 10/16/2022]
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Role of main RNA modifications in cancer: N 6-methyladenosine, 5-methylcytosine, and pseudouridine. Signal Transduct Target Ther 2022; 7:142. [PMID: 35484099 PMCID: PMC9051163 DOI: 10.1038/s41392-022-01003-0] [Citation(s) in RCA: 102] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 04/12/2022] [Accepted: 04/14/2022] [Indexed: 12/16/2022] Open
Abstract
Cancer is one of the major diseases threatening human life and health worldwide. Epigenetic modification refers to heritable changes in the genetic material without any changes in the nucleic acid sequence and results in heritable phenotypic changes. Epigenetic modifications regulate many biological processes, such as growth, aging, and various diseases, including cancer. With the advancement of next-generation sequencing technology, the role of RNA modifications in cancer progression has become increasingly prominent and is a hot spot in scientific research. This review studied several common RNA modifications, such as N6-methyladenosine, 5-methylcytosine, and pseudouridine. The deposition and roles of these modifications in coding and noncoding RNAs are summarized in detail. Based on the RNA modification background, this review summarized the expression, function, and underlying molecular mechanism of these modifications and their regulators in cancer and further discussed the role of some existing small-molecule inhibitors. More in-depth studies on RNA modification and cancer are needed to broaden the understanding of epigenetics and cancer diagnosis, treatment, and prognosis.
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Cheng Y, Qin SK, Li J, Dai GH, Shen BY, Ying JE, Ba Y, Liang H, Wang XB, Xu Y, Zhou L, Ding KF, Qin YR, Yang SJ, Guan WX, Zheng H, Wang Q, Song H, Zhu YP. A multicenter clinical study: personalized medication for advanced gastrointestinal carcinomas with the guidance of patient-derived tumor xenograft (PDTX). J Cancer Res Clin Oncol 2022; 148:673-684. [PMID: 33864522 DOI: 10.1007/s00432-021-03639-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 04/08/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Establish patient-derived tumor xenograft (PDTX) from advanced GICs and assess the clinical value and applicability of PDTX for the treatment of advanced gastrointestinal cancers. METHODS Patients with advanced GICs were enrolled in a registered multi-center clinical study (ChiCTR-OOC-17012731). The performance of PDTX was evaluated by analyzing factors that affect the engraftment rate, comparing the histological consistency between primary tumors and tumorgrafts, examining the concordance between the drug effectiveness in PDTXs and clinical responses, and identifying genetic variants and other factors associated with prognosis. RESULTS Thirty-three patients were enrolled in the study with the engraftment rate of 75.8% (25/33). The success of engraftment was independent of age, cancer types, pathological stages of tumors, and particularly sampling methods. Tumorgrafts retained the same histopathological characteristics as primary tumors. Forty-nine regimens involving 28 drugs were tested in seventeen tumorgrafts. The median time for drug testing was 134.5 days. Follow-up information was obtained about 10 regimens from 9 patients. The concordance of drug effectiveness between PDTXs and clinical responses was 100%. The tumor mutation burden (TMB) was correlated with the effectiveness of single drug regimens, while the outgrowth time of tumorgrafts was associated with the effectiveness of combined regimens. CONCLUSION The engraftment rate in advanced GICs was higher than that of other cancers and meets the acceptable standard for applying personalized therapeutic strategies. Tumorgrafts from PDTX kept attributes of the primary tumor. Predictions from PDTX modeling closely agreed with clinical drug responses. PDTX may already be clinically applicable for personalized medication in advanced GICs.
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Affiliation(s)
- Yuan Cheng
- Bayi Hospital Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Shu-Kui Qin
- Bayi Hospital Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
| | - Jin Li
- Shanghai East Hospital Affiliated to Tongji University, Shanghai, China.
