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1
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Park G, Park SJ, Kim Y. Clinicopathological significance and prognostic values of claudin18.2 expression in solid tumors: a systematic review and meta-analysis. Front Oncol 2024; 14:1453906. [PMID: 39634269 PMCID: PMC11614718 DOI: 10.3389/fonc.2024.1453906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 11/05/2024] [Indexed: 12/07/2024] Open
Abstract
OBJECTIVE Claudin18.2 has been established as a putative therapeutic target in human solid malignancies. The aim of this study is to determine claudin18.2 expression as a clinicopathological and prognostic factor in human solid tumors through a systematic review and meta-analysis. Articles were systematically reviewed for studies that included the correlation between claudin18.2 expression and clinicopathological features and prognosis in solid tumors. Meta-analysis was conducted to estimate either odds ratio and 95% confidence intervals (CIs) of clinicopathological factors or hazard ratio and 95% CIs of survival outcomes for claudin18.2 expression in all available solid tumors. RESULTS 21 studies including 5,331 patients were identified. Overall proportion of claudin18.2 positivity was 29.7%. Analyses of clinicopathological features demonstrated that claudin18.2 positivity correlated with male predominance, lower T stage, more frequent MUC5AC positivity when all primary tumors included. In subgroup analysis, gastric cancer showed significant correlation between high claudin18.2 expression and frequent EBV infection, male predominance and lower T stage. In lung cancer, claudin18.2 expression was associated with favorable overall survival. However, analyses of survival outcomes in all solid tumors showed that claudin18.2 expression was not associated with overall survival and pooled disease-free survival, tumor-specific survival, progression-free survival and relapse-free survival. CONCLUSIONS Our study emphasizes evaluation of claudin18.2 expression as a potential prognostic factor in lung adenocarcinoma and further exploration in other solid tumors as well. SYSTEMATIC REVIEW REGISTRATION https://www.crd.york.ac.uk/prospero/, identifier CRD42023468651.
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Affiliation(s)
- Gyerim Park
- Department of Hospital Pathology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Se Jun Park
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Younghoon Kim
- Department of Hospital Pathology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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2
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Wu LW, Jang SJ, Shapiro C, Fazlollahi L, Wang TC, Ryeom SW, Moy RH. Diffuse Gastric Cancer: A Comprehensive Review of Molecular Features and Emerging Therapeutics. Target Oncol 2024; 19:845-865. [PMID: 39271577 PMCID: PMC11557641 DOI: 10.1007/s11523-024-01097-2] [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] [Accepted: 08/30/2024] [Indexed: 09/15/2024]
Abstract
Diffuse-type gastric cancer (DGC) accounts for approximately one-third of gastric cancer diagnoses but is a more clinically aggressive disease with peritoneal metastases and inferior survival compared with intestinal-type gastric cancer (IGC). The understanding of the pathogenesis of DGC has been relatively limited until recently. Multiomic studies, particularly by The Cancer Genome Atlas, have better characterized gastric adenocarcinoma into molecular subtypes. DGC has unique molecular features, including alterations in CDH1, RHOA, and CLDN18-ARHGAP26 fusions. Preclinical models of DGC characterized by these molecular alterations have generated insight into mechanisms of pathogenesis and signaling pathway abnormalities. The currently approved therapies for treatment of gastric cancer generally provide less clinical benefit in patients with DGC. Based on recent phase II/III clinical trials, there is excitement surrounding Claudin 18.2-based and FGFR2b-directed therapies, which capitalize on unique biomarkers that are enriched in the DGC populations. There are numerous therapies targeting Claudin 18.2 and FGFR2b in various stages of preclinical and clinical development. Additionally, there have been preclinical advancements in exploiting unique therapeutic vulnerabilities in several models of DGC through targeting of the focal adhesion kinase (FAK) and Hippo pathways. These preclinical and clinical advancements represent a promising future for the treatment of DGC.
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Affiliation(s)
- Lawrence W Wu
- Division of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, 161 Fort Washington Avenue, Room 956, New York, NY, 10032, USA
| | - Sung Joo Jang
- Division of Surgical Sciences, Department of Surgery, Columbia University Irving Medical Center, New York, NY, USA
| | - Cameron Shapiro
- Division of Surgical Sciences, Department of Surgery, Columbia University Irving Medical Center, New York, NY, USA
| | - Ladan Fazlollahi
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Timothy C Wang
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Sandra W Ryeom
- Division of Surgical Sciences, Department of Surgery, Columbia University Irving Medical Center, New York, NY, USA
| | - Ryan H Moy
- Division of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, 161 Fort Washington Avenue, Room 956, New York, NY, 10032, USA.
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3
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Shi D, Yang Z, Cai Y, Li H, Lin L, Wu D, Zhang S, Guo Q. Research advances in the molecular classification of gastric cancer. Cell Oncol (Dordr) 2024; 47:1523-1536. [PMID: 38717722 PMCID: PMC11466988 DOI: 10.1007/s13402-024-00951-9] [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] [Accepted: 04/13/2024] [Indexed: 06/27/2024] Open
Abstract
Gastric cancer (GC) is a malignant tumor with one of the lowest five-year survival rates. Traditional first-line treatment regimens, such as platinum drugs, have limited therapeutic efficacy in treating advanced GC and significant side effects, greatly reducing patient quality of life. In contrast, trastuzumab and other immune checkpoint inhibitors, such as nivolumab and pembrolizumab, have demonstrated consistent and reliable efficacy in treating GC. Here, we discuss the intrinsic characteristics of GC from a molecular perspective and provide a comprehensive review of classification and treatment advances in the disease. Finally, we suggest several strategies based on the intrinsic molecular characteristics of GC to aid in overcoming clinical challenges in the development of precision medicine and improve patient prognosis.
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Affiliation(s)
- Dike Shi
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Jiefang Road, Hangzhou, 310009, China
| | - Zihan Yang
- Department of Gastroenterology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Yanna Cai
- Department of Gastroenterology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Hongbo Li
- Department of Gastroenterology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Lele Lin
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Jiefang Road, Hangzhou, 310009, China
| | - Dan Wu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Jiefang Road, Hangzhou, 310009, China
| | - Shengyu Zhang
- Department of Gastroenterology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Qingqu Guo
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Jiefang Road, Hangzhou, 310009, China.
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4
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Wang Y, Wang H, Shi T, Song X, Zhang X, Zhang Y, Wang X, Che K, Luo Y, Yu L, Liu B, Wei J. Immunotherapies targeting the oncogenic fusion gene CLDN18-ARHGAP in gastric cancer. EMBO Mol Med 2024; 16:2170-2187. [PMID: 39164472 PMCID: PMC11393071 DOI: 10.1038/s44321-024-00120-3] [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: 08/28/2023] [Revised: 07/31/2024] [Accepted: 08/02/2024] [Indexed: 08/22/2024] Open
Abstract
The CLDN18-ARHGAP fusion gene is an oncogenic driver newly discovered in gastric cancer. It was detected in 9% (8/87) of gastric cancer patients in our center. An immunogenic peptide specifically targeting CLDN18-ARHGAP fusion gene was generated to induce neoantigen-reactive T cells, which was proved to have specific and robust anti-tumor capacity both in in vitro coculture models and in vivo xenograft gastric cancer models. Apart from the immunogenic potential, CLDN18-ARHGAP fusion gene was also found to contribute to immune suppression by inducing a regulatory T (Treg) cell-enriched microenvironment. Mechanistically, gastric cancer cells with CLDN18-ARHGAP fusion activate PI3K/AKT-mTOR-FAS signaling, which enhances free fatty acid production of gastric cancer cells to favor the survival of Treg cells. Furthermore, PI3K inhibition could effectively reverse Treg cells upregulation to enhance anti-tumor cytotoxicity of neoantigen-reactive T cells in vitro and reduce tumor growth in the xenograft gastric cancer model. Our study identified the CLDN18-ARHGAP fusion gene as a critical source of immunogenic neoepitopes, a key regulator of the tumor immune microenvironment, and immunotherapeutic applications specific to this oncogenic fusion.
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Affiliation(s)
- Yue Wang
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Hanbing Wang
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Tao Shi
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Xueru Song
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Xin Zhang
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Yue Zhang
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Xuan Wang
- Department of Oncology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China
| | - Keying Che
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Yuting Luo
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Lixia Yu
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Baorui Liu
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Jia Wei
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
- Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, China.
- Engineering Research Center of Protein and Peptide Medicine, Nanjing University, Nanjing, China.
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Zeng Y, Lockhart AC, Jin RU. The preclinical discovery and development of zolbetuximab for the treatment of gastric cancer. Expert Opin Drug Discov 2024; 19:873-886. [PMID: 38919123 PMCID: PMC11938084 DOI: 10.1080/17460441.2024.2370332] [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: 03/31/2024] [Revised: 06/04/2024] [Accepted: 06/17/2024] [Indexed: 06/27/2024]
Abstract
INTRODUCTION Gastric cancer remains a formidable challenge in oncology with high mortality rates and few advancements in treatment. Claudin-18.2 (CLDN18.2) is a tight junction protein primarily expressed in the stomach and is frequently overexpressed in certain subsets of gastric cancers. Targeting CLDN18.2 with monoclonal antibodies, such as zolbetuximab (IMAB362), has shown promising efficacy results in combination with chemotherapy. AREAS COVERED The molecular cell biology of CLDN18.2 is discussed along with studies demonstrating the utility of CLDN18.2 expression as a biomarker and therapeutic target. Important clinical studies are reviewed, including Phase III trials, SPOTLIGHT and GLOW, which demonstrate the efficacy of zolbetuximab in combination with chemotherapy in patients with CLDN18.2-positive advanced gastric cancer. EXPERT OPINION CLDN18.2 is involved in gastric differentiation through maintenance of epithelial barrier function and coordination of signaling pathways, and its expression in gastric cancers reflects a 'gastric differentiation' program. Targeting Claudin-18.2 represents the first gastric cancer specific 'targeted' treatment. Further studies are needed to determine its role within current gastric cancer treatment sequencing, including HER2-targeted therapies and immunotherapies. Management strategies will also be needed to better mitigate zolbetuximab-related treatment side effects, including gastrointestinal (GI) toxicities.
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Affiliation(s)
- Yongji Zeng
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, USA
| | - A. Craig Lockhart
- Division of Hematology/Oncology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Ramon U. Jin
- Section of Hematology/Oncology, Department of Medicine, Baylor College of Medicine, Houston, USA
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Zhang F, Sahu V, Peng K, Wang Y, Li T, Bala P, Aitymbayev D, Sahgal P, Schaefer A, Der CJ, Ryeom S, Yoon S, Sethi N, Bass AJ, Zhang H. Recurrent RhoGAP gene fusion CLDN18-ARHGAP26 promotes RHOA activation and focal adhesion kinase and YAP-TEAD signalling in diffuse gastric cancer. Gut 2024; 73:1280-1291. [PMID: 38621923 PMCID: PMC11287566 DOI: 10.1136/gutjnl-2023-329686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 02/08/2024] [Indexed: 04/17/2024]
Abstract
OBJECTIVE Genomic studies of gastric cancer have identified highly recurrent genomic alterations impacting RHO signalling, especially in the diffuse gastric cancer (DGC) histological subtype. Among these alterations are interchromosomal translations leading to the fusion of the adhesion protein CLDN18 and RHO regulator ARHGAP26. It remains unclear how these fusion constructs impact the activity of the RHO pathway and what is their broader impact on gastric cancer development. Herein, we developed a model to allow us to study the function of this fusion protein in the pathogenesis of DGC and to identify potential therapeutic targets for DGC tumours with these alterations. DESIGN We built a transgenic mouse model with LSL-CLDN18-ARHGAP26 fusion engineered into the Col1A1 locus where its expression can be induced by Cre recombinase. Using organoids generated from this model, we evaluated its oncogenic activity and the biochemical effects of the fusion protein on the RHOA pathway and its downstream cell biological effects in the pathogenesis of DGC. RESULTS We demonstrated that induction of CLDN18-ARHGAP26 expression in gastric organoids induced the formation of signet ring cells, characteristic features of DGC and was able to cooperatively transform gastric cells when combined with the loss of the tumour suppressor geneTrp53. CLDN18-ARHGAP26 promotes the activation of RHOA and downstream effector signalling. Molecularly, the fusion promotes activation of the focal adhesion kinase (FAK) and induction of the YAP pathway. A combination of FAK and YAP/TEAD inhibition can significantly block tumour growth. CONCLUSION These results indicate that the CLDN18-ARHGAP26 fusion is a gain-of-function DGC oncogene that leads to activation of RHOA and activation of FAK and YAP signalling. These results argue for further evaluation of emerging FAK and YAP-TEAD inhibitors for these deadly cancers.
