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Shen K, Hu C, Zhang Y, Cheng X, Xu Z, Pan S. Advances and applications of multiomics technologies in precision diagnosis and treatment for gastric cancer. Biochim Biophys Acta Rev Cancer 2025; 1880:189336. [PMID: 40311712 DOI: 10.1016/j.bbcan.2025.189336] [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: 01/25/2025] [Revised: 04/24/2025] [Accepted: 04/25/2025] [Indexed: 05/03/2025]
Abstract
Gastric cancer (GC), one of the most prevalent malignancies worldwide, is distinguished by extensive genetic and phenotypic heterogeneity, posing persistent challenges to conventional diagnostic and therapeutic strategies. The significant global burden of GC highlights an urgent need to unravel its complex underlying mechanisms, discover novel diagnostic and prognostic biomarkers, and develop more effective therapeutic interventions. In this context, this review comprehensively examines the transformative roles of cutting-edge technologies, including radiomics, pathomics, genomics, transcriptomics, epigenomics, proteomics, and metabolomics, in advancing precision diagnosis and treatment for GC. Multiomics data analysis not only deepens our understanding of GC pathogenesis and molecular subtypes but also identifies promising biomarkers, facilitating the creation of tailored therapeutic approaches. Additionally, integrating multiomics approaches holds immense potential for elucidating drug resistance mechanisms, predicting patient outcomes, and uncovering novel therapeutic targets, thereby laying a robust foundation for precision medicine in the comprehensive management of GC.
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Affiliation(s)
- Ke Shen
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China; Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, China
| | - Can Hu
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, Zhejiang 310022, China; Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, 310022, China
| | - Yanqiang Zhang
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, Zhejiang 310022, China; Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, 310022, China
| | - Xiangdong Cheng
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, Zhejiang 310022, China; Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, 310022, China
| | - Zhiyuan Xu
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, Zhejiang 310022, China; Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, 310022, China.
| | - Siwei Pan
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, Zhejiang 310022, China; Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, 310022, China.
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Liu J, Huang H, Zhang X, Shen Y, Jiang D, Hu S, Li S, Yan Z, Hu W, Luo J, Yao H, Chen Y, Tang B. Unveiling the Cuproptosis in Colitis and Colitis-Related Carcinogenesis: A Multifaceted Player and Immune Moderator. RESEARCH (WASHINGTON, D.C.) 2025; 8:0698. [PMID: 40370501 PMCID: PMC12076167 DOI: 10.34133/research.0698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/11/2025] [Revised: 04/07/2025] [Accepted: 04/18/2025] [Indexed: 05/16/2025]
Abstract
Cuproptosis represents a novel mechanism of cellular demise characterized by the intracellular buildup of copper ions. Unlike other cell death mechanisms, its distinct process has drawn considerable interest for its promising applications in managing inflammatory bowel disease (IBD) and colorectal cancer (CRC). Emerging evidence indicates that copper metabolism and cuproptosis may exert dual regulatory effects within pathological cellular environments, specifically modulating oxidative stress responses, metabolic reprogramming, and immunotherapeutic efficacy. An appropriate level of copper may promote disease progression and exert synergistic effects, but exceeding a certain threshold, copper can inhibit disease development by inducing cuproptosis in pathological cells. This makes abnormal copper levels a potential new therapeutic target for IBD and CRC. This review emphasizes the dual function of copper metabolism and cuproptosis in the progression of IBD and CRC, while also exploring the potential application of copper-based therapies in disease treatment. The analysis further delineates the modulatory influence of tumor immune microenvironment on cuproptosis dynamics, while establishing the therapeutic potential of cuproptosis-targeted strategies in circumventing resistance to both conventional chemotherapeutic agents and emerging immunotherapies. This provides new research directions for the development of future cuproptosis inducers. Finally, this article discusses the latest advances in potential molecular targets of cuproptosis and their related genes in the treatment of IBD and CRC, highlighting future research priorities and unresolved issues.
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Affiliation(s)
- Jingwen Liu
- Department of Gastroenterology, the Second Affiliated Hospital,
Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Hairuo Huang
- China Medical University, Shenyang 110122, China
| | - Xiaojie Zhang
- The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China
| | - Yang Shen
- Department of Radiation Oncology, Zhongshan Hospital,
Fudan University, Shanghai 200000, China
| | - DeMing Jiang
- Biosensor National Special Laboratory, Key Laboratory for Biomedical Engineering of Education Ministry, Department of Biomedical Engineering,
Zhejiang University, Hangzhou 310007, China
| | - Shurong Hu
- Department of Gastroenterology, the Second Affiliated Hospital,
Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Shuyan Li
- Department of Nursing, the Second Affiliated Hospital,
Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Zelin Yan
- Department of Gastroenterology, the First Affiliated Hospital of Zhejiang Chinese Medical University,
Zhejiang Provincial Key Laboratory of Gastrointestinal Diseases Pathophysiology, Hangzhou 310006, China
| | - Wen Hu
- Department of Gastroenterology, the First Affiliated Hospital of Zhejiang Chinese Medical University,
Zhejiang Provincial Key Laboratory of Gastrointestinal Diseases Pathophysiology, Hangzhou 310006, China
| | - Jinhua Luo
- The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China
| | - Haibo Yao
- Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People’s Hospital,
Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou 310014, China
| | - Yan Chen
- Department of Gastroenterology, the Second Affiliated Hospital,
Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Bufu Tang
- Department of Interventional Radiology, Zhongshan Hospital,
Fudan University, Shanghai 200000, China
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Xu Z, Sun B, Wang W, Fan Y, Su J, Sun J, Gu X. Research progress on m6A and drug resistance in gastrointestinal tumors. Front Pharmacol 2025; 16:1565738. [PMID: 40356985 PMCID: PMC12066682 DOI: 10.3389/fphar.2025.1565738] [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: 01/23/2025] [Accepted: 04/21/2025] [Indexed: 05/15/2025] Open
Abstract
Gastrointestinal (GI) tumors represent a significant global health burden and are among the leading causes of cancer-related mortality worldwide. their drug resistance is one of the major challenges in cancer therapy. In recent years, epigenetic modifications, especially N6-methyladenosine (m6A) RNA modifications, have become a hot research topic. m6A modification plays an important role in gene expression and cancer progression by regulating RNA splicing, translation, stability, and degradation, which are regulated by "writers," "erasers" and "readers." In GI tumors, resistance to chemotherapy, targeted therapy, and immunotherapy is closely associated with m6A RNA modification. Therefore, the molecular mechanism of m6A modification and its targeted drug development provide new therapeutic strategies for overcoming drug resistance and therapeutic efficacy in GI tumors. In this review, the biological functions of m6A were explored, the specific resistance mechanisms of m6A in different types of GI tumors were explored, new ideas and targets for future treatment resistance were identified, and the limitations of this field were highlighted.
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Affiliation(s)
| | | | | | | | | | - Jiachun Sun
- Henan Key Laboratory of Cancer Epigenetics, Cancer Institute, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China
| | - Xinyu Gu
- Henan Key Laboratory of Cancer Epigenetics, Cancer Institute, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China
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Dong Y, Hu K, Zhang J, Zhu M, Liu M, Yuan Y, Sun X, Xu Z, Li S, Zhu Y, Zhang C, Zhang P, Liu T. ScRNA-seq of gastric cancer tissues reveals differences in the immune microenvironment of primary tumors and metastases. Oncogene 2024; 43:1549-1564. [PMID: 38555278 DOI: 10.1038/s41388-024-03012-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 03/12/2024] [Accepted: 03/15/2024] [Indexed: 04/02/2024]
Abstract
Gastric carcinoma (GC) is regarded as one of the deadliest cancer characterized by diversity and haste metastasis and suffers limited understanding of the spatial variation between primary and metastatic GC tumors. In this project, transcriptome analysis on 46 primary tumorous, adjacent non-tumorous, and metastatic GC tissues was performed. The results demonstrated that metastatic tumorous tissues had diminished CD8+ T cells compared to primary tumors, which is mechanistically attributed to being due to innate immunity differences represented by marked differences in macrophages between metastatic and primary tumors, particularly those expressing ApoE, where their abundance is linked to unfavorable prognoses. Examining variations in gene expression and interactions indicated possible strategies of immune evasion hindering the growth of CD8+ T cells in metastatic tumor tissues. More insights could be gained into the immune evasion mechanisms by portraying information about the GC ecosystem.
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Affiliation(s)
- Yu Dong
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Keshu Hu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jiayu Zhang
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Mengxuan Zhu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Mengling Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Yitao Yuan
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Xun Sun
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Zhenghang Xu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Suyao Li
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Yanjing Zhu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Chi Zhang
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Pengfei Zhang
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Tianshu Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, 20032, China.
- Center of Evidence-based Medicine, Fudan University, Shanghai, China.
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Li N, Li Z, Fu Q, Zhang B, Zhang J, Wan XB, Lu CM, Wang JB, Deng WY, Ma YJ, Bie LY, Wang MY, Li J, Xia QX, Wei C, Luo SX. Efficacy and safety of neoadjuvant sintilimab in combination with FLOT chemotherapy in patients with HER2-negative locally advanced gastric or gastroesophageal junction adenocarcinoma: an investigator-initiated, single-arm, open-label, phase II study. Int J Surg 2024; 110:2071-2084. [PMID: 38320099 PMCID: PMC11020066 DOI: 10.1097/js9.0000000000001119] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 01/09/2024] [Indexed: 02/08/2024]
Abstract
BACKGROUND The addition of immune checkpoint inhibitors to neoadjuvant chemotherapy in operable advanced gastric or gastroesophageal junction (G/GEJ) cancer aroused wide interest. This study was designed to assess the efficacy and safety of neoadjuvant sintilimab, a programmed cell death protein-1 (PD-1) inhibitor, in combination with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy for HER2-negative locally advanced G/GEJ cancer. METHODS Eligible patients with clinical stage cT4 and/or cN+M0 G/GEJ cancer were enroled in this phase II study. Patients received neoadjuvant sintilimab (200 mg every 3 weeks) for three cycles plus FLOT (50 mg/m 2 docetaxel, 80 mg/m 2 oxaliplatin, 200 mg/m 2 calcium levofolinate, 2600 mg/m 2 5-fluorouracil every 2 weeks) for four cycles before surgery, followed by four cycles of adjuvant FLOT with same dosages after resection. The primary endpoint was the pathological complete response (pCR) rate. RESULTS Thirty-two patients were enroled between August 2019 and September 2021, with a median follow-up of 34.8 (95% CI, 32.8-42.9) months. Thirty-two (100%) patients received neoadjuvant therapy, and 29 underwent surgery with an R0 resection rate of 93.1%. The pCR (TRG0) was achieved in 5 (17.2%; 95% CI, 5.8-35.8%) patients, and the major pathological response was 55.2%. Twenty-three (79.3%) patients had T downstaging, 21 (72.4%) had N downstaging, and 19 (65.5%) had overall TNM downstaging. Six (20.7%) patients experienced recurrence. Patients achieving pCR showed better event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) than non-pCR. The estimated 3-year EFS rate, 3-year DFS rate, and 3-year OS rate were 71.4% (95% CI, 57.2-89.2%), 78.8% (95% CI, 65.1-95.5%), and 70.9% (95% CI, 54.8-91.6%), respectively. The objective response rate and disease control rate were 84.4% (95% CI, 68.3-93.1%) and 96.9% (95% CI, 84.3-99.5%), respectively. Twenty-five (86.2%) received adjuvant therapy. The main grade ≥3 treatment-related adverse events (TRAEs) were lymphopenia (34.4%), neutropenia (28.1%), and leukopenia (15.6%). no patients died from TRAE. The LDH level exhibited a better predictive value to pathological responses than PD-L1 and MSI status. CONCLUSIONS The study demonstrated an encouraging efficacy and manageable safety profile of neoadjuvant sintilimab plus FLOT in HER2-negative locally advanced G/GEJ cancer, which suggested a potential therapeutic option for this population.