| | | | | | - Jie-Er Ying
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Yi Ba
- Tianjin Cancer Hospital, Tianjin, China
| | - Han Liang
- Tianjin Cancer Hospital, Tianjin, China
| | - Xin-Bo Wang
- Eastern Theater General Hospital of Chinese PLA, Nanjing, Jiangsu, China
| | - Ye Xu
- Shanghai Cancer Hospital, Shanghai, China
| | - Lin Zhou
- 302 Military Hospital of Chinese PLA, Beijing, China
| | - Ke-Feng Ding
- The Second Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, China
| | - Yan-Ru Qin
- The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, China
| | | | - Wen-Xian Guan
- Drum Tower Hospital Affiliated to Nanjing University School of Medicine, Nanjing, Jiangsu, China
| | - Hui Zheng
- Nanjing Personal Oncology Biological Technology Co. Ltd, Nanjing, Jiangsu, China
| | - Qian Wang
- Nanjing Personal Oncology Biological Technology Co. Ltd, Nanjing, Jiangsu, China
| | - Hang Song
- Nanjing Personal Oncology Biological Technology Co. Ltd, Nanjing, Jiangsu, China
| | - Yan-Ping Zhu
- Nanjing Personal Oncology Biological Technology Co. Ltd, Nanjing, Jiangsu, China
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Jiao M, Zhang F, Teng W, Zhou C. MYBL2 is a Novel Independent Prognostic Biomarker and Correlated with Immune Infiltrates in Prostate Cancer. Int J Gen Med 2022; 15:3003-3030. [PMID: 35313552 PMCID: PMC8934167 DOI: 10.2147/ijgm.s351638] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 02/17/2022] [Indexed: 12/29/2022] Open
Abstract
Purpose MYB proto-oncogene like 2 (MYBL2) is a member of the MYB family of transcription factor genes and overexpressed in many cancers. We investigated the role of MYBL2 in the malignant progression of prostate cancer (PCa) and its relationship with immune infiltrates in PCa. Methods Gene expression level, clinicopathological parameters, Gene Ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway, tumor immune infiltration analysis were based on The Cancer Genome Atlas (TCGA) dataset. Gene set enrichment analysis (GSEA) and single-sample gene set enrichment analysis (ssGSEA) were conducted to analyze the correlation between MYBL2 and immune infiltrates. The data processing analysis based on R language. The relationship between MYBL2 expression and immune response in PCa was analyzed on TIMER 2.0. Results MYBL2 was overexpressed in PCa patients, and correlated with T-stage, Gleason score, primary therapy outcome and progress free interval (PFI) event. The multivariate Cox regression analysis revealed MYBL2 was an independent risk factor for PFI (HR=1.250, 95% CI=1.016–1.537, p=0.035). The receiver operating characteristic (ROC) curve for MYBL2 (AUC=0.887) and nomogram also confirmed the diagnostic value of MYBL2 in the treatment of PCa patients. Based on mRNA expression of MYBL2, PCa patients were divided into MYBL2-high group and MYBL2-low group, and analysis of MYBL2 associated KEGG and GO pathways using R language revealed that 6 immune-related signaling pathways were enriched in MYBL2-high expression phenotype. GSEA analysis showed that 3 hallmark gene sets related to immune response were significantly enriched in MYBL2-high group, ssGSEA analysis found that MYBL2 expression correlated with the expression of many tumor immune lymphocytes (CD8+T cells, neutrophil cells, macrophage cells and so on) and immune check point inhibitors (CD276, BTLA, TNFRSF18, HAVCR2 and CD70). Conclusion MYBL2 is a novel independent prognostic biomarker and MYBL2 may play a crucial role in tumor immune microenvironment of PCa.
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Affiliation(s)
- Meng Jiao
- Department of Pathology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China
| | - Facai Zhang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, People’s Republic of China
| | - Wei Teng
- College of Business, Gachon University, Seongnam, 13120, Republic of Korea
| | - Chengjun Zhou
- Department of Pathology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China
- Correspondence: Chengjun Zhou, Department of Pathology, The Second Hospital of Shandong University, 247 Beiyuan Street, Jinan, Shandong, 250033, People’s Republic of China, Email
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Hu Y, Luo M. NORAD-sponged miR-378c alleviates malignant behaviors of stomach adenocarcinoma via targeting NRP1. Cancer Cell Int 2022; 22:79. [PMID: 35164743 PMCID: PMC8842946 DOI: 10.1186/s12935-022-02474-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 01/19/2022] [Indexed: 01/25/2023] Open
Abstract
Background Stomach adenocarcinoma (STAD) is the most common type of gastric cancer (GC), with a high recurrence rate and poor prognosis, but the potential indicators for STAD are insufficient. Methods Herein, we found that MicroRNA-378c (miR-378c) was lowly expressed in STAD, and the low expression of miR-378c was highly correlated with poor overall survival (OS), T stage, Reflux history, DSS events and PFI events of STAD patients. Results In addition, univariate analysis displayed that miR-378c was significantly associated with OS (Hazard ratio 0.735; 95% CI, 0.542–0.995; P = 0.046). Furthermore, it was validated that miR-378c inhibition accelerated STAD cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT), while they were suppressed by miR-378c overexpression. Mechanistically, Neuropilin 1 (NRP1) was confirmed as the target of miR-378c, and Lnc-NORAD was identified as its sponger. More importantly, NORAD-mediated miR-378c inhibited malignant behaviors of STAD both in vitro and in vivo. Conclusions Collectively, these results suggest miR-378c as a promising indicator for the treatment of STAD. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-022-02474-5.
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Affiliation(s)
- Yongjun Hu
- Department of General Surgery, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China
| | - Ming Luo
- Department of General Surgery, The Second Xiangya Hospital, Central South University, No.139 Renmin Middle Road, Changsha, 410011, Hunan, China.