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Affiliation(s)
- Feifei Zhang
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Varun Sahu
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
- Department of Genetics and Development, Columbia University Irving Medical Center, New York, New York, USA
| | - Ke Peng
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Medical Oncology, Fudan University, Shanghai, China
| | - Yichen Wang
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Tianxia Li
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
| | - Pratyusha Bala
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Daulet Aitymbayev
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Pranshu Sahgal
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Antje Schaefer
- Universty of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Channing J Der
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Sandra Ryeom
- Department of Surgery, Columbia University Irving Medical Center, New York, New York, USA
| | - Sam Yoon
- Department of Surgery, Columbia University Irving Medical Center, New York, New York, USA
| | - Nilay Sethi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Adam J Bass
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
- Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA
| | - Haisheng Zhang
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Signet Therapeutics, Shenzhen, China
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7
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Noda H, Sakata S, Baba S, Togashi Y, Nakano K, Hirasawa T, Nakayama I, Hata C, Takamatsu M, Sugawara E, Yamamoto N, Fujisaki J, Nunobe S, Iwakiri K, Takeuchi K, Kawachi H. Early gastric cancer with RhoGAP fusion is linked to frequent nodal metastasis and a part of microtubular-mucocellular histology. Gastric Cancer 2024; 27:772-784. [PMID: 38755445 DOI: 10.1007/s10120-024-01507-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 05/04/2024] [Indexed: 05/18/2024]
Abstract
INTRODUCTION Gastric cancer with fusion genes involving the Rho GTPase-activating protein domain (RhoGAP-GC) is mainly included in the genomically stable type of The Cancer Genome Atlas classification. Clinical implications and histological characteristics of RhoGAP-GC in the early phase remain unclear. METHODS We analyzed 878 consecutive pT1b GCs for RhoGAP and its partner genes using fluorescence in situ hybridization assay. RESULTS RhoGAP fusion was detected in 57 (6.5%) GCs. Univariate analysis revealed that female sex, middle-lower third tumor location, advanced macroscopic type, tumor diameter > 2 cm, pT1b2, lymphatic invasion, venous invasion, negative EBER-ISH, and RhoGAP fusion were significantly associated with lymph node metastasis (LNM). Multivariate analysis presented RhoGAP fusion, lymphatic invasion, tumor diameter > 2 cm, advanced macroscopic type, venous invasion, and middle-lower third tumor location as independent risk factors for LNM. Notably, RhoGAP fusion had the highest odds ratio (3.92) for LNM among analyzed parameters (95% CI 2.12-7.27; p < 0.001). Compared to non-RhoGAP-GCs, RhoGAP-GCs were significantly frequent in younger females and showed the highest incidence of lymphatic invasion (56.2%) and LNM (49.1%) (p < 0.001). Histologically, microtubular architecture with pseudo-trabecular interconnection and small aggregations of tumor cells with a varied amount of cytoplasmic mucin, named "microtubular-mucocellular (MTMC) histology," was found in 93.0% (53 of 57) of RhoGAP-GCs in the intramucosal area. MTMC histology showed high sensitivity and negative predictive value (93.0% and 99.4%, respectively) for RhoGAP fusion, albeit positive predictive value is low (34.9%). CONCLUSION RhoGAP-GC is linked to a characteristic MTMC histology and a high incidence of LNM.
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Affiliation(s)
- Hiroto Noda
- Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
- Department of Gastroenterology, Nippon Medical School Hospital, Tokyo, Japan
| | - Seiji Sakata
- Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
- Pathology Project for Molecular Targets, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
- Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Satoko Baba
- Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
- Pathology Project for Molecular Targets, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
- Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yuki Togashi
- Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
- Pathology Project for Molecular Targets, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
- Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Kaoru Nakano
- Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
- Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Toshiaki Hirasawa
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Izuma Nakayama
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Chiina Hata
- Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
- Department of Human Pathology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Manabu Takamatsu
- Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
- Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Emiko Sugawara
- Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
- Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Noriko Yamamoto
- Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
- Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Junko Fujisaki
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Souya Nunobe
- Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Katsuhiko Iwakiri
- Department of Gastroenterology, Nippon Medical School Hospital, Tokyo, Japan
| | - Kengo Takeuchi
- Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
- Pathology Project for Molecular Targets, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
- Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Hiroshi Kawachi
- Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
- Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
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8
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Jin WM, Zhu Y, Cai ZQ, He N, Yu ZQ, Li S, Yang JY. Progress of Clinical Studies Targeting Claudin18.2 for the Treatment of Gastric Cancer. Dig Dis Sci 2024; 69:2631-2647. [PMID: 38769225 DOI: 10.1007/s10620-024-08435-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Accepted: 04/10/2024] [Indexed: 05/22/2024]
Abstract
Claudin18.2 is a tight junction protein, highly selective, generally expressed only in normal gastric mucosal epithelial cells, which can effectively maintain the polarity of epithelial and endothelial cells, thus effectively regulating the permeability and conductance of the paracellular pathway. Abnormal expression of Claudin18.2 can occur in various primary malignant tumors, especially gastrointestinal tumors, and even in metastatic foci. It regulates its expression by activating the aPKC/MAPK/AP-1 pathway, and therefore, the Claudin18.2 protein is a pan-cancer target expressed in primary and metastatic lesions in human cancer types. Zolbetuximab (IMAB362), an antibody specific for Claudin18.2, has been successfully tested in a phase III clinical trial, and the results of the study showed that combining Zolbetuximab with chemotherapy notably extends patients' survival and is expected to be a potential first-line treatment for patients with Claudin18.2(+)/HER-2(-) gastric cancer. Here, we systematically describe the biological properties and oncogenic effects of Claudin18.2, centering on its clinical-pathological aspects and the progress of drug studies in gastric cancer, which can help to further explore its clinical value.
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Affiliation(s)
- Wu-Mei Jin
- Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, People's Republic of China
| | - Yan Zhu
- Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, People's Republic of China
| | - Zhi-Qiang Cai
- Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, People's Republic of China
| | - Na He
- Department of General, First Affiliated Hospital of Yangtze University, Jingzhou, People's Republic of China
| | - Zhi-Qiong Yu
- Department of Respiratory, First Affiliated Hospital of Yangtze University, Jingzhou, People's Republic of China
| | - Shuang Li
- Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, People's Republic of China
| | - Ji-Yuan Yang
- Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, People's Republic of China.
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Dawood S, Natarajan V, Danchaivijitr P. Comprehensive molecular profiling identifies actionable biomarkers for patients from Thailand and the United Arab Emirates with advanced malignancies. Front Oncol 2024; 14:1374087. [PMID: 38800398 PMCID: PMC11116666 DOI: 10.3389/fonc.2024.1374087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Accepted: 04/03/2024] [Indexed: 05/29/2024] Open
Abstract
Background Comprehensive molecular profiling of tissue samples that can help guide therapy management is not widely available across the globe. Methods Comprehensive molecular profiling through Caris Molecular Intelligence involves the analysis of DNA through next-generation sequencing, chromogenic or fluorescent in situ hybridization, pyrosequencing, and copy number alterations; RNA through whole-transcriptome sequencing and multiplex PCR of RNA; and protein through immunohistochemistry. Results Here we describe the experience of molecular profiling of tumor tissue samples from patients diagnosed with advanced solid tumors and treated in two countries, the United Arab Emirates and Thailand. Tumor cancer cases submitted to Caris Life Sciences (Phoenix, Arizona, USA) for molecular profiling from the UAE and Thailand were retrospectively analyzed (data accessed between 2019 and 2020) for their molecular alterations and clinical biomarkers, without regard to ethnicity. A total of 451 samples from 35 distinct types of advanced cancers were examined for mutations, amplifications, overexpression, exon copy number alterations, microsatellite instability, deficient mismatch repair, tumor mutational burden, and fusions. Interrogating each step of the biological pathway, from DNA to RNA to distinct protein, identified an alteration with an associated therapy for 75% of these tumor samples. The most common alterations identified included elevated PDL-1 that can be targeted with an immune checkpoint inhibitors and amplification of HER2 for which a variety of anti HER2 therapies are available. Conclusion Comprehensive molecular profiling in patients with advanced malignancies can help optimize therapeutic management allowing for improved prognostic outcome.
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Affiliation(s)
- Shaheenah Dawood
- Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
- Oncology Department, Mediclinic City Hospital, Dubai, United Arab Emirates
| | | | - Pongwut Danchaivijitr
- Division of Medical Oncology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
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10
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Yu P, Hu C, Ding G, Shi X, Xu J, Cao Y, Chen X, Wu W, Xu Q, Fang J, Huang X, Yuan S, Chen H, Wang Z, Huang L, Pang F, Du Y, Cheng X. Mutation characteristics and molecular evolution of ovarian metastasis from gastric cancer and potential biomarkers for paclitaxel treatment. Nat Commun 2024; 15:3771. [PMID: 38704377 PMCID: PMC11069556 DOI: 10.1038/s41467-024-48144-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 04/19/2024] [Indexed: 05/06/2024] Open
Abstract
Ovarian metastasis is one of the major causes of treatment failure in patients with gastric cancer (GC). However, the genomic characteristics of ovarian metastasis in GC remain poorly understood. In this study, we enroll 74 GC patients with ovarian metastasis, with 64 having matched primary and metastatic samples. Here, we show a characterization of the mutation landscape of this disease, alongside an investigation into the molecular heterogeneity and pathway mutation enrichments between synchronous and metachronous metastasis. We classify patients into distinct clonal evolution patterns based on the distribution of mutations in paired samples. Notably, the parallel evolution group exhibits the most favorable prognosis. Additionally, by analyzing the differential response to chemotherapy, we identify potential biomarkers, including SALL4, CCDC105, and CLDN18, for predicting the efficacy of paclitaxel treatment. Furthermore, we validate that CLDN18 fusion mutations improve tumor response to paclitaxel treatment in GC with ovarian metastasis in vitro and vivo.
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Affiliation(s)
- Pengfei Yu
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
| | - Can Hu
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
| | - Guangyu Ding
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
| | | | - Jingli Xu
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
| | - Yang Cao
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
| | - Xiangliu Chen
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
| | - Wei Wu
- Department of Pathology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
| | - Qi Xu
- Department of Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
| | - Jingquan Fang
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
| | - Xingmao Huang
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
| | | | - Hui Chen
- Shanghai OrigiMed Co., Ltd, Shanghai, PR China
| | | | - Ling Huang
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
| | - Fei Pang
- Shanghai OrigiMed Co., Ltd, Shanghai, PR China
| | - Yian Du
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
| | - Xiangdong Cheng
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China.