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Affiliation(s)
- Ning Li
- Departments of Medical Oncology
| | | | | | | | | | | | | | | | | | | | | | | | | | - Qing-Xin Xia
- Pathology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
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Yao G, Yuan J, Duan Q, Tan Y, Zhang Q, Chen D, Chen J. Immunoneoadjuvant therapy with immune checkpoint inhibitors of gastric cancer: an emerging exemplification : Immunoneoadjuvant therapy of gastric cancer. Invest New Drugs 2024; 42:1-13. [PMID: 37971628 DOI: 10.1007/s10637-023-01406-y] [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: 08/07/2023] [Accepted: 10/26/2023] [Indexed: 11/19/2023]
Abstract
Advances in immune checkpoint inhibitors (ICIs) have enabled more effective treatment for individuals with various types of solid tumors. Given the improved survival benefit and acceptable safety profile of ICIs in advanced gastric cancer, there is plenty of interest in the use of ICIs in the neoadjuvant setting with curative intent. Theoretically, immunoneoadjuvant with ICIs could boost the levels of endogenous tumor antigen present in the tumor to enhance T-cell priming and further enhance systemic immunity. This systemic immune response may improve the detection and elimination of the disseminated micrometastatic tumors beyond the resected tumor, which are sources of postsurgical relapse. Numerous clinical studies have begun to explore the application of ICIs in neoadjuvant treatment of gastric cancer. This article reviews the progress in the use of ICI monotherapy and in combination with alternative therapies for the treatment of gastric cancer to aid in the development of gastric cancer immunoneoadjuvant therapy and improve the overall therapeutic benefit.
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Affiliation(s)
- Guoliang Yao
- Department of hepatobiliary surgery, The first affiliated hospital of Henan university of science and technology, Henan Province, Luoyang, China
| | - Jianyong Yuan
- The 5th Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Qianqian Duan
- The State Key Lab of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co, Xuanwu District, Ltd; Building 5, No. 699-18 Xuanwu Avenue, Nanjing, Jiangsu Province, China
| | - Yuan Tan
- The State Key Lab of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co, Xuanwu District, Ltd; Building 5, No. 699-18 Xuanwu Avenue, Nanjing, Jiangsu Province, China
| | - Qin Zhang
- The State Key Lab of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co, Xuanwu District, Ltd; Building 5, No. 699-18 Xuanwu Avenue, Nanjing, Jiangsu Province, China
| | - Dongsheng Chen
- The State Key Lab of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co, Xuanwu District, Ltd; Building 5, No. 699-18 Xuanwu Avenue, Nanjing, Jiangsu Province, China
| | - Jingbo Chen
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong Province, China.
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Xie J, Chen L, Liu Q, Li XT, Lei XY. Efficacy of Chemoimmunotherapy versus Chemotherapy for Gastric Cancer: A Meta-Analysis of Survival Outcomes. Curr Med Chem 2024; 31:2649-2660. [PMID: 38265394 DOI: 10.2174/0109298673263335231121103807] [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: 05/20/2023] [Revised: 08/25/2023] [Accepted: 10/20/2023] [Indexed: 01/25/2024]
Abstract
BACKGROUND Gastric cancer has been traditionally treated with chemotherapy as the primary mode of treatment. However, recent studies have shown that chemoimmunotherapy is also effective and, in some cases, better than chemotherapy treatment. Current study aimed to find the efficacy of chemoimmunotherapy versus chemotherapy in the treatment of gastric cancer. METHODS Using electronic databases, including PubMed, Embase, and EBSCO, a thorough literature search was carried out for the years 2006 to 2023. The search strategy was designed to identify relevant studies based on chemoimmunotherapy and chemotherapy intervention, and the search was conducted using appropriate keywords and MeSH terms. The retrieved studies were screened for relevance based on their titles, abstracts, and full texts. The studies' inclusion criteria were predefined, and the selected studies were then subjected to a quality assessment using GradePro GDT. The data from selected studies were extracted and analyzed using Revman version 5.4. RESULTS The study found that chemoimmunotherapy treatment resulted in a significant improvement in overall survival (OS) with a risk ratio (RR) of 1.54 and a 95% Confidence Interval (CI) of 1.25 to 1.89. The overall effect was also found to be significant, with a p-value of less than 0.001. Furthermore, we also observed an improvement in the 1-year, 3-year, and 5-year survival rates with risk ratio (RR) of 1.09 (95% CI: 1.01, 1.17), 1.43 (95% CI: 1.28, 1.60), and 1.59 (95% CI: 1.10, 2.30), respectively. In addition, it's also found that chemoimmunotherapy treatment also resulted in an improvement in DFS with an RR of 1.94 and a 95% CI of 1.44 to 2.59. Overall, these results suggest that chemoimmunotherapy treatment can be an effective approach in comparison to chemotherapy for improving overall survival and disease-free survival in the studied population. CONCLUSION This study comparing chemoimmunotherapy versus chemotherapy for gastric cancer showed that both treatments were effective, but chemoimmunotherapy had more significant efficacy. To support these results, additional studies with a large sample size and a longer follow-up time are required.
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Affiliation(s)
- Juan Xie
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
- Institute of Translational Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Lin Chen
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Qing Liu
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Xi-Tai Li
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Xiao-Yong Lei
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
- Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, University of South China, Hengyang, Hunan, 421001, China
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Leowattana W, Leowattana P, Leowattana T. Immunotherapy for advanced gastric cancer. World J Methodol 2023; 13:79-97. [PMID: 37456977 PMCID: PMC10348086 DOI: 10.5662/wjm.v13.i3.79] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 05/11/2023] [Accepted: 05/31/2023] [Indexed: 06/20/2023] Open
Abstract
Gastric cancer (GC) is believed to be the fifth most common cancer and the third most common cause of death worldwide. Treatment techniques include radiation, chemotherapy, gastrectomy, and targeted treatments are often employed. Some hopeful results from the development of GC immunotherapy have already changed treatment approaches. Along with previous combination medicines, new immunotherapies have been developed that target distinct molecules. Despite ongoing studies into the current therapeutic options and significant improvements in this field, the prognosis for the ailment is poor. Since there are few treatment options and a delay in detection, the illness actually advances, spreads, and metastasizes. The bulk of immunotherapies in use today rely on cytotoxic immune cells, monoclonal antibodies, and gene-transferred vaccines. Immune checkpoint inhibitors have become more popular. In this review, we sought to examine the viewpoint and development of several immunotherapy treatment modalities for advanced GC, as well as the clinical results thus far reported. Additionally, we outlined tumor immune escape and tumor immunosurveillance.
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Affiliation(s)
- Wattana Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Rachatawee 10400, Bangkok, Thailand
| | - Pathomthep Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Rachatawee 10400, Bangkok, Thailand
| | - Tawithep Leowattana
- Department of Medicine, Faculty of Medicine, Srinakharinwirot University, Wattana 10110, Bangkok, Thailand
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A DSC Test for the Early Detection of Neoplastic Gastric Lesions in a Medium-Risk Gastric Cancer Area. Int J Mol Sci 2023; 24:ijms24043290. [PMID: 36834698 PMCID: PMC9966253 DOI: 10.3390/ijms24043290] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 01/30/2023] [Accepted: 02/03/2023] [Indexed: 02/10/2023] Open
Abstract
In this study, we aimed to assess the accuracy of the proposed novel, noninvasive serum DSC test in predicting the risk of gastric cancer before the use of upper endoscopy. To validate the DSC test, we enrolled two series of individuals living in Veneto and Friuli-Venezia Giulia, Italy (n = 53 and n = 113, respectively), who were referred for an endoscopy. The classification used for the DSC test to predict gastric cancer risk combines the coefficient of the patient's age and sex and serum pepsinogen I and II, gastrin 17, and anti-Helicobacter pylori immunoglobulin G concentrations in two equations: Y1 and Y2. The coefficient of variables and the Y1 and Y2 cutoff points (>0.385 and >0.294, respectively) were extrapolated using regression analysis and an ROC curve analysis of two retrospective datasets (300 cases for the Y1 equation and 200 cases for the Y2 equation). The first dataset included individuals with autoimmune atrophic gastritis and first-degree relatives with gastric cancer; the second dataset included blood donors. Demographic data were collected; serum pepsinogen, gastrin G17, and anti-Helicobacter pylori IgG concentrations were assayed using an automatic Maglumi system. Gastroscopies were performed by gastroenterologists using an Olympus video endoscope with detailed photographic documentation during examinations. Biopsies were taken at five standardized mucosa sites and were assessed by a pathologist for diagnosis. The accuracy of the DSC test in predicting neoplastic gastric lesions was estimated to be 74.657% (65%CI; 67.333% to 81.079%). The DSC test was found to be a useful, noninvasive, and simple approach to predicting gastric cancer risk in a population with a medium risk of developing gastric cancer.
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Yang K, Jin H, Gao X, Wang GC, Zhang GQ. Elucidating the molecular determinants in the process of gastrin C-terminal pentapeptide amide end activating cholecystokinin 2 receptor by Gaussian accelerated molecular dynamics simulations. Front Pharmacol 2023; 13:1054575. [PMID: 36756145 PMCID: PMC9899899 DOI: 10.3389/fphar.2022.1054575] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 12/02/2022] [Indexed: 01/24/2023] Open
Abstract
Gastrin plays important role in stimulating the initiation and development of many gastrointestinal diseases through interacting with the cholecystokinin 2 receptor (CCK2R). The smallest bioactive unit of gastrin activating CCK2R is the C-terminal tetrapeptide capped with an indispensable amide end. Understanding the mechanism of this smallest bioactive unit interacting with CCK2R on a molecular basis could provide significant insights for designing CCK2R antagonists, which can be used to treat gastrin-related diseases. To this end, we performed extensive Gaussian accelerated molecular dynamics simulations to investigate the interaction between gastrin C-terminal pentapeptide capped with/without amide end and CCK2R. The amide cap influences the binding modes of the pentapeptide with CCK2R by weakening the electrostatic attractions between the C-terminus of the pentapeptide and basic residues near the extracellular domain in CCK2R. The C-terminus with the amide cap penetrates into the transmembrane domain of CCK2R while floating at the extracellular domain without the amide cap. Different binding modes induced different conformational dynamics of CCK2R. Residue pairs in CCK2R had stronger correlated motions when binding with the amidated pentapeptide. Key residues and interactions important for CCK2R binding with the amidated pentagastrin were also identified. Our results provide molecular insights into the determinants of the bioactive unit of gastrin activating CCK2R, which would be of great help for the design of CCK2R antagonists.
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Affiliation(s)
- Kecheng Yang
- National Supercomputing Center in Zhengzhou, Zhengzhou University, Zhengzhou, China,*Correspondence: Kecheng Yang,
| | - Huiyuan Jin
- School of International Studies, Zhengzhou University, Zhengzhou, China
| | - Xu Gao
- National Supercomputing Center in Zhengzhou, Zhengzhou University, Zhengzhou, China
| | - Gang-Cheng Wang
- Department of General Surgery, Affiliated Cancer Hospitalof Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Guo-Qiang Zhang
- Department of General Surgery, Affiliated Cancer Hospitalof Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
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Bao Z, Tang Q, Chen H, Zhang B, Shi W, Gu D. An abscopal effect in a gastric cancer patient treated with combined chemoimmunotherapy and palliative radiotherapy. Immunotherapy 2022; 14:1429-1435. [PMID: 36537254 DOI: 10.2217/imt-2022-0041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
The prognosis of advanced gastric cancer remains poor. Palliative radiotherapy has been utilized to palliate bleeding in unresectable gastric cancer. Recent studies have described that a systemic immune response may be induced by local radiotherapy to the primary tumor lesion. Here we report a rare case of an abscopal effect in a patient with inoperable gastric cancer combined with tumor hemorrhage. A short course of radiotherapy was performed to palliate bleeding; additionally, the patient was treated with chemotherapy and immunotherapy. Complete response was achieved in the lung metastasis lesion. The observed abscopal effect suggests that there may be a synergistic effect between immunotherapy and radiotherapy. This case report supports the combination of immunotherapy and radiotherapy in patients with advanced gastric cancer.