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37
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Dai R, Liu M, Xiang X, Li Y, Xi Z, Xu H. OMICS Applications for Medicinal Plants in Gastrointestinal Cancers: Current Advancements and Future Perspectives. Front Pharmacol 2022; 13:842203. [PMID: 35185591 PMCID: PMC8855055 DOI: 10.3389/fphar.2022.842203] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 01/20/2022] [Indexed: 12/24/2022] Open
Abstract
Gastrointestinal cancers refer to a group of deadly malignancies of the gastrointestinal tract and organs of the digestive system. Over the past decades, considerable amounts of medicinal plants have exhibited potent anticancer effects on different types of gastrointestinal cancers. OMICS, systems biology approaches covering genomics, transcriptomics, proteomics and metabolomics, are broadly applied to comprehensively reflect the molecular profiles in mechanistic studies of medicinal plants. Single- and multi-OMICS approaches facilitate the unravelling of signalling interaction networks and key molecular targets of medicinal plants with anti-gastrointestinal cancer potential. Hence, this review summarizes the applications of various OMICS and advanced bioinformatics approaches in examining therapeutic targets, signalling pathways, and the tumour microenvironment in response to anticancer medicinal plants. Advances and prospects in this field are also discussed.
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Affiliation(s)
- Rongchen Dai
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, China
| | - Mengfan Liu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, China
| | - Xincheng Xiang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, China
| | - Yang Li
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, China
| | - Zhichao Xi
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, China
- *Correspondence: Zhichao Xi, ; Hongxi Xu,
| | - Hongxi Xu
- Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- *Correspondence: Zhichao Xi, ; Hongxi Xu,
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Wang J, Wei B, Thakur K, Wang CY, Li KX, Wei ZJ. Transcriptome Analysis Reveals the Anti-cancerous Mechanism of Licochalcone A on Human Hepatoma Cell HepG2. Front Nutr 2022; 8:807574. [PMID: 34988109 PMCID: PMC8720858 DOI: 10.3389/fnut.2021.807574] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 11/30/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma is a malignancy with a low survival rate globally, and there is imperative to unearth novel natural phytochemicals as effective therapeutic strategies. Licochalcone A is a chalcone from Glycyrrhiza that displayed various pharmacological efficacy. A globally transcriptome analysis was carried out to reveal the gene expression profiling to explore Licochalcone A's function as an anti-cancer phytochemical on HepG2 cells and investigate its potential mechanisms. Altogether, 6,061 dysregulated genes were detected (3,414 up-regulated and 2,647 down-regulated). SP1 was expected as the transcription factor that regulates the functions of most screened genes. GO and KEGG analysis was conducted, and the MAPK signaling pathway and the FoxO signaling pathway were two critical signal pathways. Protein-protein interaction (PPI) network analysis based on STRING platform to discover the hub genes (MAPK1, ATF4, BDNF, CASP3, etc.) in the MAPK signaling pathway and (AKT3, GADD45A, IL6, CDK2, CDKN1A, etc.) the FoxO signaling pathway. The protein level of essential genes that participated in significant pathways was consistent with the transcriptome data. This study will provide an inclusive understanding of the potential anti-cancer mechanism of Licochalcone A on hepatocellular, signifying Licochalcone A as a promising candidate for cancer therapy.
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Affiliation(s)
- Jun Wang
- School of Biological Food and Environment, Hefei University, Hefei, China
| | - Bo Wei
- School of Biological Food and Environment, Hefei University, Hefei, China
| | - Kiran Thakur
- School of Food and Biological Engineering, Hefei University of Technology, Hefei, China.,School of Biological Science and Engineering, North Minzu University, Yinchuan, China
| | - Chu-Yan Wang
- School of Biological Food and Environment, Hefei University, Hefei, China
| | - Ke-Xin Li
- School of Biological Food and Environment, Hefei University, Hefei, China
| | - Zhao-Jun Wei
- School of Food and Biological Engineering, Hefei University of Technology, Hefei, China.,School of Biological Science and Engineering, North Minzu University, Yinchuan, China
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Feng Y, Luo J, Liu P, Liu L, Zhu Y, Cheng G, Zheng L. Glasgow prognostic score and combined positive score for locally advanced rectal cancer. Ann Surg Treat Res 2022; 102:153-158. [PMID: 35317354 PMCID: PMC8914526 DOI: 10.4174/astr.2022.102.3.153] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/27/2022] [Accepted: 02/03/2022] [Indexed: 12/03/2022] Open
Abstract
Purpose This study was performed to investigate the association of Glasgow prognostic score (GPS), combined positive score (CPS), and clinicopathological characteristics of locally advanced rectal cancer. Methods Between February 2012 and February 2018, 103 patients with locally advanced rectal cancer treated by neoadjuvant chemoradiotherapy and total mesorectal excision (TME) were retrospectively evaluated. Results According to the classification of the GPS, 85 (82.5%), 13 (12.6%), and 5 patients (4.9%) were classified as a score of 0, 1, and 2, respectively. Patients were classified into the GPS-low group (GPS of 0, n = 85) and GPS-high group (GPS of 1 or 2, n = 18) with an area under the curve of 0.582 for overall survival (OS). The mean programmed death-ligand 1 (PD-L1) CPS of the whole group was 2.24 (range, 0–70). The PD-L1 CPS of the GPS-high group was higher than the GPS-low group (P < 0.001). Multivariate analysis by Cox proportional hazards model indicated that GPS was associated with OS and disease-free survival (DFS). Furthermore, PD-L1 CPS was associated with DFS (hazard ratio, 1.050; 95% confidence interval, 1.017–1.083; P = 0.003). Conclusion Elevated GPS was related to the PD-L1 CPS. GPS and PD-L1 CPS were associated with the prognosis of locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy followed by TME.