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11
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Echeverría-Garcés G, Ramos-Medina MJ, Vargas R, Cabrera-Andrade A, Altamirano-Colina A, Freire MP, Montalvo-Guerrero J, Rivera-Orellana S, Echeverría-Espinoza P, Quiñones LA, López-Cortés A. Gastric cancer actionable genomic alterations across diverse populations worldwide and pharmacogenomics strategies based on precision oncology. Front Pharmacol 2024; 15:1373007. [PMID: 38756376 PMCID: PMC11096557 DOI: 10.3389/fphar.2024.1373007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 04/10/2024] [Indexed: 05/18/2024] Open
Abstract
Introduction: Gastric cancer is one of the most prevalent types of cancer worldwide. The World Health Organization (WHO), the International Agency for Research on Cancer (IARC), and the Global Cancer Statistics (GLOBOCAN) reported an age standardized global incidence rate of 9.2 per 100,000 individuals for gastric cancer in 2022, with a mortality rate of 6.1. Despite considerable progress in precision oncology through the efforts of international consortia, understanding the genomic features and their influence on the effectiveness of anti-cancer treatments across diverse ethnic groups remains essential. Methods: Our study aimed to address this need by conducting integrated in silico analyses to identify actionable genomic alterations in gastric cancer driver genes, assess their impact using deleteriousness scores, and determine allele frequencies across nine global populations: European Finnish, European non-Finnish, Latino, East Asian, South Asian, African, Middle Eastern, Ashkenazi Jewish, and Amish. Furthermore, our goal was to prioritize targeted therapeutic strategies based on pharmacogenomics clinical guidelines, in silico drug prescriptions, and clinical trial data. Results: Our comprehensive analysis examined 275,634 variants within 60 gastric cancer driver genes from 730,947 exome sequences and 76,215 whole-genome sequences from unrelated individuals, identifying 13,542 annotated and predicted oncogenic variants. We prioritized the most prevalent and deleterious oncogenic variants for subsequent pharmacogenomics testing. Additionally, we discovered actionable genomic alterations in the ARID1A, ATM, BCOR, ERBB2, ERBB3, CDKN2A, KIT, PIK3CA, PTEN, NTRK3, TP53, and CDKN2A genes that could enhance the efficacy of anti-cancer therapies, as suggested by in silico drug prescription analyses, reviews of current pharmacogenomics clinical guidelines, and evaluations of phase III and IV clinical trials targeting gastric cancer driver proteins. Discussion: These findings underline the urgency of consolidating efforts to devise effective prevention measures, invest in genomic profiling for underrepresented populations, and ensure the inclusion of ethnic minorities in future clinical trials and cancer research in developed countries.
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Affiliation(s)
- Gabriela Echeverría-Garcés
- Centro de Referencia Nacional de Genómica, Secuenciación y Bioinformática, Instituto Nacional de Investigación en Salud Pública “Leopoldo Izquieta Pérez”, Quito, Ecuador
- Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Santiago, Chile
| | - María José Ramos-Medina
- German Cancer Research Center (DKFZ), Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Rodrigo Vargas
- Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Santiago, Chile
- Department of Molecular Biology, Galileo University, Guatemala City, Guatemala
| | - Alejandro Cabrera-Andrade
- Escuela de Enfermería, Facultad de Ciencias de La Salud, Universidad de Las Américas, Quito, Ecuador
- Grupo de Bio-Quimioinformática, Universidad de Las Américas, Quito, Ecuador
| | | | - María Paula Freire
- Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Américas, Quito, Ecuador
| | | | | | | | - Luis A. Quiñones
- Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Santiago, Chile
- Laboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic-Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, Santiago, Chile
- Department of Pharmaceutical Sciences and Technology, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago, Chile
| | - Andrés López-Cortés
- Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Américas, Quito, Ecuador
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12
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Waters R, Sewastjanow-Silva M, Yamashita K, Abdelhakeem A, Iwata KK, Moran D, Elsouda D, Guerrero A, Pizzi M, Vicentini ER, Shanbhag N, Ta A, Chatterjee D, Ajani JA. Retrospective Study of Claudin 18 Isoform 2 Prevalence and Prognostic Association in Gastric and Gastroesophageal Junction Adenocarcinoma. JCO Precis Oncol 2024; 8:e2300543. [PMID: 38781542 PMCID: PMC11371102 DOI: 10.1200/po.23.00543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 03/15/2024] [Accepted: 04/11/2024] [Indexed: 05/25/2024] Open
Abstract
PURPOSE Claudin 18 isoform 2 (CLDN18.2) is an emerging biomarker and therapeutic target in gastric and gastroesophageal junction (G/GEJ) adenocarcinoma. This study aimed to obtain deeper understanding of CLDN18.2 positivity patterns, prognostic implications, and associations with various demographic, clinical, and molecular characteristics in G/GEJ adenocarcinoma. METHODS Archived tumor tissue samples from 304 patients with G/GEJ adenocarcinoma in the United States were assessed for CLDN18.2 positivity by immunohistochemistry. CLDN18.2 positivity was defined as ≥50% or ≥75% of tumor cells with CLDN18 staining intensity ≥2+. CLDN18.2 positivity patterns were analyzed for association with prognosis and clinicopathologic/demographic characteristics. Where possible, CLDN18.2 positivity was analyzed for matched tissue samples to assess concordance between primary and metastatic tumors and concordance before and after chemotherapy. RESULTS The overall prevalence of CLDN18.2-positive tumors (with ≥75% cutoff) was 44.4% (n = 135 of 304). CLDN18.2-positive tumors had a prevalence of 51.4% (n = 91 of 177) in gastric and 34.6% (n = 44 of 127) in GEJ adenocarcinoma. With a ≥50% cutoff, the prevalence of CLDN18.2-positive tumors was 64.4% (n = 114 of 177) in gastric adenocarcinoma and 44.9% (n = 57 of 127) in GEJ adenocarcinoma. There was no association between overall survival and CLDN18.2 positivity using either threshold. Statistically significant associations were noted between CLDN18.2 positivity and sex, histologic type of G/GEJ adenocarcinoma, and adenocarcinoma subtype (≥75% cutoff), and metastasis site and tumor grade (≥50% cutoff). The overall concordance of CLDN18.2 positivity (≥75% cutoff) was 73% (27 of 37) for matched primary versus metastatic tumor samples and 74% (29 of 39) for matched samples before and after chemotherapy. CONCLUSION This study demonstrated that CLDN18.2 positivity did not correlate with survival in G/GEJ adenocarcinoma, consistent with published data. On the basis of matched sample analysis, CLDN18.2 appears to demonstrate >70% concordance as a biomarker. Observed correlations with certain patient/tumor characteristics warrant further study.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Anh Ta
- MD Anderson Cancer Center, Houston, TX
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13
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Nowak KM, Chetty R. Predictive and prognostic biomarkers in gastrointestinal tract tumours. Pathology 2024; 56:205-213. [PMID: 38238239 DOI: 10.1016/j.pathol.2023.12.412] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 12/28/2023] [Accepted: 12/30/2023] [Indexed: 02/18/2024]
Abstract
Tumours of the gastrointestinal tract represent nearly a quarter of all newly diagnosed tumours diagnosed in 2019. Various treatment modalities for gastrointestinal cancers exist, some of which may be guided by biomarkers. Biomarkers act as gauges of either normal or pathogenic processes or responses to an exposure or intervention. They come in many forms. This review explores established and potential molecular/immunohistochemical (IHC) predictive and prognostic biomarkers of the gastrointestinal tract.
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Affiliation(s)
- Klaudia M Nowak
- Laboratory Medicine Program, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.
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14
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Kubota Y, Shitara K. Zolbetuximab for Claudin18.2-positive gastric or gastroesophageal junction cancer. Ther Adv Med Oncol 2024; 16:17588359231217967. [PMID: 38188462 PMCID: PMC10768589 DOI: 10.1177/17588359231217967] [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: 09/09/2023] [Accepted: 11/15/2023] [Indexed: 01/09/2024] Open
Abstract
Claudins (CLDNs) are a family of major membrane proteins that form components of tight junctions. In normal tissues, CLDNs seal the intercellular space in the epithelial sheets to regulate tissue permeability, paracellular transport, and signal transduction. Claudin18.2 (CLDN18.2), a member of the CLDN family, is expressed specifically in gastric mucosal cells in normal tissue, and its expression is often retained in gastric cancer cells. CLDN18.2 is ectopically expressed in many cancers other than gastric cancer such as esophageal cancer, pancreatic cancer, biliary tract cancer, non-small-cell lung cancer, and ovarian cancer. Structurally, CLDN18.2 is localized on the apical side of the cell membrane and has extracellular loops capable of binding monoclonal antibodies. Upon malignant transformation, CLDN18.2 is exposed to the cell surface of the whole membrane, which enables the binding of monoclonal antibodies. Based on these characteristics, CLDN18.2 was considered to be optimal for target therapy, and zolbetuximab was developed which is a first-in-class chimeric immunoglobulin G1 monoclonal antibody highly specific for CLDN18.2. It binds to CLDN18.2 on the tumor cell surface and stimulates cellular and soluble immune effectors that activate antibody-dependent cytotoxicity and complement-dependent cytotoxicity. Recently, zolbetuximab combined with chemotherapy demonstrated a survival benefit in patients with CLDN18.2-positive and HER-2-negative gastric or gastroesophageal junction cancers in the global phase III SPOTLIGHT and GLOW trials. From these clinically meaningful results, CLDN18.2-targeting therapy including zolbetuximab has attracted a lot of attention. In this review, we summarize the clinical implications of CLDN18.2-positive gastric or GEJ cancer, and CLDN18.2-targeting therapy, mainly for zolbetuximab.
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Affiliation(s)
- Yohei Kubota
- Department of Clinical Oncology, St. Marianna University School of Medicine, Kanagawa, Japan
| | - Kohei Shitara
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan
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15
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Bunga OD, Danilova NV. [Claudin-18.2 and gastric cancer: from physiology to carcinogenesis]. Arkh Patol 2024; 86:92-99. [PMID: 39686903 DOI: 10.17116/patol20248606192] [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] [Indexed: 12/18/2024]
Abstract
Today a global problem for humanity is represented by cancer, in particular gastric cancer, which is characterized by high mortality and aggressive course. In this regard, there is a search for new approaches to the diagnosis and therapy of gastric cancer, one of these areas is the study of the expression level of the intercellular adhesion molecule claudin-18.2 in tumor tissue and its use as a target molecule. In the case of various pathological processes, including tumors, the expression profile of claudin-18.2 changes, which indicates its possible role in the initiation and progression of cancer. The aim of this review is to systematize the data on claudin-18.2, its role in normal cell physiology and embryology, as well as in the development of pathological processes in the stomach, its relation to the clinical and morphological characteristics of gastric cancer and importance in biological therapy.
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Affiliation(s)
- O D Bunga
- Lomonosov Moscow State University, Moscow, Russia
| | - N V Danilova
- Lomonosov Moscow State University, Moscow, Russia
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16
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Xu X, Xu S, Wan J, Wang D, Pang X, Gao Y, Ni N, Chen D, Sun X. Disturbing cytoskeleton by engineered nanomaterials for enhanced cancer therapeutics. Bioact Mater 2023; 29:50-71. [PMID: 37621771 PMCID: PMC10444958 DOI: 10.1016/j.bioactmat.2023.06.016] [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: 05/12/2023] [Revised: 06/14/2023] [Accepted: 06/20/2023] [Indexed: 08/26/2023] Open
Abstract
Cytoskeleton plays a significant role in the shape change, migration, movement, adhesion, cytokinesis, and phagocytosis of tumor cells. In clinical practice, some anti-cancer drugs achieve cytoskeletal therapeutic effects by acting on different cytoskeletal protein components. However, in the absence of cell-specific targeting, unnecessary cytoskeletal recombination in organisms would be disastrous, which would also bring about severe side effects during anticancer process. Nanomedicine have been proven to be superior to some small molecule drugs in cancer treatment due to better stability and targeting, and lower side effects. Therefore, this review summarized the recent developments of various nanomaterials disturbing cytoskeleton for enhanced cancer therapeutics, including carbon, noble metals, metal oxides, black phosphorus, calcium, silicon, polymers, peptides, and metal-organic frameworks, etc. A comprehensive analysis of the characteristics of cytoskeleton therapy as well as the future prospects and challenges towards clinical application were also discussed. We aim to drive on this emerging topic through refreshing perspectives based on our own work and what we have also learnt from others. This review will help researchers quickly understand relevant cytoskeletal therapeutic information to further advance the development of cancer nanomedicine.