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Affiliation(s)
- Zengtao Bao
- Department of Gastrointestinal Surgery, The First People's Hospital of Lianyungang, Lianyungang, 222016, PR China.,The First Affiliated Hospital of Kangda College of Nanjing Medical University, Lianyungang, 222016, PR China.,Xuzhou Medical University Affiliated Hospital of Lianyungang, Lianyungang, 222016, PR China
| | - Qiang Tang
- Department of Gastrointestinal Surgery, The First People's Hospital of Lianyungang, Lianyungang, 222016, PR China.,The First Affiliated Hospital of Kangda College of Nanjing Medical University, Lianyungang, 222016, PR China.,Xuzhou Medical University Affiliated Hospital of Lianyungang, Lianyungang, 222016, PR China
| | - Huiyu Chen
- Department of Gastrointestinal Surgery, The First People's Hospital of Lianyungang, Lianyungang, 222016, PR China.,The First Affiliated Hospital of Kangda College of Nanjing Medical University, Lianyungang, 222016, PR China.,Xuzhou Medical University Affiliated Hospital of Lianyungang, Lianyungang, 222016, PR China
| | - Baoming Zhang
- Department of Gastrointestinal Surgery, The First People's Hospital of Lianyungang, Lianyungang, 222016, PR China.,The First Affiliated Hospital of Kangda College of Nanjing Medical University, Lianyungang, 222016, PR China.,Xuzhou Medical University Affiliated Hospital of Lianyungang, Lianyungang, 222016, PR China
| | - Wenchao Shi
- Department of Gastrointestinal Surgery, The First People's Hospital of Lianyungang, Lianyungang, 222016, PR China.,The First Affiliated Hospital of Kangda College of Nanjing Medical University, Lianyungang, 222016, PR China.,Xuzhou Medical University Affiliated Hospital of Lianyungang, Lianyungang, 222016, PR China
| | - Dezhi Gu
- Department of Gastrointestinal Surgery, The First People's Hospital of Lianyungang, Lianyungang, 222016, PR China.,The First Affiliated Hospital of Kangda College of Nanjing Medical University, Lianyungang, 222016, PR China.,Xuzhou Medical University Affiliated Hospital of Lianyungang, Lianyungang, 222016, PR China
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12
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Wang CY, Ting Cheung SP, Sugimura R. Combating challenges in CAR-T cells with engineering immunology. Front Cell Dev Biol 2022; 10:969020. [PMID: 36299480 PMCID: PMC9589253 DOI: 10.3389/fcell.2022.969020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 09/14/2022] [Indexed: 03/27/2024] Open
Abstract
Chimeric antigen receptors (CAR) T cells (CAR-T) mark a significant step towards producing safe and effective personal anticancer treatments. CAR-T strategies engineers the T cells from the patients to allow specific binding to a tumour-specific antigen. CAR-Ts are a second-wave offensive strategy to clear out remaining chemotherapy-resistant tumour cells. Though showing practical antitumor abilities in multiple haematological malignancies and solid tumour cancers, the issues of antigen escape, tumour infiltration/penetration, and toxicity side effects limit the usage of prolonged CAR-T therapies. However, engineering immunology has exploited human stem cell-based CAR-T therapies and the development of CAR-M (macrophage) therapies to combat the disadvantages of conventional CAR-T therapies. In this review, we will highlight the challenges of CAR-T therapies and combat them with engineering immunology for cancer immunotherapy.
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Affiliation(s)
| | | | - Ryohichi Sugimura
- School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
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13
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Tang X, Li D, Gu Y, Zhao Y, Li A, Qi F, Liu J. Natural cell based biomimetic cellular transformers for targeted therapy of digestive system cancer. Theranostics 2022; 12:7080-7107. [PMID: 36276645 PMCID: PMC9576611 DOI: 10.7150/thno.75937] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 09/29/2022] [Indexed: 11/22/2022] Open
Abstract
Digestive system cancer is the most common cause of cancer death in the world. Although cancer treatment options are increasingly diversified, the mortality rate of malignant cancer of the digestive system remains high. Therefore, it is necessary to explore effective cancer treatment methods. Recently, biomimetic nanoparticle delivery systems based on natural cells that organically integrate the low immunogenicity, high biocompatibility, cancer targeting, and controllable, versatile functionality of smart nanocarrier design with natural cells have been expected to break through the bottleneck of tumor targeted therapy. In this review, we focus on the dynamic changes and complex cellular communications that occur in vivo in natural cells based vehicles. Recent studies on the development of advanced targeted drug delivery systems using the dynamic behaviors such as specific surface protein affinity, morphological changes, and phenotypic polarization of natural cells are summarized. In addition to drug delivery mediated by dynamic behavior, functional "delivery" based on the natural cell themselves is also involved. Aiming to make the best use of the functions of cells, providing clues for the development of advanced drug delivery platforms.
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Affiliation(s)
- Xiaomeng Tang
- Department of Pharmacy, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Dan Li
- Department of Pharmacy, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Yongwei Gu
- Department of Pharmacy, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Yunan Zhao
- Department of Pharmacy, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Aixue Li
- Department of Pharmacy, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, China
| | - Fu Qi
- Department of Pharmacy, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, China
| | - Jiyong Liu
- Department of Pharmacy, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Department of Pharmacy, Shanghai Proton and Heavy Ion Center, Shanghai 201315, China
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14
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Zhao Y, Bai Y, Shen M, Li Y. Therapeutic strategies for gastric cancer targeting immune cells: Future directions. Front Immunol 2022; 13:992762. [PMID: 36225938 PMCID: PMC9549957 DOI: 10.3389/fimmu.2022.992762] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 08/29/2022] [Indexed: 11/13/2022] Open
Abstract
Gastric cancer (GC) is a malignancy with a high incidence and mortality, and the emergence of immunotherapy has brought survival benefits to GC patients. Compared with traditional therapy, immunotherapy has the advantages of durable response, long-term survival benefits, and lower toxicity. Therefore, targeted immune cells are the most promising therapeutic strategy in the field of oncology. In this review, we introduce the role and significance of each immune cell in the tumor microenvironment of GC and summarize the current landscape of immunotherapy in GC, which includes immune checkpoint inhibitors, adoptive cell therapy (ACT), dendritic cell (DC) vaccines, reduction of M2 tumor-associated macrophages (M2 TAMs), N2 tumor-associated neutrophils (N2 TANs), myeloid-derived suppressor cells (MDSCs), effector regulatory T cells (eTregs), and regulatory B cells (Bregs) in the tumor microenvironment and reprogram TAMs and TANs into tumor killer cells. The most widely used immunotherapy strategies are the immune checkpoint inhibitor programmed cell death 1/programmed death-ligand 1 (PD-1/PD-L1) antibody, cytotoxic T lymphocyte–associated protein 4 (CTLA-4) antibody, and chimeric antigen receptor T (CAR-T) in ACT, and these therapeutic strategies have significant anti-tumor efficacy in solid tumors and hematological tumors. Targeting other immune cells provides a new direction for the immunotherapy of GC despite the relatively weak clinical data, which have been confirmed to restore or enhance anti-tumor immune function in preclinical studies and some treatment strategies have entered the clinical trial stage, and it is expected that more and more effective immune cell–based therapeutic methods will be developed and applied.
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Affiliation(s)
- Yan Zhao
- Department of Oncology and Hematology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yuansong Bai
- Department of Oncology and Hematology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Meili Shen
- Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun, China
- *Correspondence: Yapeng Li, ; Meili Shen,
| | - Yapeng Li
- The National and Local Joint Engineering Laboratory for Synthesis Technology of High Performance Polymer, College of Chemistry, Jilin University, Changchun, China
- *Correspondence: Yapeng Li, ; Meili Shen,
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15
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Tustumi F, Agareno GA, Galletti RP, da Silva RBR, Quintas JG, Sesconetto LDA, Szor DJ, Wolosker N. The Role of the Heat-Shock Proteins in Esophagogastric Cancer. Cells 2022; 11:2664. [PMID: 36078072 PMCID: PMC9454628 DOI: 10.3390/cells11172664] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 08/24/2022] [Accepted: 08/25/2022] [Indexed: 01/05/2023] Open
Abstract
Heat-shock proteins (HSPs) are a family of proteins that have received considerable attention over the last several years. They have been classified into six prominent families: high-molecular-mass HSP, 90, 70, 60, 40, and small heat shock proteins. HSPs participate in protein folding, stability, and maturation of several proteins during stress, such as in heat, oxidative stress, fever, and inflammation. Due to the immunogenic host's role in the combat against cancer cells and the role of the inflammation in the cancer control or progression, abnormal expression of these proteins has been associated with many types of cancer, including esophagogastric cancer. This study aims to review all the evidence concerning the role of HSPs in the pathogenesis and prognosis of esophagogastric cancer and their potential role in future treatment options. This narrative review gathers scientific evidence concerning HSPs in relation to esophagus and gastric cancer. All esophagogastric cancer subtypes are included. The role of HSPs in carcinogenesis, prognostication, and therapy for esophagogastric cancer are discussed. The main topics covered are premalignant conditions for gastric cancer atrophic gastritis, Barrett esophagus, and some viral infections such as human papillomavirus (HPV) and Epstein-Barr virus (EBV). HSPs represent new perspectives on the development, prognostication, and treatment of esophagogastric cancer.
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Affiliation(s)
- Francisco Tustumi
- Department of Gastroenterology, Universidade de São Paulo, Av. Dr. Enéas Carvalho de Aguiar, 255, São Paulo 05403-000, SP, Brazil
- Department of Surgery, Hospital Israelita Albert Einstein, Av. Albert Einstein, 627, São Paulo 05652-900, SP, Brazil
| | - Gabriel Andrade Agareno
- Department of Surgery, Hospital Israelita Albert Einstein, Av. Albert Einstein, 627, São Paulo 05652-900, SP, Brazil
| | - Ricardo Purchio Galletti
- Department of Surgery, Hospital Israelita Albert Einstein, Av. Albert Einstein, 627, São Paulo 05652-900, SP, Brazil
| | - Rafael Benjamim Rosa da Silva
- Department of Surgery, Hospital Israelita Albert Einstein, Av. Albert Einstein, 627, São Paulo 05652-900, SP, Brazil
| | - Julia Grams Quintas
- Department of Surgery, Hospital Israelita Albert Einstein, Av. Albert Einstein, 627, São Paulo 05652-900, SP, Brazil
| | - Lucas de Abreu Sesconetto
- Department of Surgery, Hospital Israelita Albert Einstein, Av. Albert Einstein, 627, São Paulo 05652-900, SP, Brazil
| | - Daniel José Szor
- Department of Gastroenterology, Universidade de São Paulo, Av. Dr. Enéas Carvalho de Aguiar, 255, São Paulo 05403-000, SP, Brazil
- Department of Surgery, Hospital Israelita Albert Einstein, Av. Albert Einstein, 627, São Paulo 05652-900, SP, Brazil
| | - Nelson Wolosker
- Department of Surgery, Hospital Israelita Albert Einstein, Av. Albert Einstein, 627, São Paulo 05652-900, SP, Brazil
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16
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Wang H, Zhang J, Li H, Yu H, Chen S, Liu S, Zhang C, He Y. FN1 is a prognostic biomarker and correlated with immune infiltrates in gastric cancers. Front Oncol 2022; 12:918719. [PMID: 36081567 PMCID: PMC9445423 DOI: 10.3389/fonc.2022.918719] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 07/25/2022] [Indexed: 01/13/2023] Open
Abstract
Fibronectin 1 (FN1) is a glycoprotein found throughout the extracellular matrix that has a role in the onset and progression of cancer. However, its immune relationship with gastric cancer is still unclear. FN1 was systematically reviewed by Gene Expression Profiling Interactive Analysis (GEPIA), Linked Omics, Tumor IMmune Estimation Resource (TIMER), and Kaplan–Meier (KM) plotter analysis. The TIMER, GEPIA, TISIDB, and cBioPortal databases investigated the association of FN1 with tumor immune infiltration and validated using immunohistochemistry. We discovered that tumor tissue expresses FN1 at a higher level than neighboring tissue, and those genes coexpressed with FN1 have a poor prognosis. At the same time, we discovered that increased FN1 expression was related to immunological infiltration, particularly macrophage infiltration. Using immunohistochemistry, we discovered that FN1 expression was tightly connected to M2 macrophages. It can be concluded that FN1 can affect the immunological microenvironment and is a prognostic marker in gastric cancer.
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Affiliation(s)
- Han Wang
- Department of Center for Digestive Disease, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Junchang Zhang
- Department of Center for Digestive Disease, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Huan Li
- Department of Center for Digestive Disease, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Hong Yu
- Department of Center for Digestive Disease, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Songyao Chen
- Department of Center for Digestive Disease, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Shuhao Liu
- Department of Center for Digestive Disease, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Changhua Zhang
- Department of Center for Digestive Disease, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
- *Correspondence: Changhua Zhang, ; Yulong He,
| | - Yulong He
- Department of Center for Digestive Disease, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- *Correspondence: Changhua Zhang, ; Yulong He,
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17
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Ni Y, Low JT, Silke J, O’Reilly LA. Digesting the Role of JAK-STAT and Cytokine Signaling in Oral and Gastric Cancers. Front Immunol 2022; 13:835997. [PMID: 35844493 PMCID: PMC9277720 DOI: 10.3389/fimmu.2022.835997] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 05/16/2022] [Indexed: 12/12/2022] Open
Abstract
When small proteins such as cytokines bind to their associated receptors on the plasma membrane, they can activate multiple internal signaling cascades allowing information from one cell to affect another. Frequently the signaling cascade leads to a change in gene expression that can affect cell functions such as proliferation, differentiation and homeostasis. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) and the tumor necrosis factor receptor (TNFR) are the pivotal mechanisms employed for such communication. When deregulated, the JAK-STAT and the TNF receptor signaling pathways can induce chronic inflammatory phenotypes by promoting more cytokine production. Furthermore, these signaling pathways can promote replication, survival and metastasis of cancer cells. This review will summarize the essentials of the JAK/STAT and TNF signaling pathways and their regulation and the molecular mechanisms that lead to the dysregulation of the JAK-STAT pathway. The consequences of dysregulation, as ascertained from founding work in haematopoietic malignancies to more recent research in solid oral-gastrointestinal cancers, will also be discussed. Finally, this review will highlight the development and future of therapeutic applications which modulate the JAK-STAT or the TNF signaling pathways in cancers.