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Affiliation(s)
- Yanru Feng
- Department of Radiation Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou, China
- Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, China
| | - Jialin Luo
- Department of Radiation Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou, China
- Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, China
| | - Peng Liu
- Department of Radiation Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou, China
- Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, China
| | - Luying Liu
- Department of Radiation Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou, China
- Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, China
| | - Yuan Zhu
- Department of Radiation Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou, China
- Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, China
| | - Guoping Cheng
- Department of Pathology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou, China
| | - Linfeng Zheng
- Department of Pathology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou, China
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Chen Y, Long W, Yang L, Zhao Y, Wu X, Li M, Du F, Chen Y, Yang Z, Wen Q, Yi T, Xiao Z, Shen J. Functional Peptides Encoded by Long Non-Coding RNAs in Gastrointestinal Cancer. Front Oncol 2021; 11:777374. [PMID: 34888249 PMCID: PMC8649637 DOI: 10.3389/fonc.2021.777374] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 10/28/2021] [Indexed: 12/11/2022] Open
Abstract
Gastrointestinal cancer is by far the most common malignancy and the most common cause of cancer-related deaths worldwide. Recent studies have shown that long non-coding RNAs (lncRNAs) play an important role in the epigenetic regulation of cancer cells and regulate tumor progression by affecting chromatin modifications, gene transcription, translation, and sponge to miRNAs. In particular, lncRNA has recently been found to possess open reading frame (ORF), which can encode functional small peptides or proteins. These peptides interact with its targets to regulate transcription or the signal axis, thus promoting or inhibiting the occurrence and development of tumors. In this review, we summarize the involvement of lncRNAs and the function of lncRNAs encoded small peptides in gastrointestinal cancer.
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Affiliation(s)
- Yao Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China.,Laboratory of Personalised Cell Therapy & Cell Medicines, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Weili Long
- School of Basic Medicine, Southwest Medical University, Luzhou, China
| | - Liqiong Yang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China.,Laboratory of Personalised Cell Therapy & Cell Medicines, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China.,Laboratory of Personalised Cell Therapy & Cell Medicines, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China.,Laboratory of Personalised Cell Therapy & Cell Medicines, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China.,Laboratory of Personalised Cell Therapy & Cell Medicines, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China.,Laboratory of Personalised Cell Therapy & Cell Medicines, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China.,Laboratory of Personalised Cell Therapy & Cell Medicines, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Zhihui Yang
- Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Qinglian Wen
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Tao Yi
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China.,Laboratory of Personalised Cell Therapy & Cell Medicines, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China.,Laboratory of Personalised Cell Therapy & Cell Medicines, School of Pharmacy, Southwest Medical University, Luzhou, China
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Couvineau A, Voisin T, Nicole P, Gratio V, Blais A. Orexins: A promising target to digestive cancers, inflammation, obesity and metabolism dysfunctions. World J Gastroenterol 2021; 27:7582-7596. [PMID: 34908800 PMCID: PMC8641057 DOI: 10.3748/wjg.v27.i44.7582] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 06/22/2021] [Accepted: 11/18/2021] [Indexed: 02/06/2023] Open
Abstract
Hypothalamic neuropeptides named hypocretin/orexins which were identified in 1998 regulate critical functions such as wakefulness in the central nervous system. These past 20 years had revealed that orexins/receptors system was also present in the peripheral nervous system where they participated to the regulation of multiple functions including blood pressure regulation, intestinal motility, hormone secretion, lipolyze and reproduction functions. Associated to these peripheral functions, it was found that orexins and their receptors were involved in various diseases such as acute/chronic inflammation, metabolic syndrome and cancers. The present review suggests that orexins or the orexin neural circuitry represent potential therapeutic targets for the treatment of multiple pathologies related to inflammation including intestinal bowel disease, multiple sclerosis and septic shock, obesity and digestive cancers.