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Affiliation(s)
- Xueli Xu
- School of Science, Shandong Jianzhu University, Jinan, 250101, China
| | - Shanbin Xu
- Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, China
| | - Jipeng Wan
- Department of Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - Diqing Wang
- Department of Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - Xinlong Pang
- School of Chemistry and Pharmaceutical Engineering, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250000, China
| | - Yuan Gao
- School of Chemistry and Pharmaceutical Engineering, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250000, China
| | - Nengyi Ni
- Department of Chemical and Biomolecular Engineering, National University of Singapore, 117585, Singapore
| | - Dawei Chen
- Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, China
| | - Xiao Sun
- Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, China
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17
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Liu J, Jiang D, Lei Q, Zhu Q, Zhu H. Case Report: A rare case of recurrent ascites after anti-Claudin18.2 antibody therapy for metastatic gastric cancer while responding sustainingly. Front Oncol 2023; 13:1211668. [PMID: 37681021 PMCID: PMC10482433 DOI: 10.3389/fonc.2023.1211668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 06/27/2023] [Indexed: 09/09/2023] Open
Abstract
Background Gastric cancer remains one of the deadliest malignancies in the world, thus urgently requiring effective and safe therapeutics. Claudin18.2 is a member of the tight junction protein family specifically expressed in gastric cancer cells. Monoclonal antibodies targeting Claudin18.2 have been receiving increasing attention recently. ASKB589 is a humanized monoclonal antibody targeting Claudin18.2. Case presentation This case described a 65-year-old Chinese man diagnosed with gastric cancer metastasizing to the liver and multiple lymph nodes. The biomarker examination revealed that he had proficient mismatch repair (pMMR), human epidermal growth factor receptor 2 (HER2) was negative, and the combined proportion score (CPS) of PD-L1 (22C3) was 1. After being proven to be moderately positive for Claudin18.2 expression, he received ASKB589 and CAPOX (oxaliplatin and capecitabine) chemotherapy. After a six-cycle therapy (from 14 July 2022 to 29 November 2022), the target tumor was evaluated for partial response (PR) by the investigator based on the enhanced CT scan according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. However, this patient also suffered from intolerable ascites that gradually aggravated during the therapy, which was not controlled well by the supporting therapy. Therefore, the patient stopped receiving the combined therapy in our hospital and did not receive any other anti-tumor treatment. After 4 months of discontinuation of the drug, the patient's ascites almost disappeared, while the tumor continued to reduce and almost achieved clinically complete relapse (cCR). His progression-free survival (PFS) reached at least 10 months. Conclusion This is the first case of severe ascites reported after anti-Claudin18.2 monoclonal antibody treatment for advanced gastric cancer. At the same time, the patient still benefited significantly from this incomplete treatment even after discontinuation of the drug and the PFS reached at least 10 months. The ascites might be an immune adverse effect related to the monoclonal antibody-induced antibody-dependent cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Further mechanisms remain to be investigated.
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Affiliation(s)
- Jinlu Liu
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Dan Jiang
- Department of Pathology, West China Hospital Sichuan University, Chengdu, Sichuan, China
| | - Qingqiang Lei
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Qing Zhu
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Hong Zhu
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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18
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Tao D, Guan B, Li Z, Jiao M, Zhou C, Li H. Correlation of Claudin18.2 expression with clinicopathological characteristics and prognosis in gastric cancer. Pathol Res Pract 2023; 248:154699. [PMID: 37487317 DOI: 10.1016/j.prp.2023.154699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 06/13/2023] [Accepted: 07/15/2023] [Indexed: 07/26/2023]
Abstract
OBJECTIVES Claudin18.2 (Cldn18.2) is a tight junction protein expressed in gastric epithelial cells and is an emerging target for gastric cancer (GC). This study aimed to analyze the correlation between Cldn18.2 and clinicopathological parameters in GC patients undergoing radical surgery. METHODS AND RESULTS This study included 426 GC patients who underwent radical gastrectomy. The expression of Cldn18.2 was analyzed by immunohistochemical staining and grading. The statistical results indicated that the expression of Cldn18.2 was correlated with T stage, TNM stage, Lauren classification, and the expression level of Mucin-2 (MUC2), Mucin-5AC (MUC5AC), Mucin-6 (MUC6), human epidermal growth factor receptor 2 (HER2), P53 and trefoil factor 2 (TFF2). In addition, through data mining of the Cancer Genome Atlas (TCGA) database, it is suggested that Cldn18.2 expression level is significantly correlated with the expression level of MUC5AC, MUC6, and TFF2. Besides, Cldn18.2 is related to tumor immune infiltration, programmed cell death protein 1 (PD 1) pathway, cell cycle and Wnt signaling pathway. CONCLUSIONS The expression of Cldn18.2 was closely related to gastric-type GC, so gastric-type GC patients may benefit more from targeted drugs targeting Cldn18.2. In GC cells, depletion of Cldn18.2 may influence cell cycle and immune response by affecting Wnt signaling pathway and PD 1 pathway.
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Affiliation(s)
- Daoyu Tao
- Department of Pathology, The Second Hospital of Shandong University, Jinan 250012, Shandong, China
| | - Bingxin Guan
- Department of Pathology, The Second Hospital of Shandong University, Jinan 250012, Shandong, China
| | - Zengxian Li
- Department of Gastrointestinal Surgery, The Second Hospital of Shandong University, Jinan 250012, Shandong, China
| | - Meng Jiao
- Department of Pathology, The Second Hospital of Shandong University, Jinan 250012, Shandong, China
| | - Chengjun Zhou
- Department of Pathology, The Second Hospital of Shandong University, Jinan 250012, Shandong, China
| | - Hui Li
- Department of Pathology, The Second Hospital of Shandong University, Jinan 250012, Shandong, China.
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19
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Cao D, Xu H, Li L, Ju Z, Zhai B. Molecular characteristics of gastric cancer with ERBB2 amplification. Heliyon 2023; 9:e18654. [PMID: 37554835 PMCID: PMC10405018 DOI: 10.1016/j.heliyon.2023.e18654] [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: 06/28/2022] [Revised: 07/18/2023] [Accepted: 07/24/2023] [Indexed: 08/10/2023] Open
Abstract
Gastric cancer is a prevalent malignancy with a high degree of heterogeneity, which has led to a poor therapeutic response. Though there are numerous HER2-targeted medicines for HER2+ gastric cancer, many trials have not indicated an improvement in overall survival. Here 29 ERBB2 amplification (ERBB2-Amp) type gastric cancer samples with WES and RNA-seq data were selected for investigation, which copy-number aberration (CNA) was +2. Initially, the somatic mutation and copy number variant (CNV) of them, which might cause resistance to HER2-targeted therapies, were systematically investigated evaluated, as well as their mutation signatures. Moreover, 37 modules were identified using weighted gene co-expression network analysis (WGCNA), including the blue module related to DFS status and lightcyan module correlated with ARHGAP26_ARHGAP6_CLDN18 rearrangement. In addition, focal adhesion and ECM-receptor interaction pathways were considerably enriched in the turquoise module with ERBB2 gene. ExportNetworkToCytoscape determined that MIEN1 and GRB7 are tightly connected to ERBB2., Finally, 14 single-cell intestinal gastric cancer samples were investigated, and it was shown that the TFAP2A transcription factor regulon was highly expressed in ERBB2high group, as was the EMT score. Overall, our data provide comprehensive molecular characteristics of ERBB2-Amp type gastric cancer, which offers additional information to improve HER2-targeted gastric cancer treatment.
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Affiliation(s)
- Dongyan Cao
- Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200032, China
- Henan Railway Food Safety Management Engineering Technology Research Center, Zhengzhou Railway Vocational & Technology College, Zhengzhou, 451460, China
| | - Hongping Xu
- Henan Railway Food Safety Management Engineering Technology Research Center, Zhengzhou Railway Vocational & Technology College, Zhengzhou, 451460, China
| | - Longteng Li
- Henan Railway Food Safety Management Engineering Technology Research Center, Zhengzhou Railway Vocational & Technology College, Zhengzhou, 451460, China
| | - Zheng Ju
- Henan Railway Food Safety Management Engineering Technology Research Center, Zhengzhou Railway Vocational & Technology College, Zhengzhou, 451460, China
- The Data Systems Department, 3D Medicines Inc., Shanghai, 201114, China
| | - Baiqiang Zhai
- Henan Railway Food Safety Management Engineering Technology Research Center, Zhengzhou Railway Vocational & Technology College, Zhengzhou, 451460, China
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20
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Saito-Adachi M, Hama N, Totoki Y, Nakamura H, Arai Y, Hosoda F, Rokutan H, Yachida S, Kato M, Fukagawa A, Shibata T. Oncogenic structural aberration landscape in gastric cancer genomes. Nat Commun 2023; 14:3688. [PMID: 37349325 PMCID: PMC10287692 DOI: 10.1038/s41467-023-39263-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 06/05/2023] [Indexed: 06/24/2023] Open
Abstract
Structural variants (SVs) are responsible for driver events in gastric cancer (GC); however, their patterns and processes remain poorly understood. Here, we examine 170 GC whole genomes to unravel the oncogenic structural aberration landscape in GC genomes and identify six rearrangement signatures (RSs). Non-random combinations of RSs elucidate distinctive GC subtypes comprising one or a few dominant RS that are associated with specific driver events (BRCA1/2 defects, mismatch repair deficiency, and TP53 mutation) and epidemiological backgrounds. Twenty-seven SV hotspots are identified as GC driver candidates. SV hotspots frequently constitute complexly clustered SVs involved in driver gene amplification, such as ERBB2, CCNE1, and FGFR2. Further deconstruction of the locally clustered SVs uncovers amplicon-generating profiles characterized by super-large SVs and intensive segmental amplifications, contributing to the extensive amplification of GC oncogenes. Comprehensive analyses using adjusted SV allele frequencies indicate the significant involvement of extra-chromosomal DNA in processes linked to specific RSs.
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Affiliation(s)
- Mihoko Saito-Adachi
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Natsuko Hama
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Yasushi Totoki
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan
- Department of Cancer Genome Informatics, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Hiromi Nakamura
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Yasuhito Arai
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Fumie Hosoda
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Hirofumi Rokutan
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Shinichi Yachida
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan
- Department of Cancer Genome Informatics, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Mamoru Kato
- Division of Bioinformatics, National Cancer Center Research Institute, Tokyo, Japan
| | - Akihiko Fukagawa
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Tatsuhiro Shibata
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
- Laboratory of Molecular Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
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21
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Chen J, Xu Z, Hu C, Zhang S, Zi M, Yuan L, Cheng X. Targeting CLDN18.2 in cancers of the gastrointestinal tract: New drugs and new indications. Front Oncol 2023; 13:1132319. [PMID: 36969060 PMCID: PMC10036590 DOI: 10.3389/fonc.2023.1132319] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 02/27/2023] [Indexed: 03/12/2023] Open
Abstract
Cancers of the gastrointestinal (GI) tract greatly contribute to the global cancer burden and cancer-related death. Claudin-18.2(CLDN18.2), a transmembrane protein, is a major component of tight junctions and plays an important role in the maintenance of barrier function. Its characteristic widespread expression in tumour tissues and its exposed extracellular loops make it an ideal target for researchers to develop targeted strategies and immunotherapies for cancers of the GI tract. In the present review, we focus on the expression pattern of CLDN18.2 and its clinical significance in GI cancer. We also discuss the tumour-promoting and/or tumour-inhibiting functions of CLDN18.2, the mechanisms regulating its expression, and the current progress regarding the development of drugs targeting CLDN18.2 in clinical research.