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Affiliation(s)
- Yanhong Ni
- Central Laboratory, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Jun T. Low
- Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - John Silke
- Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Lorraine A. O’Reilly
- Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
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18
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Xu R, Chen L, Wei W, Tang Q, Yu Y, Hu Y, Kadasah S, Xie J, Yu H. Single-Cell Sequencing Analysis Based on Public Databases for Constructing a Metastasis-Related Prognostic Model for Gastric Cancer. Appl Bionics Biomech 2022; 2022:7061263. [PMID: 35528539 PMCID: PMC9068325 DOI: 10.1155/2022/7061263] [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: 02/24/2022] [Revised: 03/21/2022] [Accepted: 03/28/2022] [Indexed: 01/09/2023] Open
Abstract
Background Although incidences of gastric cancer have decreased in recent years, the disease remains a significant danger to human health. Lack of early symptoms often leads to delayed diagnosis of gastric cancer, so that many patients miss the opportunity for surgery. Treatment for advanced gastric cancer is often limited. Immunotherapy, targeted therapy, and the mRNA vaccine have all emerged as potentially viable treatments for advanced gastric cancer. However, our understanding of the immune microenvironment of gastric cancer is far from sufficient; now is the time to explore this microenvironment. Methods In our study, using TCGA dataset and the GEO dataset GSE62254, we performed in-depth transcriptome and single-cell sequencing analyses based on public databases. We analyzed differential gene expressions of immune cells in metastatic and nonmetastatic gastric cancer and constructed a prognostic model of gastric cancer patients based on these differential gene expressions. We also screened candidate vaccine genes for gastric cancer. Results This prognostic model can accurately predict the prognosis of gastric cancer patients by dividing them into high-risk and low-risk groups. In addition to this, we identified a candidate vaccine gene for gastric cancer: PTPN6. Conclusions Our study could provide new ideas for the treatment of gastric cancer.
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Affiliation(s)
- Rubin Xu
- Department of General Surgery, Fuyang Hospital Affiliated to Anhui Medical University, Fuyang, Anhui, China
| | - Liang Chen
- Department of General Surgery, Fuyang Hospital Affiliated to Anhui Medical University, Fuyang, Anhui, China
| | - Wei Wei
- Department of General Surgery, Fuyang Hospital Affiliated to Anhui Medical University, Fuyang, Anhui, China
| | - Qikai Tang
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, Jiangsu 210029, China
| | - You Yu
- Second School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yiming Hu
- College of Pharmacy, Jiangsu Ocean University, Lianyungang, Jiangsu, China
| | - Sultan Kadasah
- Department of Biology, Faculty of Science, University of Bisha, Saudi Arabia
| | - Jiaheng Xie
- Department of Burn and Plastic Surgery, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, Jiangsu, China
| | - Hongzhu Yu
- Department of General Surgery, Fuyang Hospital Affiliated to Anhui Medical University, Fuyang, Anhui, China
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19
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Kim EY, Abdul-Ghafar J, Chong Y, Yim K. Calculated Tumor-Associated Neutrophils Are Associated with the Tumor-Stroma Ratio and Predict a Poor Prognosis in Advanced Gastric Cancer. Biomedicines 2022; 10:708. [PMID: 35327509 PMCID: PMC8945075 DOI: 10.3390/biomedicines10030708] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/17/2022] [Accepted: 03/17/2022] [Indexed: 11/23/2022] Open
Abstract
The tumor-associated neutrophils (TANs) value and tumor-stroma ratio (TSR) are promising prognostic parameters in the tumor microenvironment. We aimed to evaluate the prognostic role and relationship of TANs and TSR in gastric cancer. Our study comprised 157 patients who underwent gastrectomy for advanced gastric cancer. TANs were assessed by immunohistochemical staining (CD15 and CD66b) and were analyzed with an image analyzer. TANs have been known to have different functional subpopulations of N1 (anti-tumor) and N2 (pro-tumor). We developed "calculated TANs with pro-tumor function (cN2; CD15 minus CD66b)". The TSR was evaluated using hematoxylin and eosin staining. High-grade CD15-positive, cN2 in the tumor center, and TSR were significantly related to poor disease-free survival (DFS). TSR and cN2 were independent prognostic factors for DFS (hazard ratio (HR) = 2.614; p = 0.001, HR = 3.976; p = 0.002) and cN2 in the tumor center showed a positive correlation with TSR (R = 0.179, p = 0.025). While CD66b stained both N1 and N2, CD15 detected most of N2. Combining both markers revealed a novel cN2, which was an independent marker of poor prognosis. The transformation from N1 to N2 predominantly occurred in the tumor center, and was associated with TSR.
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Affiliation(s)
- Eun Young Kim
- Department of Surgery, Uijeongbu St. Mary Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea;
| | - Jamshid Abdul-Ghafar
- Department of Hospital Pathology, Uijeongbu St. Mary Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (J.A.-G.); (Y.C.)
| | - Yosep Chong
- Department of Hospital Pathology, Uijeongbu St. Mary Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (J.A.-G.); (Y.C.)
| | - Kwangil Yim
- Department of Hospital Pathology, Uijeongbu St. Mary Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (J.A.-G.); (Y.C.)
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20
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Faghfuri E, Shadbad MA, Faghfouri AH, Soozangar N. Cellular immunotherapy in gastric cancer: adoptive cell therapy and dendritic cell-based vaccination. Immunotherapy 2022; 14:475-488. [PMID: 35232264 DOI: 10.2217/imt-2021-0285] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer (GC) is one of the most frequently diagnosed malignancies. Recent studies have highlighted cellular immunotherapy (CI) as a promising approach for treating this disease. Among the CI-based approaches, adoptive cell therapy and dendritic cell-based vaccination are commonly studied in preclinical and clinical trials. Here we review the current evidence on the potentiality of CI in treating GC, the targets for adoptive cell therapy, ongoing clinical trials, constraints and the future outlook. The results suggest that there is a need to identify novel biomarkers that predict which GC patients will most likely respond to these approaches. Also, CI plus chemotherapy or immune checkpoint inhibitors can improve the survival of patients with late-stage GC. Therefore, this approach can be promising for treating these patients.
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Affiliation(s)
- Elnaz Faghfuri
- Digestive Disease Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | | | | | - Narges Soozangar
- Digestive Disease Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
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21
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Immune Score Predicts Outcomes of Gastric Cancer Patients Treated with Adjuvant Chemoradiotherapy. JOURNAL OF ONCOLOGY 2022; 2021:9344124. [PMID: 34987582 PMCID: PMC8723845 DOI: 10.1155/2021/9344124] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 11/01/2021] [Indexed: 02/06/2023]
Abstract
Background Substantial evidence has demonstrated that tumor-infiltrating lymphocytes (TILs) are correlated with patient prognosis. The TIL-based immune score (IS) affects prognosis in various cancers, but its prognostic impact in gastric cancer (GC) patients treated with adjuvant chemoradiotherapy remains unclear. Methods A total of 101 GC patients who received chemoradiotherapy after gastrectomy were retrospectively analyzed in this study. Immunohistochemistry staining for CD3+ and CD8+ T-cell counts in both tumor center (CT) and invasive margin (IM) regions was built into the IS. Patients were then divided into three groups based on their differential IS levels. The correlation between IS and clinical parameters was analyzed. The prognostic impact of IS and clinical parameters was evaluated using Kaplan-Meier analysis and Cox proportional hazard regression analysis. Receiver operating characteristic (ROC) curves were plotted to compare the area under the curve (AUC) of IS with other clinical parameters. Nomograms for disease-free survival (DFS) and overall survival (OS) prediction were constructed based on the identified parameters. Results Finally, 20 (19.8%), 57 (56.4%), and 24 (23.8%) GC patients were identified with low, intermediate, and high IS levels, respectively. GC patients with higher IS levels exhibited better DFS (p < 0.001) and OS (p < 0.001). IS was an independent prognostic factor for both DFS (p < 0.001) and OS (p < 0.001) in multivariate analysis. IS presented a better predictive ability than the traditional pathological tumor-node-metastasis (pTNM) staging system (AUC: 0.801 vs. 0.677 and 0.800 vs. 0.660, respectively) with respect to both DFS and OS. The C-index of the nomograms for DFS and OS prediction was 0.737 and 0.774, respectively. Conclusions IS is a strong predictive factor for both DFS and OS in GC patients treated with adjuvant chemoradiotherapy, which may complement the traditional pTNM staging system.
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22
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El Gharib K, Khoury M, Kourie HR. HER2 in gastric adenocarcinoma: where do we stand today? Per Med 2021; 19:67-78. [PMID: 34881639 DOI: 10.2217/pme-2021-0004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Aim: HER2 is a proto-oncogene expressed in 10-30% of gastric adenocarcinomas and is an ideal target for inhibition in malignancy with high recurrence and dismal survival rates. Materials & methods: A systematic search was conducted via PubMed, Google Scholar and the clinicaltrials.gov database to report the results of ongoing and past studies investigating HER2 inhibitors in gastric cancer. Results: Twenty-five studies were included; ToGA trial is the pivotal trial approving the use of trastuzumab in metastatic gastric cancer, followed by more studies investigating other HER2 inhibitors in this setting, as well as in local and locoregional malignancy. Conclusion: Anti-HER2 molecules are proving efficacy and safety in gastric cancer; the evidence is growing and association with other cancer agents is under investigation.
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Affiliation(s)
- Khalil El Gharib
- Department of Internal Medicine, Staten Island University Hospital, NY 10305, USA
| | - Makram Khoury
- Hematology-Oncology Department, Faculty of Medicine, Saint Joseph University, Beirut, 17-5208, Lebanon
| | - Hampig Raphael Kourie
- Hematology-Oncology Department, Faculty of Medicine, Saint Joseph University, Beirut, 17-5208, Lebanon
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Liu Y, Cheng L, Huang W, Cheng X, Peng W, Shi D. Genome Instability-Related miRNAs Predict Survival, Immune Landscape, and Immunotherapy Responses in Gastric Cancer. J Immunol Res 2021; 2021:2048833. [PMID: 34761007 PMCID: PMC8575650 DOI: 10.1155/2021/2048833] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Revised: 09/23/2021] [Accepted: 10/16/2021] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Increasing evidence suggests that microRNAs (miRNAs) are involved in genome instability (GI) and drive the occurrence of tumors. However, the role of GI-related miRNAs in gastric cancer (GC) remains largely unknown. Herein, we developed a novel GI-related miRNA signature (GIMiSig) and further investigated its role in prognosis, the immune landscape, and immunotherapy responses in GC patients. METHODS An analysis of somatic mutation data on 434 gastric cancer cases from The Cancer Genome Atlas (TCGA) database was performed, thereby generating genome stability (GS) and GI groups. By detecting differentially expressed miRNAs between the GS and GI groups that were associated with overall survival, 8 miRNAs were identified and used to construct the GIMiSig. RESULTS The GIMiSig showed high accuracy in detecting GC patients. Using GIMiSig to stratify the patients into the high- and low-risk subgroups to predict survival outperformed the use of regular clinical features such as age, gender, or disease stage. Patients with low risk had a more favorable survival time than those with high risk. More importantly, the high-risk patients were associated with decreased UBQLN4 expression, higher accumulation of immune cells, lower Titin (TTN) mutation frequency, worse immunotherapy efficacy, and cancer-associated pathways. Conversely, the low-risk patients were characterized by UBQLN4 overexpression, lower fraction of immune cells, higher TTN mutation frequency, better response to immunotherapy, and GI-related pathways. CONCLUSION In summary, we constructed a novel GIMiSig that could stratify GC patients into distinct risk groups that have different survival outcomes and immunotherapy efficacy. The results may provide new clues for improving GC outcomes.