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Affiliation(s)
- Alain Couvineau
- INSERM UMR1149/Inflammation Research Center, Team “From inflammation to cancer in digestive diseases” labeled by “la Ligue Nationale contre le Cancer”, University of Paris, DHU UNITY, Paris 75018, France
| | - Thierry Voisin
- INSERM UMR1149/Inflammation Research Center, Team “From inflammation to cancer in digestive diseases” labeled by “la Ligue Nationale contre le Cancer”, University of Paris, DHU UNITY, Paris 75018, France
| | - Pascal Nicole
- INSERM UMR1149/Inflammation Research Center, Team “From inflammation to cancer in digestive diseases” labeled by “la Ligue Nationale contre le Cancer”, University of Paris, DHU UNITY, Paris 75018, France
| | - Valerie Gratio
- INSERM UMR1149/Inflammation Research Center, Team “From inflammation to cancer in digestive diseases” labeled by “la Ligue Nationale contre le Cancer”, University of Paris, DHU UNITY, Paris 75018, France
| | - Anne Blais
- UMR PNCA, AgroParisTech, INRA, Université Paris-Saclay, Paris 75005, France
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Bolandi N, Derakhshani A, Hemmat N, Baghbanzadeh A, Asadzadeh Z, Afrashteh Nour M, Brunetti O, Bernardini R, Silvestris N, Baradaran B. The Positive and Negative Immunoregulatory Role of B7 Family: Promising Novel Targets in Gastric Cancer Treatment. Int J Mol Sci 2021; 22:ijms221910719. [PMID: 34639059 PMCID: PMC8509619 DOI: 10.3390/ijms221910719] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 09/28/2021] [Accepted: 10/01/2021] [Indexed: 12/30/2022] Open
Abstract
Gastric cancer (GC), with a heterogeneous nature, is the third leading cause of death worldwide. Over the past few decades, stable reductions in the incidence of GC have been observed. However, due to the poor response to common treatments and late diagnosis, this cancer is still considered one of the lethal cancers. Emerging methods such as immunotherapy with immune checkpoint inhibitors (ICIs) have transformed the landscape of treatment for GC patients. There are presently eleven known members of the B7 family as immune checkpoint molecules: B7-1 (CD80), B7-2 (CD86), B7-H1 (PD-L1, CD274), B7-DC (PDCD1LG2, PD-L2, CD273), B7-H2 (B7RP1, ICOS-L, CD275), B7-H3 (CD276), B7-H4 (B7x, B7S1, Vtcn1), B7-H5 (VISTA, Gi24, DD1α, Dies1 SISP1), B7-H6 (NCR3LG1), B7-H7 (HHLA2), and Ig-like domain-containing receptor 2 (ILDR2). Interaction of the B7 family of immune-regulatory ligands with the corresponding receptors resulted in the induction and inhibition of T cell responses by sending co-stimulatory and co-inhibitory signals, respectively. Manipulation of the signals provided by the B7 family has significant potential in the management of GC.
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Affiliation(s)
- Nadia Bolandi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 516615731, Iran; (N.B.); (A.D.); (N.H.); (A.B.); (Z.A.); (M.A.N.)
- Department of Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia 571478334, Iran
| | - Afshin Derakhshani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 516615731, Iran; (N.B.); (A.D.); (N.H.); (A.B.); (Z.A.); (M.A.N.)
- Laboratory of Experimental Pharmacology, IRCCS Istituto Tumori Giovanni Paolo II, 70124 Bari, Italy
| | - Nima Hemmat
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 516615731, Iran; (N.B.); (A.D.); (N.H.); (A.B.); (Z.A.); (M.A.N.)
| | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 516615731, Iran; (N.B.); (A.D.); (N.H.); (A.B.); (Z.A.); (M.A.N.)
| | - Zahra Asadzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 516615731, Iran; (N.B.); (A.D.); (N.H.); (A.B.); (Z.A.); (M.A.N.)
| | - Mina Afrashteh Nour
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 516615731, Iran; (N.B.); (A.D.); (N.H.); (A.B.); (Z.A.); (M.A.N.)
- Department of Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia 571478334, Iran
| | - Oronzo Brunetti
- Medical Oncology Unit—IRCCS Istituto Tumori “Giovanni Paolo II” of Bari, 70124 Bari, Italy;
| | - Renato Bernardini
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 97, 95100 Catania, Italy;
| | - Nicola Silvestris
- Medical Oncology Unit—IRCCS Istituto Tumori “Giovanni Paolo II” of Bari, 70124 Bari, Italy;
- Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari, 70124 Bari, Italy
- Correspondence: (N.S.); (B.B.); Tel.: +98-413-3371440 (B.B.); Fax: +98-413-3371311 (B.B.)
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 516615731, Iran; (N.B.); (A.D.); (N.H.); (A.B.); (Z.A.); (M.A.N.)
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz 516615731, Iran
- Pharmaceutical Analysis Research Center, Tabriz University of Medical Sciences, Tabriz 516615731, Iran
- Correspondence: (N.S.); (B.B.); Tel.: +98-413-3371440 (B.B.); Fax: +98-413-3371311 (B.B.)
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Songjang W, Nensat C, Pongcharoen S, Jiraviriyakul A. The role of immunogenic cell death in gastrointestinal cancer immunotherapy (Review). Biomed Rep 2021; 15:86. [PMID: 34512974 PMCID: PMC8411483 DOI: 10.3892/br.2021.1462] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 07/30/2021] [Indexed: 12/24/2022] Open
Abstract
Modern cancer immunotherapy techniques are aimed at enhancing the responses of the patients' immune systems to fight against the cancer. The main promising strategies include active vaccination of tumor antigens, passive vaccination with antibodies specific to cancer antigens, adoptive transfer of cancer-specific T cells and manipulation of the patient's immune response by inhibiting immune checkpoints. The application of immunogenic cell death (ICD) inducers has been proven to enhance the immunity of patients undergoing various types of immunotherapy. The dying, stressed or injured cells release or present molecules on the cell surface, which function as either adjuvants or danger signals for detection by the innate immune system. These molecules are now termed 'damage-associated molecular patterns'. The term 'ICD' indicates a type of cell death that triggers an immune response against dead-cell antigens, particularly those derived from cancer cells, and it was initially proposed with regards to the effects of anticancer chemotherapy with conventional cytotoxic drugs. The aim of the present study was to review and discuss the role and mechanisms of ICD as a promising combined immunotherapy for gastrointestinal tumors.