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Affiliation(s)
- Jinxia Chen
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Zhiyuan Xu
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China
- Zhejiang Key Lab of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer, Zhejiang Cancer Hospital, Hangzhou, China
| | - Can Hu
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China
- Zhejiang Key Lab of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer, Zhejiang Cancer Hospital, Hangzhou, China
| | - Shengjie Zhang
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China
- Zhejiang Key Lab of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer, Zhejiang Cancer Hospital, Hangzhou, China
| | - Mengli Zi
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Li Yuan
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China
- Zhejiang Key Lab of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer, Zhejiang Cancer Hospital, Hangzhou, China
- *Correspondence: Li Yuan, ; Xiangdong Cheng,
| | - Xiangdong Cheng
- Department of Gastric Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China
- Zhejiang Key Lab of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer, Zhejiang Cancer Hospital, Hangzhou, China
- *Correspondence: Li Yuan, ; Xiangdong Cheng,
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22
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Chen W, Tan M, Yu C, Liao G, Kong D, Bai J, Yang B, Gong H. ARHGAP6 inhibits bladder cancer cell viability, migration, and invasion via β-catenin signaling and enhances mitomycin C sensitivity. Hum Cell 2023; 36:786-797. [PMID: 36715867 DOI: 10.1007/s13577-023-00860-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 01/17/2023] [Indexed: 01/31/2023]
Abstract
The Rho/ROCK pathway regulates diverse cellular processes and contributes to the development and advancement of several types of human cancers. This study investigated the role of specific Rho GTPase-activating proteins (RhoGAP), ARHGAP6, in bladder cancer (BC). In this study, ARHGAP6 expression in BC and its clinical significance were investigated. In vitro and in vivo assays were used to explore the tumor-related function and the underlying molecular mechanism ARHGAP6 of in BC. The mRNA and protein levels of ARHGAP6 significantly reduced in human BC tissues and cell lines compared with corresponding adjacent non-cancerous tissues and normal urothelial cells. In vitro, ARHGAP6 overexpression markedly decreased the viability, migration, and invasion of BC cells. Interestingly, low ARHGAP6 expression in BC strongly correlated with poor patient survival and was highly associated with metastasis and β-catenin signaling. Furthermore, ARHGAP6 expression strongly influenced the sensitivity of BC cells to mitomycin C treatment. Together, our results demonstrate that ARHGAP6 plays critical roles in regulating the proliferation, migration, invasion, and metastasis of BC cells possibly via the modulation of β-catenin and strongly influences the chemosensitivity of BC cells.
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Affiliation(s)
- Weihua Chen
- Department of Urology, Shanghai East Hospital, Tongji University, Shanghai, 200120, China
| | - Mingyue Tan
- Department of Urology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200021, Shanghai, China
| | - Chao Yu
- Department of Urology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Guoqiang Liao
- Department of Urology, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, No. 1500 Zhouyuan Road, Pudong, 201318, Shanghai, China
| | - Dehui Kong
- Department of Radiology, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Jie Bai
- Department of Urology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Bo Yang
- Department of Urology, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, No. 1500 Zhouyuan Road, Pudong, 201318, Shanghai, China.
| | - Hua Gong
- Department of Urology, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, No. 1500 Zhouyuan Road, Pudong, 201318, Shanghai, China.
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23
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Xiao H, Wang G, Zhao M, Shuai W, Ouyang L, Sun Q. Ras superfamily GTPase activating proteins in cancer: Potential therapeutic targets? Eur J Med Chem 2023; 248:115104. [PMID: 36641861 DOI: 10.1016/j.ejmech.2023.115104] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 01/06/2023] [Accepted: 01/07/2023] [Indexed: 01/11/2023]
Abstract
To search more therapeutic strategies for Ras-mutant tumors, regulators of the Ras superfamily involved in the GTP/GDP (guanosine triphosphate/guanosine diphosphate) cycle have been well concerned for their anti-tumor potentials. GTPase activating proteins (GAPs) provide the catalytic group necessary for the hydrolysis of GTPs, which accelerate the switch by cycling between GTP-bound active and GDP-bound inactive forms. Inactivated GAPs lose their function in activating GTPase, leading to the continuous activation of downstream signaling pathways, uncontrolled cell proliferation, and eventually carcinogenesis. A growing number of evidence has shown the close link between GAPs and human tumors, and as a result, GAPs are believed as potential anti-tumor targets. The present review mainly summarizes the critically important role of GAPs in human tumors by introducing the classification, function and regulatory mechanism. Moreover, we comprehensively describe the relationship between dysregulated GAPs and the certain type of tumor. Finally, the current status, research progress, and clinical value of GAPs as therapeutic targets are also discussed, as well as the challenges and future direction in the cancer therapy.
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Affiliation(s)
- Huan Xiao
- State Key Laboratory of Biotherapy and Cancer Center, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, 610041, China
| | - Guan Wang
- State Key Laboratory of Biotherapy and Cancer Center, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, 610041, China
| | - Min Zhao
- State Key Laboratory of Biotherapy and Cancer Center, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, 610041, China
| | - Wen Shuai
- State Key Laboratory of Biotherapy and Cancer Center, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, 610041, China
| | - Liang Ouyang
- State Key Laboratory of Biotherapy and Cancer Center, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, 610041, China
| | - Qiu Sun
- State Key Laboratory of Biotherapy and Cancer Center, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, 610041, China.
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24
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Tong Y, Cheng PSW, Or CS, Yue SSK, Siu HC, Ho SL, Law SYK, Tsui WY, Chan D, Ma S, Lee SP, Chan ASY, Chan AS, Yun SW, Hui HS, Yuen ST, Leung SY, Yan HHN. Escape from cell-cell and cell-matrix adhesion dependence underscores disease progression in gastric cancer organoid models. Gut 2023; 72:242-255. [PMID: 35705367 DOI: 10.1136/gutjnl-2022-327121] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 05/27/2022] [Indexed: 01/27/2023]
Abstract
OBJECTIVE Cell-cell (CC) and cell-matrix (CM) adhesions are essential for epithelial cell survival, yet dissociation-induced apoptosis is frequently circumvented in malignant cells. DESIGN We explored CC and CM dependence in 58 gastric cancer (GC) organoids by withdrawing either ROCK inhibitor, matrix or both to evaluate their tumorigenic potential in terms of apoptosis resistance, correlation with oncogenic driver mutations and clinical behaviour. We performed mechanistic studies to determine the role of diffuse-type GC drivers: ARHGAP fusions, RHOA and CDH1, in modulating CC (CCi) or CM (CMi) adhesion independence. RESULTS 97% of the tumour organoids were CMi, 66% were CCi and 52% were resistant to double withdrawal (CCi/CMi), while normal organoids were neither CMi nor CCi. Clinically, the CCi/CMi phenotype was associated with an infiltrative tumour edge and advanced tumour stage. Moreover, the CCi/CMi transcriptome signature was associated with poor patient survival when applied to three public GC datasets. CCi/CMi and CCi phenotypes were enriched in diffuse-type GC organoids, especially in those with oncogenic driver perturbation of RHO signalling via RHOA mutation or ARHGAP fusions. Inducible knockout of ARHGAP fusions in CCi/CMi tumour organoids led to resensitisation to CC/CM dissociation-induced apoptosis, upregulation of focal adhesion and tight junction genes, partial reversion to a more normal cystic phenotype and inhibited xenograft formation. Normal gastric organoids engineered with CDH1 or RHOA mutations became CMi or CCi, respectively. CONCLUSIONS The CCi/CMi phenotype has a critical role in malignant transformation and tumour progression, offering new mechanistic information on RHO-ROCK pathway inhibition that contributes to GC pathogenicity.
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Affiliation(s)
- Yin Tong
- Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China.,Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China
| | - Priscilla S W Cheng
- Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China
| | - Chung Sze Or
- Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China
| | - Sarah S K Yue
- Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China
| | - Hoi Cheong Siu
- Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China
| | - Siu Lun Ho
- Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China
| | - Simon Y K Law
- Department of Surgery, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China
| | - Wai Yin Tsui
- Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China
| | - Dessy Chan
- Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China
| | - Stephanie Ma
- School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
| | - Siu Po Lee
- Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China
| | - Annie S Y Chan
- Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China
| | - April S Chan
- Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China
| | - Shui Wa Yun
- Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China
| | - Ho Sang Hui
- Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China
| | - Siu Tsan Yuen
- Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China.,Department of Pathology, St. Paul's Hospital, No. 2, Eastern Hosptial Road, Causeway Bay, Hong Kong SAR, China
| | - Suet Yi Leung
- Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China .,Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China.,The Jockey Club Centre for Clinical Innovation and Discovery, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
| | - Helen H N Yan
- Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China .,Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China
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25
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Miladinovic B, Faria MÂ, Ribeiro M, Sobral MMC, Ferreira IMPLVO. Delphinidin-3-rutinoside from Blackcurrant Berries ( Ribes nigrum): In Vitro Antiproliferative Activity and Interactions with Other Phenolic Compounds. Molecules 2023; 28:molecules28031286. [PMID: 36770953 PMCID: PMC9920764 DOI: 10.3390/molecules28031286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 01/25/2023] [Accepted: 01/25/2023] [Indexed: 01/31/2023] Open
Abstract
Blackcurrant berries (Rigrum L.) are of great interest for food scientists/technologists as a source of delphinidin-3-rutinoside (D3R). This is an uncommon phenolic compound in diets that unveils potent antiproliferative activity besides its colour. Other phenolic compounds, such as chlorogenic acid (CA) and epicatechin (EC), also known by their antiproliferative effects, are abundant in foods and beverages. To design smart food/supplements combinations containing blackcurrant and improved anticancer properties at the gastrointestinal level, there is the need for more data concerning the combined effects of those molecules. In this work, synergistic, additive, or antagonistic effects against gastric and intestinal cancers of D3R, CA, and EC were assessed in vitro. The antiproliferative activity of D3R, CA, and EC, alone and in binary combinations (D3R+CA, D3R+EC, and CA+EC) on NCI-N87 (gastric) and Caco-2 (intestinal) cells, was assessed following the Chou-Talalay theorem at equipotent contributions (i.e., (IC50)1/(IC50)2). D3R presented the strongest antiproliferative activity of the single molecules tested, with IC50 values of 24.9 µM and 102.5 µM on NCI-N87 and Caco-2 cells, respectively. The combinations D3R+CA and CA+EC were synergic against NCI-N87 until IC50 and IC75, respectively, while D3R+EC shifted from slight antagonism to synergism at higher doses. On Caco-2 cells, antagonism at low doses and synergism at high doses was observed. Therefore, the synergisms observed on the gastric cancer model at low doses occurred on the colon model only at high doses. Data herein described is vital to the targeted smart design of foods and supplements, as it is foreseen that the same combination of phenolic compounds causes different interactions/effects depending on the dose and gastrointestinal compartment.