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Affiliation(s)
- Yaqiong Liu
- Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
- Regenerative Medicine Institute (REMEDI), CURAM, National University of Ireland Galway, H91TK33, Galway, Ireland
| | - Lin Cheng
- Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Wei Huang
- Department of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Xin Cheng
- Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Weijun Peng
- Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Dazun Shi
- Department of Gynecology and Obstetrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
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24
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Preclinical pharmacology modeling of chimeric antigen receptor T therapies. Curr Opin Pharmacol 2021; 61:49-61. [PMID: 34619442 DOI: 10.1016/j.coph.2021.08.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 08/09/2021] [Indexed: 12/27/2022]
Abstract
Chimeric antigen receptor (CAR) T cells have largely been successful in treating hematological malignancies in the clinic but have not been as effective in treating solid tumors, in part, owing to poor access and the immunosuppressive tumor microenvironment. In addition, CAR-T therapy can cause potentially life-threatening side effects, including cytokine release syndrome and neurotoxicity. Current preclinical testing of CAR-T therapy efficacy is typically performed in mouse tumor models, which often fails to predict toxicity. Recent developments in humanized models and transgenic mice as well as in vitro three-dimensional organoids in early development and nonhuman primate models are being adopted for CAR-T cell efficacy and toxicity assessment. However, because no single model perfectly recapitulates the human immune system and tumor microenvironment, careful model selection based on their respective pros and cons is crucial for adequate evaluation of different CAR-T treatments, so that their clinical development can be better supported.
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25
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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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26
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Wang DK, Zuo Q, He QY, Li B. Targeted Immunotherapies in Gastrointestinal Cancer: From Molecular Mechanisms to Implications. Front Immunol 2021; 12:705999. [PMID: 34447376 PMCID: PMC8383067 DOI: 10.3389/fimmu.2021.705999] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 07/26/2021] [Indexed: 12/12/2022] Open
Abstract
Gastrointestinal cancer is a leading cause of cancer-related mortality and remains a major challenge for cancer treatment. Despite the combined administration of modern surgical techniques and chemoradiotherapy (CRT), the overall 5-year survival rate of gastrointestinal cancer patients in advanced stage disease is less than 15%, due to rapid disease progression, metastasis, and CRT resistance. A better understanding of the mechanisms underlying cancer progression and optimized treatment strategies for gastrointestinal cancer are urgently needed. With increasing evidence highlighting the protective role of immune responses in cancer initiation and progression, immunotherapy has become a hot research topic in the integrative management of gastrointestinal cancer. Here, an overview of the molecular understanding of colorectal cancer, esophageal cancer and gastric cancer is provided. Subsequently, recently developed immunotherapy strategies, including immune checkpoint inhibitors, chimeric antigen receptor T cell therapies, tumor vaccines and therapies targeting other immune cells, have been described. Finally, the underlying mechanisms, fundamental research and clinical trials of each agent are discussed. Overall, this review summarizes recent advances and future directions for immunotherapy for patients with gastrointestinal malignancies.
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Affiliation(s)
| | | | | | - Bin Li
- Ministry of Education (MOE), Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, Jinan University, Guangzhou, China
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27
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Jin Y, Tao L, Jin S, Cai W. Patterns of immune infiltration in gastric cancer and their clinical significance. Jpn J Clin Oncol 2021; 51:1067-1079. [PMID: 33890063 DOI: 10.1093/jjco/hyab054] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 01/15/2020] [Accepted: 03/29/2021] [Indexed: 01/02/2023] Open
Abstract
OBJECTIVE The malignant phenotypes of cancer are defined not only by its intrinsic tumor cells but also by the tumor-infiltrating immune cells activated and recruited to the cancer microenvironment. However, a comprehensive introduction of gastric cancer immune cell infiltration has not been identified so far. METHODS In this study, we comprehensively analyzed the tumor-infiltrating immune cells abundance in gastric cancer for the first time by CIBERSORT. The meta-analysis, single-sample gene set enrichment analysis and hierarchical agglomerative clustering were used to measure and evaluate the respective proportions of 22 cell types of immune infiltration using normalized gene expression data. The fraction of tumor-infiltrating immune cells subpopulations was also evaluated to determine the associations with clinical features and molecular subtypes. RESULTS Tumor-infiltrating immune cells are extensively involved in the pathogenesis and development of the gastric cancer. We discovered Tfh and activated CD4+ memory T cells were associated with poorer overall survival and Progression-free survival (PFS), but that naïve B cells were opposite for PFS. Unsupervised clustering analysis revealed there existed three tumor-infiltrating immune cells subgroups with distinct survival patterns. Specially, cluster 1 showed significantly better clinical outcome than other two clusters. CONCLUSIONS Collectively, our data explored the differences of tumor-infiltrating immune cells in gastric cancer, and these variations were likely to be important clues for prognosis and management of its future clinical implementation.
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Affiliation(s)
- Yin Jin
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Liping Tao
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Shuqing Jin
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Weiyang Cai
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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28
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Cheng Z, Liu G, Huang C, Zhao X. Upregulation of circRNA_100395 sponges miR-142-3p to inhibit gastric cancer progression by targeting the PI3K/AKT axis. Oncol Lett 2021; 21:419. [PMID: 33841580 PMCID: PMC8020390 DOI: 10.3892/ol.2021.12680] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 01/20/2021] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer (GC) has a high morbidity and mortality, hence it is very important to elucidate the molecular pathogenesis mechanism of GC progression in order to find new treatment strategies. The present study aimed to explore the biological function of circular RNA_100395 (circRNA_100395) in GC. The expression level of circRNA_100395 in GC tissues, as well as normal epithelial cells and various gastric cancer cell lines, was detected using reverse transcription-quantitative PCR. Cell Counting Kit-8, EdU assay, flow cytometry and Transwell assays were performed to investigate cell proliferation, apoptosis, migration and invasion, respectively. A dual-luciferase reporter assay was performed to detect the correlation between circRNA_100395 and micro (mi)RNA-142-3p. Western blotting was performed to elucidate the potential regulatory mechanism. circRNA_100395 expression was found to be increased in GC tissues and cell lines. However, miR-142-3p expression was significantly reduced. Besides, low expression levels of circRNA_100395 were associated with poor tumor differentiation, advanced Tumor-Node-Metastasis stage, lymph node metastasis and shorter overall survival time. Moreover, overexpression of circRNA_100395 suppressed cell proliferation, increased the apoptosis rate and suppressed cell invasion and migration by inhibiting the PI3K/AKT signaling pathway. These findings also showed that miRNA-142-3p rescued the antitumor effects induced by circRNA_100395-overexpression. cirRNA_100395-overexpression had antitumor effects via regulating the miR-142-3p signaling pathway, which might be a promising treatment target for GC.
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Affiliation(s)
- Zhiyi Cheng
- Department of Gastrointestinal Surgery, Hospital Affiliated 5 to Nantong University, Taizhou People's Hospital, Taizhou, Jiangsu 225300, P.R. China
| | - Guiyuan Liu
- Department of Gastrointestinal Surgery, Hospital Affiliated 5 to Nantong University, Taizhou People's Hospital, Taizhou, Jiangsu 225300, P.R. China
| | - Chuanjiang Huang
- Department of Gastrointestinal Surgery, Hospital Affiliated 5 to Nantong University, Taizhou People's Hospital, Taizhou, Jiangsu 225300, P.R. China
| | - Xiaojun Zhao
- Department of Gastrointestinal Surgery, Hospital Affiliated 5 to Nantong University, Taizhou People's Hospital, Taizhou, Jiangsu 225300, P.R. China
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Serum CD4 Is Associated with the Infiltration of CD4 +T Cells in the Tumor Microenvironment of Gastric Cancer. J Immunol Res 2021; 2021:6539702. [PMID: 34258299 PMCID: PMC8246328 DOI: 10.1155/2021/6539702] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 02/16/2021] [Indexed: 12/14/2022] Open
Abstract
Serum CD4, CD8, and CD19 are markers of systemic inflammation. However, there is little evidence on the influence of inflammation on the tumor microenvironment and the prognostic indicators of gastric cancer (GC). In this study, two hundred and eight patients who underwent radical gastrectomy for GC were included. Preoperative peripheral blood samples were used to analyze Serum CD4, CD8, and CD19. The optimal cutoff levels for CD4, CD8, and CD19 were defined by receiver operating characteristic curve analysis (CD4 = 38.85%, CD8 = 14.35%, and CD19 = 7.40%). The areas with specific CD4+T cells, CD8+T cells, and CD19+B cells within the tumor microenvironment were measured in paraffin sections by immunohistochemistry and analyzed by Image-Pro Plus. 94 patients had low CD4, and 124 patients had high CD4 levels. 31 patients had low CD8, and 187 patients had high CD8 levels. 64 patients had low CD19, and 154 patients had high CD19 levels. Infiltration of CD4+T cells was associated with serum CD4 (P < 0.001). Serum CD4 and CD19 and the infiltration of CD4+T cells, CD8+T cells, and CD19+B cells were significant in predicting the prognosis of GC. Low CD4 level, infiltration of CD8+T cells, and high infiltration of CD4+T cells and CD19+B cells were correlated with worse overall survival in multivariate analysis. Collectively, our results provide evidence that serum CD4 is associated with the infiltration of CD4+T cells in the tumor microenvironment, which indicates the prognostic value of systemic inflammation in GC.
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30
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Yan T, Wang X, Wei G, Li H, Hao L, Liu Y, Yu X, Zhu W, Liu P, Zhu Y, Zhou X. Exosomal miR-10b-5p mediates cell communication of gastric cancer cells and fibroblasts and facilitates cell proliferation. J Cancer 2021; 12:2140-2150. [PMID: 33754012 PMCID: PMC7974515 DOI: 10.7150/jca.47817] [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] [Received: 05/05/2020] [Accepted: 01/07/2021] [Indexed: 02/06/2023] Open
Abstract
Tumor microenvironment interacts with gastric cancer (GC) cells and affects tumor development. The communication between GC cells and fibroblasts has not been clearly studied and understood. MiR-10b-5p was found highly expressed in tissue and serum samples of patients with advanced stages (stage III+IV) than that in early stage patients (stage I+II). The expression determination of serum exosomal microRNA was also shown with high expression of miR-10b-5p in GC patients with advanced stages. Dual-luciferase activity assays indicated that miR-10b-5p targeted PTEN in GC cells and KLF11 in fibroblasts. The silence of miR-10b-5p up-regulated the expression of PTEN and repressed PI3K/Akt/mTORC1 signaling in GC cells. Clonogenic assay and MTT assay demonstrated that miR-10b-5p inhibitor could significantly reduce the colony formation and cell viability of GC cells. And the incubation of exosomal miR-10b-5p could increase the proliferation of GC cells. Immunohistochemistry staining revealed that high expression of α-SMA was detected in GC tissues with advanced stages. The overexpression of miR-10b-5p down-regulated KLF11 expression and elevated TGFβR1 expression in fibroblasts. In addition, miR-10b-5p inhibitor blocked the secretion of TGFβ1 in GC cells and the directional migration of fibroblasts. Therefore, up-regulated exosomal miR-10b-5p is involved in the interaction of GC cells and fibroblasts in tumor microenvironment via participating in the regulation of TGFβ signaling pathway.