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Affiliation(s)
- Worawat Songjang
- Department of Medical Technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
- Integrative Biomedical Research Unit (IBRU), Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Chatchai Nensat
- Biomedical Sciences, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Sutatip Pongcharoen
- Division of Immunology, Department of Medicine, Faculty of Medicine, Naresuan University, Phitsanulok 65000, Thailand
| | - Arunya Jiraviriyakul
- Department of Medical Technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
- Integrative Biomedical Research Unit (IBRU), Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
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Wang Y, Jiao X, Li S, Chen H, Wei X, Liu C, Gong J, Zhang X, Wang X, Peng Z, Qi C, Wang Z, Wang Y, Zhuo N, Zou J, Zhang H, Li J, Shen L, Lu Z. Alterations in DNA damage response and repair genes as potential biomarkers for immune checkpoint blockade in gastrointestinal cancer. Cancer Biol Med 2021; 19:j.issn.2095-3941.2020.0708. [PMID: 34570439 PMCID: PMC9425187 DOI: 10.20892/j.issn.2095-3941.2020.0708] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 04/06/2021] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVE Immune checkpoint inhibitors (ICIs) have achieved remarkable results in cancer treatments. However, there is no effective predictive biomarker for gastrointestinal (GI) cancer. METHODS We conducted integrative analyses of the genomic and survival data of ICI-treated GI cancer patients from the Memorial Sloan Kettering Cancer Center cohort (MSK-GI, n = 227), the Janjigian cohort (n = 40), and the Peking University Cancer Hospital & Institute cohort (PUCH, n = 80) to determine the possible associations between DNA damage response and repair (DDR) gene mutations and clinical outcomes. Data from The Cancer Genome Atlas database were analyzed to determine the possible correlations between DDR gene mutations and the tumor microenvironment. RESULTS In the MSK cohort, the presence of ≥ 2 DDR gene mutations was correlated with prolonged overall survival (OS). The Janjigian and PUCH cohorts further confirmed that subgroups with ≥ 2 DDR gene mutations displayed a prolonged OS and a higher durable clinical benefit. Furthermore, the DDR gene mutation load could be considered as an independent prognostic factor, and exhibited a potential predictive value for survival in GI cancer patients treated with ICIs. Mechanistically, we showed that the presence of ≥ 2 DDR gene mutations was correlated with higher levels of tumor mutation burden, neoantigen, and T cell infiltration. CONCLUSIONS The DDR gene mutation status was correlated with favorable clinical outcomes in GI cancer patients receiving ICIs, which could serve as a potential biomarker to guide patient selection for immunotherapy.
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Affiliation(s)
- Yujiao Wang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Xi Jiao
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Shuang Li
- Department of Gastric & Colorectal Surgery, The First Hospital of Jilin University, Changchun 130021, China
| | - Huan Chen
- Genecast Precision Medicine Technology Institute, Beijing 100192, China
| | - Xin Wei
- Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Chang Liu
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Jifang Gong
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Xiaotian Zhang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Xicheng Wang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Zhi Peng
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Changsong Qi
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Zhenghang Wang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Yanni Wang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Na Zhuo
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Jianling Zou
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Henghui Zhang
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Jian Li
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Lin Shen
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Zhihao Lu
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China
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Sumransub N, Vantanasiri K, Prakash A, Lou E. Advances and new frontiers for immunotherapy in colorectal cancer: Setting the stage for neoadjuvant success? Mol Ther Oncolytics 2021; 22:1-12. [PMID: 34307839 PMCID: PMC8280480 DOI: 10.1016/j.omto.2021.05.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Immunotherapy in the metastatic setting has drastically altered the landscape of treatment for various types of malignancy, including colorectal cancer. The category of immune checkpoint inhibitors has especially emerged as a class of therapy predicated on a more comprehensive understanding of immune cell-cancer cell regulation and evolution of the tumor microenvironment over time. Strategies including adoptive cellular therapies, tumor vaccines, and antibodies have also demonstrated the ability to enhance antitumor immunity. In this article, we provide a comprehensive review of the current landscape of immunotherapeutic strategies in colorectal cancer and provide insight into how these strategies may evolve in the next decade and be adapted to more localized forms of cancers of the colon and rectum. We provide particular focus on various combination approaches under investigation for reversing cancer-induced immunosuppression, especially in mismatch repair-proficient/microsatellite-stable colorectal tumors. Finally, we summarize current understanding on a recently identified integral factor in local immune regulation, the colonic microbiome. The aim of this article is to identify current challenges and barriers to improvement and to specify opportunities for applying knowledge in the immunotherapy sphere to rational design of clinical trials intended to improve survival and related outcomes in patients treated in the neoadjuvant setting.