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Affiliation(s)
- Bojana Miladinovic
- Department of Pharmacy, Faculty of Medicine, University of Niš, Dr Zoran Djindjic blvd. 81, 18000 Niš, Serbia
| | - Miguel Ângelo Faria
- LAQV/REQUIMTE, Departamento de Ciências Químicas, Laboratório de Bromatologia e Hidrologia, Faculdade de Farmácia—Universidade do Porto, 4050-313 Porto, Portugal
| | - Mafalda Ribeiro
- LAQV/REQUIMTE, Departamento de Ciências Químicas, Laboratório de Bromatologia e Hidrologia, Faculdade de Farmácia—Universidade do Porto, 4050-313 Porto, Portugal
| | - Maria Madalena Costa Sobral
- LAQV/REQUIMTE, Departamento de Ciências Químicas, Laboratório de Bromatologia e Hidrologia, Faculdade de Farmácia—Universidade do Porto, 4050-313 Porto, Portugal
| | - Isabel M. P. L. V. O. Ferreira
- LAQV/REQUIMTE, Departamento de Ciências Químicas, Laboratório de Bromatologia e Hidrologia, Faculdade de Farmácia—Universidade do Porto, 4050-313 Porto, Portugal
- Correspondence: ; Tel.: +351-2204-28639 or +351-2260-93390
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26
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Zeng Y, Jin RU. Molecular pathogenesis, targeted therapies, and future perspectives for gastric cancer. Semin Cancer Biol 2022; 86:566-582. [PMID: 34933124 DOI: 10.1016/j.semcancer.2021.12.004] [Citation(s) in RCA: 90] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 11/29/2021] [Accepted: 12/11/2021] [Indexed: 01/27/2023]
Abstract
Gastric cancer is a major source of global cancer mortality with limited treatment options and poor patient survival. As our molecular understanding of gastric cancer improves, we are now beginning to recognize that these cancers are a heterogeneous group of diseases with incredibly unique pathogeneses and active oncogenic pathways. It is this molecular diversity and oftentimes lack of common oncogenic driver mutations that bestow the poor treatment responses that oncologists often face when treating gastric cancer. In this review, we will examine the treatments for gastric cancer including up-to-date molecularly targeted therapies and immunotherapies. We will then review the molecular subtypes of gastric cancer to highlight the diversity seen in this disease. We will then shift our discussion to basic science and gastric cancer mouse models as tools to study gastric cancer molecular heterogeneity. Furthermore, we will elaborate on a molecular process termed paligenosis and the cyclical hit model as key events during gastric cancer initiation that impart nondividing mature differentiated cells the ability to re-enter the cell cycle and accumulate disparate genomic mutations during years of chronic inflammation and injury. As our basic science understanding of gastric cancer advances, so too must our translational and clinical efforts. We will end with a discussion regarding single-cell molecular analyses and cancer organoid technologies as future translational avenues to advance our understanding of gastric cancer heterogeneity and to design precision-based gastric cancer treatments. Elucidation of interpatient and intratumor heterogeneity is the only way to advance future cancer prevention, diagnoses and treatment.
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Affiliation(s)
- Yongji Zeng
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, USA
| | - Ramon U Jin
- Section of Hematology/Oncology, Department of Medicine, Baylor College of Medicine, Houston, USA.
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27
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Lei ZN, Teng QX, Tian Q, Chen W, Xie Y, Wu K, Zeng Q, Zeng L, Pan Y, Chen ZS, He Y. Signaling pathways and therapeutic interventions in gastric cancer. Signal Transduct Target Ther 2022; 7:358. [PMID: 36209270 PMCID: PMC9547882 DOI: 10.1038/s41392-022-01190-w] [Citation(s) in RCA: 121] [Impact Index Per Article: 40.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 08/14/2022] [Accepted: 09/07/2022] [Indexed: 11/23/2022] Open
Abstract
Gastric cancer (GC) ranks fifth in global cancer diagnosis and fourth in cancer-related death. Despite tremendous progress in diagnosis and therapeutic strategies and significant improvements in patient survival, the low malignancy stage is relatively asymptomatic and many GC cases are diagnosed at advanced stages, which leads to unsatisfactory prognosis and high recurrence rates. With the recent advances in genome analysis, biomarkers have been identified that have clinical importance for GC diagnosis, treatment, and prognosis. Modern molecular classifications have uncovered the vital roles that signaling pathways, including EGFR/HER2, p53, PI3K, immune checkpoint pathways, and cell adhesion signaling molecules, play in GC tumorigenesis, progression, metastasis, and therapeutic responsiveness. These biomarkers and molecular classifications open the way for more precise diagnoses and treatments for GC patients. Nevertheless, the relative significance, temporal activation, interaction with GC risk factors, and crosstalk between these signaling pathways in GC are not well understood. Here, we review the regulatory roles of signaling pathways in GC potential biomarkers, and therapeutic targets with an emphasis on recent discoveries. Current therapies, including signaling-based and immunotherapies exploited in the past decade, and the development of treatment for GC, particularly the challenges in developing precision medications, are discussed. These advances provide a direction for the integration of clinical, molecular, and genomic profiles to improve GC diagnosis and treatments.
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Affiliation(s)
- Zi-Ning Lei
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Qiu-Xu Teng
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Qin Tian
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Wei Chen
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Yuhao Xie
- Institute for Biotechnology, St. John's University, Queens, NY, 11439, USA
| | - Kaiming Wu
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Qianlin Zeng
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Leli Zeng
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China.
| | - Yihang Pan
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China.
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA.
- Institute for Biotechnology, St. John's University, Queens, NY, 11439, USA.
| | - Yulong He
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China.
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28
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Abstract
Gastric cancer (GC) is one of the most common lethal malignant neoplasms worldwide, with limited treatment options for both locally advanced and/or metastatic conditions, resulting in a dismal prognosis. Although the widely used morphological classifications may be helpful for endoscopic or surgical treatment choices, they are still insufficient to guide precise and/or personalized therapy for individual patients. Recent advances in genomic technology and high-throughput analysis may improve the understanding of molecular pathways associated with GC pathogenesis and aid in the classification of GC at the molecular level. Advances in next-generation sequencing have enabled the identification of several genetic alterations through single experiments. Thus, understanding the driver alterations involved in gastric carcinogenesis has become increasingly important because it can aid in the discovery of potential biomarkers and therapeutic targets. In this article, we review the molecular classifications of GC, focusing on The Cancer Genome Atlas (TCGA) classification. We further describe the currently available biomarker-targeted therapies and potential biomarker-guided therapies. This review will help clinicians by providing an inclusive understanding of the molecular pathology of GC and may assist in selecting the best treatment approaches for patients with GC.
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Affiliation(s)
- Moonsik Kim
- Department of Pathology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Korea
| | - An Na Seo
- Department of Pathology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Korea.
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29
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ARHGAP-RhoA signaling provokes homotypic adhesion-triggered cell death of metastasized diffuse-type gastric cancer. Oncogene 2022; 41:4779-4794. [PMID: 36127398 DOI: 10.1038/s41388-022-02469-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/06/2022] [Accepted: 09/07/2022] [Indexed: 11/09/2022]
Abstract
Genetic alteration of Rho GTPase-activating proteins (ARHGAP) and GTPase RhoA is a hallmark of diffuse-type gastric cancer and elucidating its biological significance is critical to comprehensively understanding this malignancy. Here, we report that gene fusions of ARHGAP6/ARHGAP26 are frequent genetic events in peritoneally-metastasized gastric and pancreatic cancer. From the malignant ascites of patients, we established gastric cancer cell lines that spontaneously gain hotspot RHOA mutations or four different ARHGAP6/ARHGAP26 fusions. These alterations critically downregulate RhoA-ROCK-MLC2 signaling, which elicits cell death. Omics and functional analyses revealed that the downstream signaling initiates actin stress fibers and reinforces intercellular junctions via several types of catenin. E-cadherin-centered homotypic adhesion followed by lysosomal membrane permeabilization is a pivotal mechanism in cell death. These findings support the tumor-suppressive nature of ARHGAP-RhoA signaling and might indicate a new avenue of drug discovery against this refractory cancer.
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30
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Chen J, Li L, Liu TY, Fu HF, Lai YH, Lei X, Xu JF, Yu JS, Xia YJ, Zhang TH, Yang DJ, He YL. CPEB3 suppresses gastric cancer progression by inhibiting ADAR1-mediated RNA editing via localizing ADAR1 mRNA to P bodies. Oncogene 2022; 41:4591-4605. [PMID: 36068334 DOI: 10.1038/s41388-022-02454-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 08/22/2022] [Accepted: 08/24/2022] [Indexed: 11/09/2022]
Abstract
Deciphering the crosstalk between RNA-binding proteins and corresponding RNAs will provide a better understanding of gastric cancer (GC) progression. The comprehensive bioinformatics study identified cytoplasmic polyadenylation element-binding protein 3 (CPEB3) might play a vital role in GC progression. Then we found CPEB3 was downregulated in GC and correlated with prognosis. In addition, CPEB3 suppressed GC cell proliferation, invasion and migration in vitro, as well as tumor growth and metastasis in vivo. Mechanistic study demonstrated CPEB3 interacted with 3'-UTR of ADAR1 mRNA through binding to CPEC nucleotide element, and then inhibited its translation by localizing it to processing bodies (P bodies), eventually leading to the suppression of ADAR1-mediated RNA editing. Microscale thermophoresis assay further revealed that the direct interaction between CPEB3 and GW182, the P-body's major component, was through the 440-698AA region of CPEB3 binding to the 403-860AA region of GW182. Finally, AAV9-CPEB3 was developed and administrated in mouse models to assess its potential value in gene therapy. We found AAV9-CPEB3 inhibited GC growth and metastasis. Besides, AAV9-CPEB3 induced hydropic degeneration in mouse liver, but did not cause kidney damage. These findings concluded that CPEB3 suppresses GC progression by inhibiting ADAR1-mediated RNA editing via localizing ADAR1 mRNA to P bodies.
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Affiliation(s)
- Jian Chen
- Center for Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Lu Li
- Department of Clinical Microbiology Laboratory, Institute of Laboratory Medicine, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China
| | - Tian-Yu Liu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Hua-Feng Fu
- Center for Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yuan-Hui Lai
- Department of Thyroid and Breast Surgery, The Eastern Division of the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xiong Lei
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Jun-Fa Xu
- Department of Clinical Immunology, Institute of Laboratory Medicine, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China
| | - Ji-Shang Yu
- Center for Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yu-Jian Xia
- Center for Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Tian-Hao Zhang
- Center for Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Dong-Jie Yang
- Center for Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
| | - Yu-Long He
- Center for Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. .,Digestive Medicine Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China.
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31
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Shin MJ, Im SH, Kim W, Ahn H, Shin TJ, Chung HJ, Yoon DK. Recyclable Periodic Nanostructure Formed by Sublimable Liquid Crystals for Robust Cell Alignment. LANGMUIR : THE ACS JOURNAL OF SURFACES AND COLLOIDS 2022; 38:3765-3774. [PMID: 35302783 DOI: 10.1021/acs.langmuir.1c03359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
We demonstrate a facile method to fabricate a recyclable cell-alignment scaffold using nanogrooves based on sublimable liquid crystal (LC) material. Randomly and uniaxially arranged smectic LC structures are obtained, followed by sublimation and recondensation processes, which directly produce periodic nanogrooves with dimensions of a couple of hundreds of nanometers. After treatment with osmium tetroxide (OsO4), the nanogroove can serve as a scaffold to efficiently induce directed cell growth without causing cytotoxicity, and it can be used repeatedly. Together, various cell types are applied to the nanogroove, proving the scaffold's broad applicability. Depending on the nanotopography of the LC structures, cells exhibit different morphologies and gene expression patterns, compared to cells on standard glass substrates, according to microscopic observation and qPCR. Furthermore, cell sheets can be formed, which consist of oriented cells that can be repeatedly formed and transferred to other substrates, while maintaining its organization. We believe that our cell-aligning scaffold may pave the way for the soft material field to bioengineering, which can involve fundamentals in cell behavior and function, as well as applications for regenerative medicine.