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Affiliation(s)
- Ting Yan
- Safety Assessment and Research Center for Drug, Pesticide and Veterinary Drug of Jiangsu Province, Nanjing Medical University, Nanjing 211166, China
| | - Xiaping Wang
- Department of Pathology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210000, China
| | - Guohua Wei
- Department of Anesthesiology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Hai Li
- Department of Pathology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Leiyu Hao
- Department of Physiology, Nanjing Medical University, Nanjing 211166, China
| | - Yan Liu
- Department of Physiology, Nanjing Medical University, Nanjing 211166, China
| | - Xinqian Yu
- Department of Physiology, Nanjing Medical University, Nanjing 211166, China
| | - Wei Zhu
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Ping Liu
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Yichao Zhu
- Department of Physiology, Nanjing Medical University, Nanjing 211166, China.,State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China
| | - Xin Zhou
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
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31
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Tian C, Jing H, Wang C, Wang W, Cui Y, Chen J, Sha D. Prognostic role of tumour-infiltrating lymphocytes assessed by H&E-stained section in gastric cancer: a systematic review and meta-analysis. BMJ Open 2021; 11:e044163. [PMID: 33518526 PMCID: PMC7853025 DOI: 10.1136/bmjopen-2020-044163] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVES Some studies have identified tumour-infiltrating lymphocytes (TILs) in H&E-stained sections of gastric cancer, but the prognostic and clinicopathological significance of this remains unclear. The objective of this study is to evaluate the associations between H&E-based TIL density and prognosis and clinicopathological characteristics of patients with gastric cancer. DESIGN Systematic review and meta-analysis. DATA SOURCES Cochrane Library, PubMed and Embase databases were searched through 25 February 2020. ELIGIBILITY CRITERIA Studies evaluating the correlations between TILs assessed by H&E-stained sections and prognosis and clinicopathological characteristics of gastric cancer were included. DATA EXTRACTION AND SYNTHESIS Relevant data were extracted and risks of bias were assessed independently by two reviewers. HR and relative risk (RR) with 95% CI were pooled by random-effect models to estimate the associations between TIL density and overall survival (OS) and clinicopathological characteristics, respectively. RESULTS We enrolled nine studies including 2835 cases for the present meta-analysis. High TILs were associated with superior OS (HR=0.68, 95% CI 0.52 to 0.87, p=0.003) compared with low TILs. High TILs were significantly associated with lower depth of invasion (T3-T4 vs T1-T2) (RR=0.58, 95% CI 0.50 to 0.66, p<0.001), less lymph node involvement (presence vs absence) (RR=0.68, 95% CI 0.56 to 0.81, p<0.001) and earlier TNM (tumour, node, metastasis) stage (III-IV vs I-II) (RR=0.68, 95% CI 0.55 to 0.83, p<0.001). TIL density was not associated with age, gender, Lauren classification or histological grade. The methodology for evaluating TIL and its cut-off value varied across different studies, which might affect the results of our meta-analysis. CONCLUSIONS Our meta-analysis suggests that H&E-based TIL density is a reliable biomarker to predict the clinical outcomes of patients with gastric cancer. Multicentre, prospective studies are needed to further confirm our findings. PROSPERO REGISTRATION NUMBER CRD42020169877.
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Affiliation(s)
- Chunfang Tian
- Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Haiyan Jing
- Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Caixia Wang
- Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Weibo Wang
- Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Yangang Cui
- Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Jianpeng Chen
- Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Dan Sha
- Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
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32
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Zhao DY, Sun XZ, Yao SK. Mining The Cancer Genome Atlas database for tumor mutation burden and its clinical implications in gastric cancer. World J Gastrointest Oncol 2021; 13:37-57. [PMID: 33510848 PMCID: PMC7805270 DOI: 10.4251/wjgo.v13.i1.37] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 11/08/2020] [Accepted: 11/28/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Tumor mutational burden (TMB) is an important independent biomarker for the response to immunotherapy in multiple cancers. However, the clinical implications of TMB in gastric cancer (GC) have not been fully elucidated. AIM To explore the landscape of mutation profiles and determine the correlation between TMB and microRNA (miRNA) expression in GC. METHODS Genomic, transcriptomic, and clinical data from The Cancer Genome Atlas were used to obtain mutational profiles and investigate the statistical correlation between mutational burden and the overall survival of GC patients. The difference in immune infiltration between high- and low-TMB subgroups was evaluated by Wilcoxon rank-sum test. Furthermore, miRNAs differentially expressed between the high- and low-TMB subgroups were identified and the least absolute shrinkage and selection operator method was employed to construct a miRNA-based signature for TMB prediction. The biological functions of the predictive miRNAs were identified with DIANA-miRPath v3.0. RESULTS C>T single nucleotide mutations exhibited the highest mutation incidence, and the top three mutated genes were TTN, TP53, and MUC16 in GC. High TMB values (top 20%) were markedly correlated with better survival outcome, and multivariable regression analysis indicated that TMB remained prognostic independent of TNM stage, histological grade, age, and gender. Different TMB levels exhibited different immune infiltration patterns. Significant differences between the high- and low-TMB subgroups were observed in the infiltration of CD8+ T cells, M1 macrophages, regulatory T cells, and CD4+ T cells. In addition, we developed a miRNA-based signature using 23 differentially expressed miRNAs to predict TMB values of GC patients. The predictive performance of the signature was confirmed in the testing and the whole set. Receiver operating characteristic curve analysis demonstrated the optimal performance of the signature. Finally, enrichment analysis demonstrated that the set of miRNAs was significantly enriched in many key cancer and immune-related pathways.
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Affiliation(s)
- Dong-Yan Zhao
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
- Graduate school, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Xi-Zhen Sun
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
- Graduate school, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Shu-Kun Yao
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
- Graduate school, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
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Association between Inflammation and Function of Cell Adhesion Molecules Influence on Gastrointestinal Cancer Development. Cells 2021; 10:cells10010067. [PMID: 33406733 PMCID: PMC7824562 DOI: 10.3390/cells10010067] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 12/09/2020] [Accepted: 12/29/2020] [Indexed: 12/16/2022] Open
Abstract
Gastrointestinal cancer is highly associated with inflammatory processes inducing the release of cytokines from cancer or immune cells, including interferons, interleukins, chemokines, colony-stimulating factors, and growth factors, which promote or suppress tumor progression. Inflammatory cytokines within the tumor microenvironment promote immune cell infiltration. Infiltrating immune, and tumor-surrounding stromal cells support tumor growth, angiogenesis, metastasis, and immunosuppression through communication with inflammatory cytokines and cell adhesion molecules. Notably, infiltrating immune and tumor cells present immunosuppressive molecules, such as programmed death-ligand 1 (PD-L1) and CD80/CD86. Suppression of cytotoxic T cells promotes tumor avoidance of immune surveillance and greater malignancy. Moreover, glycosylation and sialylation of proteins hyperexpressed on the cancer cell surface have been shown to enhance immune escape and metastasis. Cytokine treatments and immune checkpoint inhibitors are widely used in clinical practice. However, the tumor microenvironment is a rapidly changing milieu involving several factors. In this review, we have provided a summary of the interactions of inflammation and cell adhesion molecules between cancer and other cell types, to improve understanding of the tumor microenvironment.
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34
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Xie J, Fu L, Jin L. Immunotherapy of gastric cancer: Past, future perspective and challenges. Pathol Res Pract 2020; 218:153322. [PMID: 33422778 DOI: 10.1016/j.prp.2020.153322] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 12/08/2020] [Accepted: 12/13/2020] [Indexed: 12/12/2022]
Abstract
Gastric cancer is considered as the third leading cause of deaths and the fifth most common cancers worldwide. Common treatment approaches include chemotherapy, radiation, gastric resection and targeted therapies. The emergence of gastric cancer immunotherapy has already shown some promising results and have altered the therapeutic procedures. Now, different combination therapies as well as novel immunotherapies targeting new molecules have been proposed. Despite ongoing investigations on the therapeutic options and significant advancements in this regard, the disease is poorly prognosed. In fact, limited therapeutic options and delayed diagnosis lead to the progression, dissemination and metastasis of the disease. Current immunotherapies are mostly based on cytotoxic immunocytes, monoclonal antibodies and gene transferred vaccines. The use of Immune checkpoint inhibitors (ICIs) have grown rapidly. In this review, we aimed to explore perspective and progression of different approaches of immunotherapy in the treatment of GC and the clinical outcomes reported so far. We also summarized the tumor immunosurveillance and tumor immunoescape.
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Affiliation(s)
- Jun Xie
- Department of Gastroenterology Surgery, Affiliated Hospital of Shaoxing University, Shaoxing 312000, Zhejiang Province, China
| | - Liping Fu
- Department of Nuclear Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
| | - Li Jin
- Department of Pathology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China.
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Wang B, Zhang Y. An immune-relevant signature of nine genes as a prognostic biomarker in patients with gastric carcinoma. Open Med (Wars) 2020; 15:850-859. [PMID: 33336043 PMCID: PMC7718618 DOI: 10.1515/med-2020-0142] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 06/19/2020] [Accepted: 07/08/2020] [Indexed: 12/26/2022] Open
Abstract
Background As one of the most common malignant tumors worldwide, the morbidity and mortality of gastric carcinoma (GC) are gradually increasing. The aim of this study was to construct a signature according to immune-relevant genes to predict the survival outcome of GC patients using The Cancer Genome Altas (TCGA). Methods Univariate Cox regression analysis was used to assess the relationship between immune-relevant genes regarding the prognosis of patients with GC. The least absolute shrinkage and selection operator (LASSO) Cox regression model was used to select prognostic immune-relevant genes and to establish the signature for the prognostic evaluation of patients with GC. Multivariate Cox regression analysis and Kaplan–Meier survival analysis were used to assess the independent prognostic ability of the immune-relevant gene signature. Results A total of 113 prognostic immune-relevant genes were identified using univariate Cox proportional hazards regression analysis. A signature of nine immune-relevant genes was constructed using the LASSO Cox regression. The GC samples were assigned to two groups (low- and high risk) according to the optimal cutoff value of the signature score. Compared with the patients in the high-risk group, patients in the low-risk group had a significantly better prognosis in the TCGA and GSE84437 cohorts (log-rank test P < 0.001). Multivariate Cox regression analysis demonstrated that the signature of nine immune-relevant genes might serve as an independent predictor of GC. Conclusions Our results showed that the signature of nine immune-relevant genes may potentially serve as a prognostic prediction for patients with GC, which may contribute to the decision-making of personalized treatment for the patients.
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Affiliation(s)
- Bing Wang
- Department of Oncology, The Second Hospital of Dalian Medical University, No.467 Zhongshan Road, Shahekou District, Dalian, Liaoning, China
| | - Yang Zhang
- Department of Oncology, The Second Hospital of Dalian Medical University, No.467 Zhongshan Road, Shahekou District, Dalian, Liaoning, China
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Zhang C, Chen Z, Chong X, Chen Y, Wang Z, Yu R, Sun T, Chen X, Shao Y, Zhang X, Gao J, Shen L. Clinical implications of plasma ctDNA features and dynamics in gastric cancer treated with HER2-targeted therapies. Clin Transl Med 2020; 10:e254. [PMID: 33377634 PMCID: PMC7737756 DOI: 10.1002/ctm2.254] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 11/25/2020] [Accepted: 11/29/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is confronted with limited options for precision medicine. Human epidermal growth factor receptor 2 (HER2) is the principal druggable target of GC, yet proper biomarkers for response/resistance prediction remain unveiled. METHODS From 40 GC patients received HER2-targeted therapy, a total of 327 peripheral blood plasma specimens was collected including baseline and treatment time points. Circulating tumor DNA (ctDNA) was extracted and sequenced with a target panel of 425 genes. Experimental validation of resistant mutations was carried out in NIH-3T3 cell line. RESULTS Genomic features, including ERBB2 copy number variation (CNV), total copy number load, and tumor mutation burdens (TMBs), dynamically changed along with the treatment process and correlated with disease progression. Plasma ctDNA-based diagnosis was more sensitive than conventional computed tomography scanning in 40% of investigated patients, gaining additional time for clinical management. Compared to baseline, new gene alterations were emerged in 12 patients who developed drug resistance during treatment. ERBB2 mutations potentially related to Pyrotinib resistance were identified in plasma ctDNA of one patient and functional analysis of their downstream signaling pathways was carried out in NIH-3T3 cell line. TMB exhibited more power than ERBB2 CNV in predicting treatment responses and prognosis for HER2-targeted therapy in GC patients. Interestingly, survival analysis indicated that patients harboring both HER2 (ERBB2) positivity and high TMB might gain more therapeutic benefits from immune checkpoint inhibitors instead of HER2-targeted regimens that required further studies and validations CONCLUSIONS: Our work showed that the dynamic surveillance of plasma ctDNA genomic features provided instructive information for the precision medication of GC patients.