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Affiliation(s)
- Nuttavut Sumransub
- Department of Medicine, University of Minnesota, 420 Delaware St., SE, MMC 480, Minneapolis, MN 55455, USA
| | - Kornpong Vantanasiri
- Department of Medicine, University of Minnesota, 420 Delaware St., SE, MMC 480, Minneapolis, MN 55455, USA
| | - Ajay Prakash
- Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, 160 E. 34th St., New York, NY 10016, USA
| | - Emil Lou
- Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, 420 Delaware St., SE, MMC 480, Minneapolis, MN 55455, USA
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Adoptive T-cell immunotherapy in digestive tract malignancies: Current challenges and future perspectives. Cancer Treat Rev 2021; 100:102288. [PMID: 34525422 DOI: 10.1016/j.ctrv.2021.102288] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 08/31/2021] [Accepted: 09/02/2021] [Indexed: 12/15/2022]
Abstract
Multiple systemic treatments are currently available for advanced cancers of the digestive tract, but none of them is curative. Adoptive T-cell immunotherapy refers to the extraction, modification and re-infusion of autologous or allogenic T lymphocytes for therapeutic purposes. A number of clinical trials have investigated either non-engineered T cells (i.e., lymphokine-activated killer cells, cytokine induced killer cells, or tumor-infiltrating lymphocytes) or engineered T cells (T cell receptor-redirected T cells or chimeric antigen receptor T cells) in patients with digestive tract malignancies over the past two decades, with variable degrees of success. While the majority of completed trials have been primarily aimed at assessing the safety of T-cell transfer strategies, a new generation of studies is being designed to formally evaluate the antitumor potential of adoptive T-cell immunotherapy in both the metastatic and adjuvant settings. In this review, we provide an overview of completed and ongoing clinical trials of passive T-cell immunotherapy in patients with cancers of the digestive tract, focusing on present obstacles and future strategies for achieving potential success.
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Hu Y, Chen C, Tong X, Chen S, Hu X, Pan B, Sun X, Chen Z, Shi X, Hu Y, Shen X, Xue X, Lu M. NSUN2 modified by SUMO-2/3 promotes gastric cancer progression and regulates mRNA m5C methylation. Cell Death Dis 2021; 12:842. [PMID: 34504059 PMCID: PMC8429414 DOI: 10.1038/s41419-021-04127-3] [Citation(s) in RCA: 122] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 08/08/2021] [Accepted: 08/23/2021] [Indexed: 12/16/2022]
Abstract
The 5-methylcytosine (m5C) RNA methyltransferase NSUN2 is involved in the regulation of cell proliferation and metastasis formation and is upregulated in multiple cancers. However, the biological significance of NSUN2 in gastric cancer (GC) and the modification of NSUN2 itself have not been fully investigated. Here, we analyzed the expression level of NSUN2 in tissue microarrays containing 403 GC tissues by immunohistochemistry. NSUN2 was upregulated in GC, and that it was a predictor of poor prognosis. NSUN2 promotes the proliferation, migration, and invasion of GC cells in vitro. We also demonstrated that small ubiquitin-like modifier (SUMO)-2/3 interacts directly with NSUN2 by stabilizing it and mediating its nuclear transport. This facilitates the carcinogenic activity of NSUN2. Furthermore, m5C bisulfite sequencing (Bis-seq) in NSUN2-deficient GC cells showed that m5C-methylated genes are involved in multiple cancer-related signaling pathways. PIK3R1 and PCYT1A may be the target genes that participate in GC progression. Our findings revealed a novel mechanism by which NSUN2 functions in GC progression. This may provide new treatment options for GC patients.
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Affiliation(s)
- Yuanbo Hu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Wenzhou Medical University, Wenzhou, China
| | - Chenbin Chen
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Wenzhou Medical University, Wenzhou, China
| | - Xinya Tong
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Wenzhou Medical University, Wenzhou, China
| | - Sian Chen
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Wenzhou Medical University, Wenzhou, China
| | - Xianjing Hu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Wenzhou Medical University, Wenzhou, China
| | - Bujian Pan
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Wenzhou Medical University, Wenzhou, China
| | - Xiangwei Sun
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Wenzhou Medical University, Wenzhou, China
| | - Zhiyuan Chen
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Wenzhou Medical University, Wenzhou, China
| | - Xinyu Shi
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Wenzhou Medical University, Wenzhou, China
| | - Yingying Hu
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Wenzhou Medical University, Wenzhou, China
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xian Shen
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
| | - Xiangyang Xue
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Wenzhou Medical University, Wenzhou, China.