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Affiliation(s)
- Min Jeong Shin
- Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea
| | - San Hae Im
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea
| | - Wantae Kim
- Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea
| | - Hyungju Ahn
- Pohang Accelerator Laboratory, POSTECH, Pohang, 37673, Republic of Korea
| | - Tae Joo Shin
- Graduate School of Semiconductor Materials and Devices Engineering, UNIST, Ulsan, 44919, Republic of Korea
| | - Hyun Jung Chung
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea
- Graduate School of Nanoscience and Technology, orea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea
| | - Dong Ki Yoon
- Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea
- Graduate School of Nanoscience and Technology, orea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea
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Loss of KAP3 decreases intercellular adhesion and impairs intracellular transport of laminin in signet ring cell carcinoma of the stomach. Sci Rep 2022; 12:5050. [PMID: 35322078 PMCID: PMC8943207 DOI: 10.1038/s41598-022-08904-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 03/14/2022] [Indexed: 12/14/2022] Open
Abstract
Signet-ring cell carcinoma (SRCC) is a unique subtype of gastric cancer that is impaired for cell-cell adhesion. The pathogenesis of SRCC remains unclear. Here, we show that expression of kinesin-associated protein 3 (KAP3), a cargo adaptor subunit of the kinesin superfamily protein 3 (KIF3), a motor protein, is specifically decreased in SRCC of the stomach. CRISPR/Cas9-mediated gene knockout experiments indicated that loss of KAP3 impairs the formation of circumferential actomyosin cables by inactivating RhoA, leading to the weakening of cell-cell adhesion. Furthermore, in KAP3 knockout cells, post-Golgi transport of laminin, a key component of the basement membrane, was inhibited, resulting in impaired basement membrane formation. Together, these findings uncover a potential role for KAP3 in the pathogenesis of SRCC of the stomach.
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33
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Diffuse gastric cancer: Emerging mechanisms of tumor initiation and progression. Biochim Biophys Acta Rev Cancer 2022; 1877:188719. [PMID: 35307354 DOI: 10.1016/j.bbcan.2022.188719] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 03/10/2022] [Accepted: 03/11/2022] [Indexed: 02/07/2023]
Abstract
Gastric cancer is globally the fourth leading cause of cancer-related deaths. Patients with diffuse-type gastric cancer (DGC) particularly have a poor prognosis that only marginally improved over the last decades, as conventional chemotherapies are frequently ineffective and specific therapies are unavailable. Early-stage DGC is characterized by intramucosal lesions of discohesive cells, which can be present for many years before the emergence of advanced DGC consisting of highly proliferative and invasive cells. The mechanisms underlying the key steps of DGC development and transition to aggressive tumors are starting to emerge. Novel mouse- and organoid models for DGC, together with multi-omic analyses of DGC tumors, revealed contributions of both tumor cell-intrinsic alterations and gradual changes in the tumor microenvironment to DGC progression. In this review, we will discuss how these recent findings are leading towards an understanding of the cellular and molecular mechanisms responsible for DGC initiation and malignancy, which may provide opportunities for targeted therapies.
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34
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Rahi H, Olave MC, Fritchie KJ, Greipp PT, Halling KC, Kipp BR, Graham RP. Gene Fusions in Gastrointestinal Tract cancers. Genes Chromosomes Cancer 2022; 61:285-297. [PMID: 35239225 DOI: 10.1002/gcc.23035] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 02/24/2022] [Accepted: 02/25/2022] [Indexed: 11/10/2022] Open
Abstract
Fusion genes have been identified a wide array of human neoplasms including hematologic and solid tumors, including gastrointestinal tract neoplasia. A fusion gene is the product of parts of two genes which are joined together following a deletion, translocation or chromosomal inversion. Together with single nucleotide variants, insertions, deletions, and amplification, fusion genes represent one of the key genomic mechanisms for tumor development. Detecting fusions in the clinic is accomplished by a variety of techniques including break-apart fluorescence in situ hybridization (FISH), reverse transcription-polymerase chain reaction (RT-PCR), and next-generation sequencing (NGS). Some recurrent gene fusions have been successfully targeted by small molecule or monoclonal antibody therapies (i.e. targeted therapies), while others are used for as biomarkers for diagnostic and prognostic purposes. The purpose of this review article is to discuss the clinical utility of detection of gene fusions in carcinomas and neoplasms arising primarily in the digestive system. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Hamed Rahi
- Division of Laboratory of Genetics and Genomics, Mayo Clinic, Rochester, MN, USA
| | - Maria C Olave
- Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA
| | - Karen J Fritchie
- Division of Anatomic Pathology, Cleveland Clinic, Cleveland, OH, USA
| | - Patricia T Greipp
- Division of Laboratory of Genetics and Genomics, Mayo Clinic, Rochester, MN, USA
| | - Kevin C Halling
- Division of Laboratory of Genetics and Genomics, Mayo Clinic, Rochester, MN, USA.,Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA
| | - Benjamin R Kipp
- Division of Laboratory of Genetics and Genomics, Mayo Clinic, Rochester, MN, USA.,Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA
| | - Rondell P Graham
- Division of Laboratory of Genetics and Genomics, Mayo Clinic, Rochester, MN, USA.,Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA
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35
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Takei S, Kawazoe A, Shitara K. The New Era of Immunotherapy in Gastric Cancer. Cancers (Basel) 2022; 14:cancers14041054. [PMID: 35205802 PMCID: PMC8870470 DOI: 10.3390/cancers14041054] [Citation(s) in RCA: 105] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/14/2022] [Accepted: 02/16/2022] [Indexed: 12/20/2022] Open
Abstract
Simple Summary Advanced gastric cancer remains a malignancy with a poor prognosis, with a median survival of about 12–15 months. In recent years, immune checkpoint inhibitors have emerged as a new standard of care for several malignancies, including advanced gastric cancer, and have demonstrated good clinical benefit in some populations. In this review paper, we describe the current status of immunotherapy in gastric cancer, with a focus on molecular and immunological profiles, biomarkers, major clinical trials, and novel immunotherapies. Abstract Immune checkpoint inhibitors (ICIs) such as anti-programmed cell death-1 (PD-1) or programmed cell death ligand-1 (PD-L1) monoclonal antibodies have prolonged survival in various types of malignancies, including advanced gastric cancer (AGC). Nivolumab, a monoclonal anti-PD-1 antibody, showed an improvement in overall survival at a later-line therapy in unselected AGC patients in the ATTRACTION-2 study or in combination with chemotherapy as first-line therapy in the global CheckMate-649 study. Another monoclonal anti-PD-1 antibody, pembrolizumab, showed single agent activity in tumors with high microsatellite instability or high tumor mutational burden. Furthermore, a recent KEYNOTE-811 study demonstrated significant improvement in response rate with pembrolizumab combined with trastuzumab and chemotherapy for HER2-positive AGC. Based on these results, ICIs are now incorporated into standard treatment for AGC patients. As a result of pivotal clinical trials, three anti-PD-1 antibodies were approved for AGC: nivolumab combined with chemotherapy as first-line treatment or nivolumab monotherapy as third- or later-line treatment in Asian countries; pembrolizumab for previously treated microsatellite instability-high (MSI-H) or tumor mutational burden-high AGC, or pembrolizumab combined with trastuzumab and chemotherapy for HER2-positive AGC in the United States; and dostarlimab for previously treated MSI-H AGC in the United States. However, a substantial number of patients have showed resistance to ICIs, highlighting the importance of the better selection of patients or further combined immunotherapy. This review focused on molecular and immunological profiles, pivotal clinical trials of ICIs with related biomarkers, and investigational immunotherapy for AGC.
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Roles of fusion genes in digestive system cancers: dawn for cancer precision therapy. Crit Rev Oncol Hematol 2022; 171:103622. [PMID: 35124200 DOI: 10.1016/j.critrevonc.2022.103622] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 02/01/2022] [Accepted: 02/02/2022] [Indexed: 11/21/2022] Open
Abstract
For advanced and advanced tumors of the digestive system, personalized, precise treatment could be a lifesaving medicine. With the development of next-generation sequencing technology, detection of fusion genes in solid tumors has become more extensive. Some fusion gene targeting therapies have been written into the guidelines for digestive tract tumors, such as for neurotrophic receptor tyrosine kinase, fibroblast growth factor receptor 2. There are also many fusion genes being investigated as potential future therapeutic targets. This review focuses on the current detection methods for fusion genes, fusion genes written into the digestive system tumor guidelines, and potential fusion gene therapy targets in different organs to discuss the possibility of clinical treatments for these targets in digestive system tumors.
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37
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Fixing the GAP: the role of RhoGAPs in cancer. Eur J Cell Biol 2022; 101:151209. [DOI: 10.1016/j.ejcb.2022.151209] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 01/29/2022] [Accepted: 02/08/2022] [Indexed: 12/12/2022] Open
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38
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Abstract
Gastric cancer (GC) is a leading contributor to global cancer incidence and mortality. Pioneering genomic studies, focusing largely on primary GCs, revealed driver alterations in genes such as ERBB2, FGFR2, TP53 and ARID1A as well as multiple molecular subtypes. However, clinical efforts targeting these alterations have produced variable results, hampered by complex co-alteration patterns in molecular profiles and intra-patient genomic heterogeneity. In this Review, we highlight foundational and translational advances in dissecting the genomic cartography of GC, including non-coding variants, epigenomic aberrations and transcriptomic alterations, and describe how these alterations interplay with environmental influences, germline factors and the tumour microenvironment. Mapping of these alterations over the GC life cycle in normal gastric tissues, metaplasia, primary carcinoma and distant metastasis will improve our understanding of biological mechanisms driving GC development and promoting cancer hallmarks. On the translational front, integrative genomic approaches are identifying diverse mechanisms of GC therapy resistance and emerging preclinical targets, enabled by technologies such as single-cell sequencing and liquid biopsies. Validating these insights will require specifically designed GC cohorts, converging multi-modal genomic data with longitudinal data on therapeutic challenges and patient outcomes. Genomic findings from these studies will facilitate 'next-generation' clinical initiatives in GC precision oncology and prevention.
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Affiliation(s)
- Khay Guan Yeoh
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Gastroenterology and Hepatology, National University Health System, Singapore, Singapore
- Singapore Gastric Cancer Consortium, Singapore, Singapore
| | - Patrick Tan
- Singapore Gastric Cancer Consortium, Singapore, Singapore.
- Cancer and Stem Cell Biology, Duke-NUS Medical School Singapore, Singapore, Singapore.
- Genome Institute of Singapore, Singapore, Singapore.
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
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39
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Claudins and Gastric Cancer: An Overview. Cancers (Basel) 2022; 14:cancers14020290. [PMID: 35053454 PMCID: PMC8773541 DOI: 10.3390/cancers14020290] [Citation(s) in RCA: 75] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 01/02/2022] [Accepted: 01/03/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Gastric cancer (GC) is one of the most common cancers and the third leading cause of cancer deaths worldwide, with a high frequency of recurrence and metastasis, and a poor prognosis. This review presents novel biological and clinical significance of claudin (CLDN) expression in GC, especially CLDN18, and clinical trials centered around CLDN18.2. It also presents new findings for other CLDNs. Abstract Despite recent improvements in diagnostic ability and treatment strategies, advanced gastric cancer (GC) has a high frequency of recurrence and metastasis, with poor prognosis. To improve the treatment results of GC, the search for new treatment targets from proteins related to epithelial–mesenchymal transition (EMT) and cell–cell adhesion is currently being conducted. EMT plays an important role in cancer metastasis and is initiated by the loss of cell–cell adhesion, such as tight junctions (TJs), adherens junctions, desmosomes, and gap junctions. Among these, claudins (CLDNs) are highly expressed in some cancers, including GC. Abnormal expression of CLDN1, CLDN2, CLDN3, CLDN4, CLDN6, CLDN7, CLDN10, CLDN11, CLDN14, CLDN17, CLDN18, and CLDN23 have been reported. Among these, CLDN18 is of particular interest. In The Cancer Genome Atlas, GC was classified into four new molecular subtypes, and CLDN18–ARHGAP fusion was observed in the genomically stable type. An anti-CLDN18.2 antibody drug was recently developed as a therapeutic drug for GC, and the results of clinical trials are highly predictable. Thus, CLDNs are highly expressed in GC as TJs and are expected targets for new antibody drugs. Herein, we review the literature on CLDNs, focusing on CLDN18 in GC.