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Affiliation(s)
- Cheng Zhang
- Department of Gastrointestinal OncologyKey laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing)Peking University Cancer Hospital & InstituteBeijingChina
| | - Zuhua Chen
- Department of OncologyTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Xiaoyi Chong
- Department of Gastrointestinal OncologyKey laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing)Peking University Cancer Hospital & InstituteBeijingChina
| | - Yang Chen
- Department of Gastrointestinal OncologyKey laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing)Peking University Cancer Hospital & InstituteBeijingChina
| | - Zhenghang Wang
- Department of Gastrointestinal OncologyKey laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing)Peking University Cancer Hospital & InstituteBeijingChina
| | - Ruoying Yu
- Translational Medicine Research InstituteGeneseeq Technology IncTorontoOntarioCanada
| | | | - Xiaoxi Chen
- Translational Medicine Research InstituteGeneseeq Technology IncTorontoOntarioCanada
| | - Yang Shao
- Nanjing Geneseeq Technology IncNanjingChina
| | - Xiaotian Zhang
- Department of Gastrointestinal OncologyKey laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing)Peking University Cancer Hospital & InstituteBeijingChina
| | - Jing Gao
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeShenzhenChina
| | - Lin Shen
- Department of Gastrointestinal OncologyKey laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing)Peking University Cancer Hospital & InstituteBeijingChina
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El Gharib K, Kourie HR. Is ramucirumab still the only second-line treatment in metastatic gastric cancer? Pharmacogenomics 2020; 21:1203-1206. [PMID: 33030093 DOI: 10.2217/pgs-2020-0118] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Affiliation(s)
- Khalil El Gharib
- Department of Hematology & Oncology, Faculty of Medicine, Saint Joseph University, Beirut, Lebanon
| | - Hampig Raphael Kourie
- Department of Hematology & Oncology, Faculty of Medicine, Saint Joseph University, Beirut, Lebanon
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Jin K, Ren C, Liu Y, Lan H, Wang Z. An update on colorectal cancer microenvironment, epigenetic and immunotherapy. Int Immunopharmacol 2020; 89:107041. [PMID: 33045561 DOI: 10.1016/j.intimp.2020.107041] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 09/13/2020] [Accepted: 09/21/2020] [Indexed: 12/27/2022]
Abstract
Colorectal cancer (CRC) is considered as the second most common cancer worldwide. For the past few years, the role of immunotherapy has been extensively studied and it has been demonstrated that its related approaches, such as programmed death-1 (PD-1) inhibitors, are promising. In addition to identifying molecular characteristics of tumor cells, recent studies are mainly focused on the profiling of tumor microenvironment. Dissecting immune status of a tumor is interesting, since development of a tumor is associated with deficiencies relate to immune defense, immune surveillance and immune hemostasis. In this review, we discuss main obstacles of immunotherapy including immunosuppressive niche and low immunogenicity of CRC as well as reviewing current achievements in immunotherapy.
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Affiliation(s)
- Ketao Jin
- Department of Colorectal Surgery, Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang 321000, China
| | - Chengcheng Ren
- Rehabilitation & Sports Medicine Research Institute of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, China
| | - Yuyao Liu
- Department of Colorectal Surgery, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing 312000, Zhejiang Province, PR China
| | - Huanrong Lan
- Department of Breast and Thyroid Surgery, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing 312000, Zhejiang Province, PR China
| | - Zhen Wang
- Rehabilitation & Sports Medicine Research Institute of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, China.
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Immunophenotype based on inflammatory cells, PD-1/PD-L1 signalling pathway and M2 macrophages predicts survival in gastric cancer. Br J Cancer 2020; 123:1625-1632. [PMID: 32943749 PMCID: PMC7687887 DOI: 10.1038/s41416-020-01053-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 08/14/2020] [Accepted: 08/26/2020] [Indexed: 12/13/2022] Open
Abstract
Background Immune response against cancer has prognostic impact but its role in gastric cancer is poorly known. The aim of the study was to assess the prognostic significance of immune cell score (CD3+, CD8+), tumour immune escape (PD-L1, PD-1) and immune tolerance (Clever-1). Methods After exclusion of Epstein-Barr virus positive (n = 4) and microsatellite instable (n = 6) tumours, the study included 122 patients with GC undergoing D2 gastrectomy. CD3+ and CD8+ based ICS, PD-L1, PD-1 and Clever-1 expressions were evaluated. Differences in survival were examined using Cox regression adjusted for confounders. The primary outcome was 5-year survival. Results The 5-year overall survival rate was 43.4%. High ICS was associated with improved overall survival (adjusted HR 0.48 (95% CI 0.26–0.87)) compared to low ICS. In the high ICS group, patients with PD-L1 expression (5-year survival 69.2 vs. 53.1%, p = 0.317), high PD-1 (5-year survival 70.6 vs. 55.3% p = 0.312) and high Clever-1 (5-year survival 72.0% vs. 45.5% (p = 0.070) had poor prognosis. Conclusions High ICS was associated with improved survival. In the high ICS group, patients with high PD-L1, PD-1 and Clever-1 had poor prognosis highlighting the importance of immune escape and immune tolerance in GC.
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Abstract
PURPOSE OF REVIEW Immunotherapy and tumor microenvironment have been at the forefront of cancer research over the past several decades. Here, we will review the role of immunotherapy in advanced gastroesophageal cancers including targeted antibodies, immunomodulating agents, vaccines, oncolytic virus therapy, and adoptive immunotherapy, and discuss the future direction for immunotherapy in this population. RECENT FINDINGS Targeted antibodies are already standard-of-care. An anti-PD-1 monoclonal antibody is currently FDA approved for second-line treatment of locally advanced or metastatic ESCC, as well as beyond second-line treatment of advanced G/GEJ cancers, and recent data suggests it may be considered in first-line treatment of advanced G/GEJ cancers. Combination therapies such as immunotherapy plus chemotherapy and/or radiotherapy, vaccines, oncolytic viral therapy, and adoptive immunotherapy in varying combinations are currently under active investigation. Several trials are ongoing and are hoped to reach more efficacious and individualized treatment options in advanced gastroesophageal cancer, where novel treatment options are desperately needed.
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CAR-T Cell Therapy-An Overview of Targets in Gastric Cancer. J Clin Med 2020; 9:jcm9061894. [PMID: 32560392 PMCID: PMC7355670 DOI: 10.3390/jcm9061894] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 06/14/2020] [Accepted: 06/15/2020] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is one of the most commonly diagnosed malignancies and, unfortunately, still has a high mortality rate. Recent research points to CAR-T immunotherapy as a promising treatment for this disease. Using genetically engineered T cells designed to target a previously selected antigen, researchers are able to harness the natural anti-tumor activity of T cells. For therapy to be successful, however, it is essential to choose antigens that are present on tumor cells but not on healthy cells. In this review, we present an overview of the most important targets for CAR-T therapy in the context of GC, including their biologic function and therapeutic application. A number of clinical studies point to the following as important markers in GC: human epidermal growth factor receptor 2, carcinoembryonic antigen, mucin 1, epithelial cell adhesion molecule, claudin 18.2, mesothelin, natural-killer receptor group 2 member D, and folate receptor 1. Although these markers have been met with some success, the search for new and improved targets continues. Key among these novel biomarkers are the B7H6 ligand, actin-related protein 2/3 (ARP 2/3), neuropilin-1 (NRP-1), desmocollin 2 (DSC2), anion exchanger 1 (AF1), and cancer-related antigens CA-72-4 and CA-19-9.
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Immunotherapy in gastrointestinal cancer: The current scenario and future perspectives. Cancer Treat Rev 2020; 88:102030. [PMID: 32505807 DOI: 10.1016/j.ctrv.2020.102030] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 05/07/2020] [Accepted: 05/09/2020] [Indexed: 02/06/2023]
Abstract
Gastrointestinal cancers include colorectal, gastric, oesophageal, pancreatic and liver cancers. They continue to be a significant cause of mortality and morbidity worldwide. Current treatment strategies include chemotherapy, surgery, radiotherapy and targeted therapies. Immunotherapy has recently been incorporated in treatment regimens for some gastrointestinal malignancies and research into different immune modifying treatments is being carried out in this context. Approaches to immune modulation such as vaccination, adoptive cell therapy and checkpoint inhibition have shown varying clinical benefit, with most of the benefit seen in checkpoint inhibition. This review summarises recent advances and future direction of immunotherapy in patients with gastrointestinal malignancies.
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Harvey JB, Phan LH, Villarreal OE, Bowser JL. CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers. Front Immunol 2020; 11:508. [PMID: 32351498 PMCID: PMC7174602 DOI: 10.3389/fimmu.2020.00508] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Accepted: 03/05/2020] [Indexed: 02/06/2023] Open
Abstract
CD73, a cell surface 5'nucleotidase that generates adenosine, has emerged as an attractive therapeutic target for reprogramming cancer cells and the tumor microenvironment to dampen antitumor immune cell evasion. Decades of studies have paved the way for these findings, starting with the discovery of adenosine signaling, particularly adenosine A2A receptor (A2AR) signaling, as a potent suppressor of tissue-devastating immune cell responses, and evolving with studies focusing on CD73 in breast cancer, melanoma, and non-small cell lung cancer. Gastrointestinal (GI) cancers are a major cause of cancer-related deaths. Evidence is mounting that shows promise for improving patient outcomes through incorporation of immunomodulatory strategies as single agents or in combination with current treatment options. Recently, several immune checkpoint inhibitors received FDA approval for use in GI cancers; however, clinical benefit is limited. Investigating molecular mechanisms promoting immunosuppression, such as CD73, in GI cancers can aid in current efforts to extend the efficacy of immunotherapy to more patients. In this review, we discuss current clinical and basic research studies on CD73 in GI cancers, including gastric, liver, pancreatic, and colorectal cancer, with special focus on the potential of CD73 as an immunotherapy target in these cancers. We also present a summary of current clinical studies targeting CD73 and/or A2AR and combination of these therapies with immune checkpoint inhibitors.
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Affiliation(s)
- Jerry B. Harvey
- Department of Anesthesiology, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Luan H. Phan
- Department of Anesthesiology, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Oscar E. Villarreal
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Jessica L. Bowser
- Department of Anesthesiology, The University of Texas Health Science Center at Houston, Houston, TX, United States
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Baj J, Brzozowska K, Forma A, Maani A, Sitarz E, Portincasa P. Immunological Aspects of the Tumor Microenvironment and Epithelial-Mesenchymal Transition in Gastric Carcinogenesis. Int J Mol Sci 2020; 21:2544. [PMID: 32268527 PMCID: PMC7177728 DOI: 10.3390/ijms21072544] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 03/30/2020] [Accepted: 04/02/2020] [Indexed: 12/11/2022] Open
Abstract
Infection with Helicobacter pylori, a Gram-negative, microaerophilic pathogen often results in gastric cancer in a subset of affected individuals. This explains why H. pylori is the only bacterium classified as a class I carcinogen by the World Health Organization. Several studies have pinpointed mechanisms by which H. pylori alters signaling pathways in the host cell to cause diseases. In this article, the authors have reviewed 234 studies conducted over a span of 18 years (2002-2020). The studies investigated the various mechanisms associated with gastric cancer induction. For the past 1.5 years, researchers have discovered new mechanisms contributing to gastric cancer linked to H. pylori etiology. Alongside alteration of the host signaling pathways using oncogenic CagA pathways, H. pylori induce DNA damage in the host and alter the methylation of DNA as a means of perturbing downstream signaling. Also, with H. pylori, several pathways in the host cell are activated, resulting in epithelial-to-mesenchymal transition (EMT), together with the induction of cell proliferation and survival. Studies have shown that H. pylori enhances gastric carcinogenesis via a multifactorial approach. What is intriguing is that most of the targeted mechanisms and pathways appear common with various forms of cancer.
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Affiliation(s)
- Jacek Baj
- Chair and Department of Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (A.F.); (A.M.)
| | - Karolina Brzozowska
- Chair and Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Alicja Forma
- Chair and Department of Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (A.F.); (A.M.)
| | - Amr Maani
- Chair and Department of Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (A.F.); (A.M.)
| | - Elżbieta Sitarz
- Chair and 1st Department of Psychiatry, Psychotherapy and Early Intervention, Medical University of Lublin, Gluska Street 1, 20-439 Lublin, Poland;
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, 70124 Bari, Italy;
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Thanh Huong P, Gurshaney S, Thanh Binh N, Gia Pham A, Hoang Nguyen H, Thanh Nguyen X, Pham-The H, Tran PT, Truong Vu K, Xuan Duong N, Pelucchi C, La Vecchia C, Boffetta P, Nguyen HD, Luu HN. Emerging Role of Circulating Tumor Cells in Gastric Cancer. Cancers (Basel) 2020; 12:E695. [PMID: 32183503 PMCID: PMC7140068 DOI: 10.3390/cancers12030695] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Revised: 03/11/2020] [Accepted: 03/13/2020] [Indexed: 02/07/2023] Open
Abstract
With over 1 million incidence cases and more than 780,000 deaths in 2018, gastric cancer (GC) was ranked as the 5th most common cancer and the 3rd leading cause of cancer deaths worldwide. Though several biomarkers, including carcinoembryonic antigen (CEA), cancer antigen 19-9 (CA19-9), and cancer antigen 72-4 (CA72-4), have been identified, their diagnostic accuracies were modest. Circulating tumor cells (CTCs), cells derived from tumors and present in body fluids, have recently emerged as promising biomarkers, diagnostically and prognostically, of cancers, including GC. In this review, we present the landscape of CTCs from migration, to the presence in circulation, biologic properties, and morphologic heterogeneities. We evaluated clinical implications of CTCs in GC patients, including diagnosis, prognosis, and therapeutic management, as well as their application in immunotherapy. On the one hand, major challenges in using CTCs in GC were analyzed, from the differences of cut-off values of CTC positivity, to techniques used for sampling, storage conditions, and CTC molecular markers, as well as the unavailability of relevant enrichment and detection techniques. On the other hand, we discussed future perspectives of using CTCs in GC management and research, including the use of circulating tumor microembolies; of CTC checkpoint blockade in immunotherapy; and of organoid models. Despite the fact that there are remaining challenges in techniques, CTCs have potential as novel biomarkers and/or a non-invasive method for diagnostics, prognostics, and treatment monitoring of GC, particularly in the era of precision medicine.