| | - Mingdong Lu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
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Alain C, Pascal N, Valérie G, Thierry V. Orexins/Hypocretins and Cancer: A Neuropeptide as Emerging Target. Molecules 2021; 26:4849. [PMID: 34443437 PMCID: PMC8398691 DOI: 10.3390/molecules26164849] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 08/03/2021] [Accepted: 08/06/2021] [Indexed: 02/05/2023] Open
Abstract
Over 20 years ago, orexin neuropeptides (Orexin-A/hypocretin-1 and Orexin-B/hypocretins-2) produced from the same precursor in hypothalamus were identified. These two neurotransmitters and their receptors (OX1R and OX1R), present in the central and peripheral nervous system, play a major role in wakefulness but also in drug addiction, food consumption, homeostasis, hormone secretion, reproductive function, lipolysis and blood pressure regulation. With respect to these biological functions, orexins were involved in various pathologies encompassing narcolepsy, neurodegenerative diseases, chronic inflammations, metabolic syndrome and cancers. The expression of OX1R in various cancers including colon, pancreas and prostate cancers associated with its ability to induce a proapoptotic activity in tumor cells, suggested that the orexins/OX1R system could have a promising therapeutic role. The present review summarizes the relationship between cancers and orexins/OX1R system as an emerging target.
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Affiliation(s)
- Couvineau Alain
- INSERM UMR1149/Inflammation Research Center (CRI), Team “From Inflammation to Cancer in Digestive Diseases” Labeled by “la Ligue Nationale Contre le Cancer”, University of Paris, DHU UNITY, 75018 Paris, France; (N.P.); (G.V.); (V.T.)
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Ghidini M, Fusco N, Salati M, Khakoo S, Tomasello G, Petrelli F, Trapani D, Petrillo A. The Emergence of Immune-checkpoint Inhibitors in Colorectal Cancer Therapy. Curr Drug Targets 2021; 22:1021-1033. [PMID: 33563194 DOI: 10.2174/1389450122666210204204415] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 12/06/2020] [Accepted: 12/30/2020] [Indexed: 12/24/2022]
Abstract
Immunotherapy has revolutionized the treatment landscape in a number of solid tumors. In colorectal cancer, evidence suggests that microsatellite high (MSI-H) tumors are the most responsive to immune checkpoint blockade due to increased neo-antigen load and a favorable tumor microenvironment. Indeed, Pembrolizumab now represents a first-line option in such patients. However, MSI-H tumors represent the minority and a proportion of patients' progress despite initially responding. Trials are investigating different immunotherapy combinatorial strategies to enhance immune response in less immunogenic colorectal tumors. Such strategies include dual immune checkpoint blockade, combining immune checkpoint inhibitors with other treatment modalities such as radiotherapy, chemotherapy or other biological or targeted agents. Moreover, there is an increasing drive to identify biomarkers to better select patients most likely to respond to immunotherapy and understand intrinsic and acquired resistance mechanisms. Apart from MSI-H tumors, there is a strong rationale to suggest that tumors with alterations in DNA polymerase epsilon and DNA polymerase delta are also likely to respond to immunotherapy and trials in this subpopulation are underway. Other strategies such as priming O6-methylguanineDNA methyltransferase silenced tumors with alkylating agents to make them receptive to immune checkpoint blockade are also being investigated. Here we discuss different colorectal subpopulations together with their likelihood of response to immune checkpoint blockade and strategies to overcome barriers to a successful clinical outcome. We summarize evidence from published clinical trials and provide an overview of trials in progress whilst discussing newer immunotherapy strategies such as adoptive cell therapies and cancer vaccines.
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Affiliation(s)
- Michele Ghidini
- Medical Oncology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Nicola Fusco
- Department of Oncology and Hemato-Oncology, University of Milan, Italy
| | - Massimiliano Salati
- PhD Program, Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Shelize Khakoo
- Department of Medicine, The Royal Marsden Hospital NHS Foundation Trust, London and Surrey, United Kingdom
| | - Gianluca Tomasello
- Medical Oncology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Fausto Petrelli
- Medical Oncology Unit, Azienda Socio-Sanitaria Territoriale Bergamo Ovest, Treviglio, Bergamo, Italy
| | - Dario Trapani
- Division of Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
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Vaccines in Gastrointestinal Malignancies: From Prevention to Treatment. Vaccines (Basel) 2021; 9:vaccines9060647. [PMID: 34199248 PMCID: PMC8231997 DOI: 10.3390/vaccines9060647] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 06/05/2021] [Accepted: 06/09/2021] [Indexed: 12/22/2022] Open
Abstract
Gastrointestinal (GI) malignancies are some of the most common and devastating malignancies and include colorectal, gastric, esophageal, hepatocellular, and pancreatic carcinomas, among others. Five-year survival rates for many of these malignancies remain low. The majority presents at an advanced stage with limited treatment options and poor overall survival. Treatment is advancing but not at the same speed as other malignancies. Chemotherapy and radiation treatments are still only partially effective in GI malignancies and cause significant side effects. Thus, there is an urgent need for novel strategies in the treatment of GI malignancies. Recently, immunotherapy and checkpoint inhibitors have entered as potential new therapeutic options for patients, and thus, cancer vaccines may play a major role in the future of treatment for these malignancies. Further advances in understanding the interaction between the tumor and immune system have led to the development of novel agents, such as cancer vaccines.
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