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Affiliation(s)
- Phung Thanh Huong
- Department of Biochemistry, Hanoi University of Pharmacy, Hanoi 10000, Vietnam;
| | - Sanjeev Gurshaney
- Cancer Division, Burnett School of Biomedical Science, College of Medicine, University of Central Florida, Orlando, FL 32827, USA;
| | - Nguyen Thanh Binh
- Department of Pharmaceutical Management and Economics, Hanoi University of Pharmacy, Hanoi 10000, Vietnam;
| | - Anh Gia Pham
- Department of Surgical Oncology, Viet-Duc University Hospital, Hanoi 10000, Vietnam; (A.G.P.); (H.H.N.); (X.T.N.)
| | - Huy Hoang Nguyen
- Department of Surgical Oncology, Viet-Duc University Hospital, Hanoi 10000, Vietnam; (A.G.P.); (H.H.N.); (X.T.N.)
| | - Xuan Thanh Nguyen
- Department of Surgical Oncology, Viet-Duc University Hospital, Hanoi 10000, Vietnam; (A.G.P.); (H.H.N.); (X.T.N.)
| | - Hai Pham-The
- Department of Pharmaceutical Chemistry, Hanoi University of Pharmacy, Hanoi 10000, Vietnam; (H.P.-T.); (P.-T.T.)
| | - Phuong-Thao Tran
- Department of Pharmaceutical Chemistry, Hanoi University of Pharmacy, Hanoi 10000, Vietnam; (H.P.-T.); (P.-T.T.)
| | - Khanh Truong Vu
- Department of Gastroenterology, Bach Mai Hospital, Hanoi 10000, Vietnam;
| | | | - Claudio Pelucchi
- Department of Clinical, Sciences and Community Health, University of Milan, 20133 Milan, Italy; (C.P.); (C.L.V.)
| | - Carlo La Vecchia
- Department of Clinical, Sciences and Community Health, University of Milan, 20133 Milan, Italy; (C.P.); (C.L.V.)
| | - Paolo Boffetta
- Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, Division of Hematology and Medical Oncology, New York, NY 10029, USA;
| | - Hung D. Nguyen
- Cancer Division, Burnett School of Biomedical Science, College of Medicine, University of Central Florida, Orlando, FL 32827, USA;
| | - Hung N. Luu
- Department of Epidemiology, University of Pittsburg Graduate School of Public Health, Pittsburg, PA 15261, USA
- Division of Cancer Control and Population Sciences, UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA
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Refolo MG, Lotesoriere C, Messa C, Caruso MG, D'Alessandro R. Integrated immune gene expression signature and molecular classification in gastric cancer: New insights. J Leukoc Biol 2020; 108:633-646. [PMID: 32170872 DOI: 10.1002/jlb.4mr0120-221r] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 01/03/2020] [Accepted: 01/24/2020] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer (GC) is characterized by extreme heterogeneity due to histopathological differences, molecular characteristics, and immune gene expression signature. Until recently, several targeted therapies failed due to this complexity. The recent immunotherapy resulted in more effective and safe approaches in several malignancies. All tumors could be considered potentially immunogenic and the new knowledge regarding the interactions among tumor cells, immune cells, and tumor microenvironment (TME) allowed to reverse possible immune resistance. The immune response is a complex multisteps process that finely regulates the balance between the recognition of non-self and the prevention of autoimmunity. Cancer cells can use these pathways to suppress tumor immunity as a major mechanism of immune resistance. The recent molecular classifications of GCs by The Cancer Genome Atlas (TCGA) and by the Asian Cancer Research (ACRG) networks, together with the identification of multiple biomarkers, open new perspectives for stratification of patients who might benefit from a long-term immune checkpoint therapy. One of the major processes that contribute to an immunosuppressive microenvironment is represented by tumor angiogenesis. The cellular mechanisms inducing both angiogenesis and immunosuppressive responses are often reached by the same cell types and soluble factors, such as vascular endothelial growth factor A (VEGFA). Recent studies point out that combinatorial strategies should be adapted as useful therapeutic approach to reverse the immunosuppressive status of microenvironment occurring in a relevant percentage of gastric tumors.
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Affiliation(s)
- Maria Grazia Refolo
- Laboratory of Cellular and Molecular Biology, Department of Clinical Pathology, Castellana Grotte, Bari, Italy
| | - Claudio Lotesoriere
- Medical Oncology Unit, National Institute of Gastroenterology, "Saverio de Bellis" Research Hospital, Castellana Grotte, Bari, Italy
| | - Caterina Messa
- Laboratory of Cellular and Molecular Biology, Department of Clinical Pathology, Castellana Grotte, Bari, Italy
| | - Maria Gabriella Caruso
- Ambulatory of Clinical Nutrition, National Institute of Gastroenterology, "Saverio de Bellis" Research Hospital, Castellana Grotte, Bari, Italy
| | - Rosalba D'Alessandro
- Laboratory of Cellular and Molecular Biology, Department of Clinical Pathology, Castellana Grotte, Bari, Italy
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Abstract
Gastric cancer is an active topic of clinical and basic research due to high morbidity and mortality. To date, gastrectomy and chemotherapy are the only therapeutic options for gastric cancer patients, but drug resistance, either acquired or primary, is the main cause for treatment failure. Differences in development and response to cancer treatments have been observed among ethnically diverse GC patient populations. In spite of major incidence, GC Asian patients have a significantly better prognosis and response to treatments than Caucasian ones due to genetic discordances between the two populations. Gene therapy could be an alternative strategy to overcome such issues and especially CRISPR/Cas9 represents one of the most intriguing gene-editing system. Thus, in this review article, we want to provide an update on the currently used therapies for the treatment of advanced GC. Graphical abstract.
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Pernot S, Terme M, Radosevic-Robin N, Castan F, Badoual C, Marcheteau E, Penault-Llorca F, Bouche O, Bennouna J, Francois E, Ghiringhelli F, De La Fouchardiere C, Samalin E, Baptiste Bachet J, Borg C, Boige V, Voron T, Stanbury T, Tartour E, Gourgou S, Malka D, Taieb J. Infiltrating and peripheral immune cell analysis in advanced gastric cancer according to the Lauren classification and its prognostic significance. Gastric Cancer 2020; 23:73-81. [PMID: 31267360 DOI: 10.1007/s10120-019-00983-3] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 06/25/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND The correlation between immune cells and the Lauren classification subtypes and their prognostic impact in advanced gastric cancer (AGC) are unknown. METHODS Circulating natural killer (NK) cells, CD4+ and CD8+ T cells, regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) were quantified in peripheral blood mononuclear cells (PBMCs) from 67 patients with untreated AGC enrolled in the PRODIGE 17-ACCORD 20 trial. CD56+ cells (NK), CD8+, and FoxP3+ (Treg) tumor-infiltrating lymphocytes (TILs) were assessed in tumor samples. RESULTS Circulating NK and Treg proportions were significantly lower in patients with diffuse/mixed-type AGC (n = 27) than those with intestinal type (n = 40; median 6.3% vs 11.5%; p = 0.02 and median 3.3% vs 5.2%; p = 0.03, respectively). Proportions of circulating MDSC, CD4+ and CD8+ T cells were not associated with one pathological type. Among tumor-infiltrating cells, CD8+ T cells, but not NK or FoxP3+ cells, were significantly lower in diffuse/mixed-type AGC (median 21 vs 59 cells/field; p = 0.009). Patients with high circulating NK cell counts (> 17%) had a better overall survival than those with < 17% (HR 0.40; 95% CI [0.15-1.06]; p = 0.04). Patients with high CD8+ TIL counts (> 31 cells/field) had significantly longer overall survival (HR 0.44; 95% CI [0.21-0.92]; p = 0.02). The prognostic value of CD8+ TILs was maintained after adjustment for confounding factors, including the Lauren classification (HR = 0.42; 95% CI [0.18-0.96]; p = 0.039). CONCLUSION Diffuse/mixed-type AGC has lower rates of CD8+ TILs and circulating NK cells and Tregs than the intestinal type. This "cold tumor" phenotype may be associated with a worse outcome.
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Affiliation(s)
- Simon Pernot
- Université de Paris, PARCC, INSERM, 75015, Paris, France. .,Hôpital Européen Georges-Pompidou, APHP; Department of GI oncology, Université de Paris, Paris, France.
| | - Magali Terme
- Université de Paris, PARCC, INSERM, 75015, Paris, France
| | - Nina Radosevic-Robin
- Department of Biopathology, Centre Jean Perrin and University Clermont Auvergne/INSERM U1240, Clermont-Ferrand, France
| | - Florence Castan
- Biometrics Unit, Institut du Cancer Montpellier-Val d'Aurelle, Université de Montpellier, Montpellier, France
| | - Cécile Badoual
- Université de Paris, PARCC, INSERM, 75015, Paris, France.,Department of Pathology, Université de Paris, Sorbonne Paris Cité, Paris, France
| | | | - Fréderique Penault-Llorca
- Department of Biopathology, Centre Jean Perrin and University Clermont Auvergne/INSERM U1240, Clermont-Ferrand, France
| | | | - Jaafar Bennouna
- Institut de Cancérologie de l'Ouest-Site René Gauducheau, Saint Herblain, France
| | | | | | | | - Emmanuelle Samalin
- Institut du Cancer Montpellier-Val d'Aurelle, Université de Montpellier, Montpellier, France
| | | | | | - Valérie Boige
- Département de Médecine Oncologique, Gustave Roussy, Université Paris-Saclay, 94805, Villejuif, France
| | - Thibault Voron
- Université de Paris, PARCC, INSERM, 75015, Paris, France
| | | | - Eric Tartour
- Université de Paris, PARCC, INSERM, 75015, Paris, France
| | - Sophie Gourgou
- Biometrics Unit, Institut du Cancer Montpellier-Val d'Aurelle, Université de Montpellier, Montpellier, France
| | - David Malka
- Département de Médecine Oncologique, Gustave Roussy, Université Paris-Saclay, 94805, Villejuif, France
| | - Julien Taieb
- Université de Paris, PARCC, INSERM, 75015, Paris, France.,Hôpital Européen Georges-Pompidou, APHP; Department of GI oncology, Université de Paris, Paris, France
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Venkata Prasuja N. Immunotherapeutics of Gastrointestinal Malignancies. IMMUNOTHERAPY FOR GASTROINTESTINAL MALIGNANCIES 2020:51-60. [DOI: 10.1007/978-981-15-6487-1_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/06/2023]
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50
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Rizzo A, Mollica V, Ricci AD, Maggio I, Massucci M, Rojas Limpe FL, Fabio FD, Ardizzoni A. Third- and later-line treatment in advanced or metastatic gastric cancer: a systematic review and meta-analysis. Future Oncol 2019; 16:4409-4418. [PMID: 31793342 DOI: 10.2217/fon-2019-0429] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Aim: We performed a systematic review and meta-analysis to investigate the efficacy and safety of third-line (TLT) and salvage treatment (ST) in advanced or metastatic gastric cancer. Materials & methods: Eligible studies included randomized clinical trials assessing TLT and ST versus placebo or best supportive care. Outcomes of interest included: overall survival, objective response rate and disease control rate in TLT; progression-free survival in ST; grade 3-4 adverse events in ST. Results: The use of TLT and ST was superior to placebo or best supportive care in terms of prolonging overall survival and progression-free survival. Hematological toxicities were more frequent in ST. Conclusion: TLT and ST are considerable and tolerable treatment options for patients with advanced or metastatic gastric cancer. Given the substantial heterogeneities affecting the efficacy analyses, these results have to be interpreted cautiously.
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Affiliation(s)
- Alessandro Rizzo
- Division of Medical Oncology, S Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Veronica Mollica
- Division of Medical Oncology, S Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Angela Dalia Ricci
- Division of Medical Oncology, S Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Ilaria Maggio
- Division of Medical Oncology, S Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Maria Massucci
- Division of Medical Oncology, S Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | | | - Francesca Di Fabio
- Division of Medical Oncology, S Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Andrea Ardizzoni
- Division of Medical Oncology, S Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
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