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40
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Kyuno D, Takasawa A, Takasawa K, Ono Y, Aoyama T, Magara K, Nakamori Y, Takemasa I, Osanai M. Claudin-18.2 as a therapeutic target in cancers: cumulative findings from basic research and clinical trials. Tissue Barriers 2022; 10:1967080. [PMID: 34486479 PMCID: PMC8794250 DOI: 10.1080/21688370.2021.1967080] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 08/06/2021] [Accepted: 08/07/2021] [Indexed: 12/25/2022] Open
Abstract
Claudins are major components of tight junctions that maintain cell polarity and intercellular adhesion. The dynamics of claudins in cancer cells have attracted attention as a therapeutic target. During carcinogenesis, claudin expression is generally downregulated; however, overexpression of claudin-18.2 has been observed in several types of cancers. Upregulated and mislocalized claudin-18.2 expression in cancer cells has been suggested as a therapeutic target. Research on claudin-18.2 has revealed its involvement in carcinogenesis. Clinical trials using zolbetuximab, a monoclonal antibody targeting claudin-18.2, for patients with advanced cancer yielded positive results with few high-grade adverse events; thus, it is expected to be a novel and effective therapeutic. Here, we review current insights into the role that claudin-18.2 plays in basic cancer research and clinical applications. A better understanding of these roles will facilitate the development of new treatment strategies for cancer patients with poor prognoses.
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Affiliation(s)
- Daisuke Kyuno
- Department of Pathology, Sapporo Medical University, Sapporo, Japan
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, Sapporo, Japan
| | - Akira Takasawa
- Department of Pathology, Sapporo Medical University, Sapporo, Japan
| | - Kumi Takasawa
- Department of Pathology, Sapporo Medical University, Sapporo, Japan
| | - Yusuke Ono
- Department of Pathology, Sapporo Medical University, Sapporo, Japan
| | - Tomoyuki Aoyama
- Department of Pathology, Sapporo Medical University, Sapporo, Japan
| | - Kazufumi Magara
- Department of Pathology, Sapporo Medical University, Sapporo, Japan
| | - Yuna Nakamori
- Department of Pathology, Sapporo Medical University, Sapporo, Japan
| | - Ichiro Takemasa
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, Sapporo, Japan
| | - Makoto Osanai
- Department of Pathology, Sapporo Medical University, Sapporo, Japan
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The role of GTPase-activating protein ARHGAP26 in human cancers. Mol Cell Biochem 2021; 477:319-326. [PMID: 34716859 PMCID: PMC8755663 DOI: 10.1007/s11010-021-04274-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Accepted: 10/07/2021] [Indexed: 12/11/2022]
Abstract
Rho GTPases are molecular switches that play an important role in regulating the behavior of a variety of tumor cells. RhoA GTPase-activating protein 26 (ARHGAP26) is a GTPase-activating protein and inhibits the activity of Rho GTPases by promoting the hydrolytic ability of Rho GTPases. It also affects tumorigenesis and progression of various tumors through several methods, including formation of abnormal fusion genes and circular RNA. This review summarizes the biological functions and molecular mechanisms of ARHGAP26 in different tumors, proposes the potential clinical value of ARHGAP26 in cancer treatment, and discusses current issues that need to be addressed.
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42
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Biomarker-targeted therapies for advanced-stage gastric and gastro-oesophageal junction cancers: an emerging paradigm. Nat Rev Clin Oncol 2021; 18:473-487. [PMID: 33790428 DOI: 10.1038/s41571-021-00492-2] [Citation(s) in RCA: 169] [Impact Index Per Article: 42.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/22/2021] [Indexed: 02/02/2023]
Abstract
Advances in cancer biology and sequencing technology have enabled the selection of targeted and more effective treatments for individual patients with various types of solid tumour. However, only three molecular biomarkers have thus far been demonstrated to predict a response to targeted therapies in patients with gastric and/or gastro-oesophageal junction (G/GEJ) cancers: HER2 positivity for trastuzumab and trastuzumab deruxtecan, and microsatellite instability (MSI) status and PD-L1 expression for pembrolizumab. Despite this lack of clinically relevant biomarkers, distinct molecular subtypes of G/GEJ cancers have been identified and have informed the development of novel agents, including receptor tyrosine kinase inhibitors and monoclonal antibodies, several of which are currently being tested in ongoing trials. Many of these trials include biomarker stratification, and some include analysis of circulating tumour DNA (ctDNA), which both enables the noninvasive assessment of biomarker expression and provides an indication of the contributions of intratumoural heterogeneity to response and resistance. The results of these studies might help to optimize the selection of patients to receive targeted therapies, thus facilitating precision medicine approaches for patients with G/GEJ cancers. In this Review, we describe the current evidence supporting the use of targeted therapies in patients with G/GEJ cancers and provide guidance on future research directions.
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Choudhary A, Madbhagat P, Sreepadmanabh M, Bhardwaj V, Chande A. Circular RNA as an Additional Player in the Conflicts Between the Host and the Virus. Front Immunol 2021; 12:602006. [PMID: 34122399 PMCID: PMC8194355 DOI: 10.3389/fimmu.2021.602006] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 05/04/2021] [Indexed: 11/22/2022] Open
Abstract
Circular RNA (circRNA), a relatively new member of the non-coding RNA family, has spurred great interest among researchers following its discovery as a ubiquitous class within the RNA world. Rapid progress in circRNA biology has coincided with its identification in a plethora of diverse roles including regulation of gene expression and probable coding potential, as well as competing interactions with proteins and microRNAs in various pathological conditions. Emerging evidence suggests that circRNAs also function in viral infections. The deregulation of circRNAs during viral infection has prompted investigations into the possibilities of circRNA as a competing endogenous RNA (ceRNA) that modulates response to infection. Recently, viruses have been shown to encode circRNAs with proviral functions, providing a strong impetus for focused efforts to elucidate the networks coaxed by circRNAs during infection. This review elaborates on recent insights gained on the roles of circRNAs during virus infection and immunity.
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Affiliation(s)
- Aditi Choudhary
- Molecular Virology Laboratory, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Bhopal, Bhopal, India
| | - Pratibha Madbhagat
- Molecular Virology Laboratory, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Bhopal, Bhopal, India
| | - M Sreepadmanabh
- Molecular Virology Laboratory, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Bhopal, Bhopal, India
| | - Vipin Bhardwaj
- Molecular Virology Laboratory, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Bhopal, Bhopal, India
| | - Ajit Chande
- Molecular Virology Laboratory, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Bhopal, Bhopal, India
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44
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Díaz Del Arco C, Estrada Muñoz L, Ortega Medina L, Fernández Aceñero MJ. [Update on gastric cancer. New molecular classifications]. REVISTA ESPANOLA DE PATOLOGIA : PUBLICACION OFICIAL DE LA SOCIEDAD ESPANOLA DE ANATOMIA PATOLOGICA Y DE LA SOCIEDAD ESPANOLA DE CITOLOGIA 2021; 54:102-113. [PMID: 33726886 DOI: 10.1016/j.patol.2020.06.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 05/17/2020] [Accepted: 06/01/2020] [Indexed: 06/12/2023]
Abstract
Gastric cancer (GC) is an aggressive tumor, which is usually diagnosed at an advanced stage and shows high mortality rates. Several GC classifications have been published, based on features such as tumor location, endoscopic features or microscopic architecture. However, TNM stage remains the mainstay of GC management and treatment. In the last years, technical advances have allowed us to investigate the biological heterogeneity of GC and develop new molecular classifications. This knowledge may enhance current classifications, and has the potential to refine GC management and aid in the identification of new molecular targets. In this literature review we have summarized the main findings in epidemiology, screening, classification systems and treatment of GC, focusing on the molecular alterations and new molecular classifications published in the last years.
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Affiliation(s)
- Cristina Díaz Del Arco
- Universidad Complutense de Madrid, España; Anatomía Patológica, Hospital Clínico San Carlos, Madrid, España.
| | | | - Luis Ortega Medina
- Universidad Complutense de Madrid, España; Anatomía Patológica, Hospital Clínico San Carlos, Madrid, España
| | - Ma Jesús Fernández Aceñero
- Universidad Complutense de Madrid, España; Anatomía Patológica, Hospital General Universitario Gregorio Marañón, Madrid, España
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45
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Du Z, Zhang X, Gao W, Yang J. Differentially expressed genes PCCA, ECHS1, and HADH are potential prognostic biomarkers for gastric cancer. Sci Prog 2021; 104:368504211011344. [PMID: 33881965 PMCID: PMC10358502 DOI: 10.1177/00368504211011344] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Gastric cancer (GC) is one of the most common malignant tumors in the world. As far as we know, no biomarker has been widely accepted for early diagnosis and prognosis prediction of GC. The purpose of this study is to find potential biomarkers to predict the prognosis of GC. The differentially expressed gene (DEG) was analyzed from GSE93774. Enrichr was used to analyze the gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, the enrichment of transcription factors (TF), miRNA, and kinase. GO analysis showed DEGs was enriched in the process of amino acid metabolism. Pathway results showed DEGs was mainly enriched in cell cycle. Propionyl CoA carboxylase alpha (PCCA), Enoyl coenzyme A hydratase short chain 1 (ECHS1), and 3-hydroxyacyl-CoA dehydrogenase (HADH) have prognostic value in patients with GC. ECHS1 and HADH genes were significantly associated with disease-free survival. There was a significant correlation between PCCA and overall survival rate. The results of this study suggest that PCCA, ECHS1, and HADH may be new biomarkers for predicting the prognosis of GC.
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Affiliation(s)
- Zhongxiang Du
- Clinical Laboratory, Danyang People’s Hospital of Jiangsu Province, Danyang, Jiangsu, China
| | - Xiajun Zhang
- Clinical Laboratory, Danyang People’s Hospital of Jiangsu Province, Danyang, Jiangsu, China
| | - Weiya Gao
- Clinical Laboratory, Danyang People’s Hospital of Jiangsu Province, Danyang, Jiangsu, China
| | - Jie Yang
- Clinical Laboratory, Danyang People’s Hospital of Jiangsu Province, Danyang, Jiangsu, China
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46
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Mo Y, Liu Y, Lu A, Zhang H, Tang L. Role of circRNAs in viral infection and their significance for diagnosis and treatment (Review). Int J Mol Med 2021; 47:88. [PMID: 33786618 PMCID: PMC8018182 DOI: 10.3892/ijmm.2021.4921] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 03/08/2021] [Indexed: 12/14/2022] Open
Abstract
Circular RNAs (circRNAs) are a class of non-coding RNAs with a circular, covalent structure that lack both 5' ends and 3' poly(A) tails, which are stable and specific molecules that exist in eukaryotic cells and are highly conserved. The role of circRNAs in viral infections is being increasingly acknowledged, since circRNAs have been discovered to be involved in several viral infections (such as hepatitis B virus infection and human papilloma virus infection) through a range of circRNA/microRNA/mRNA regulatory axes. These findings have prompted investigations into the potential of circRNAs as targets for the diagnosis and treatment of viral infection-related diseases. The aim of the present review was to systematically examine and discuss the role of circRNAs in several common viral infections, as well as their potential as diagnostic markers and therapeutic targets.
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Affiliation(s)
- Yuyao Mo
- School of Life Science, Central South University, Changsha, Hunan 410013, P.R. China
| | - Yuze Liu
- School of Life Science, Central South University, Changsha, Hunan 410013, P.R. China
| | - Anni Lu
- School of Life Science, Central South University, Changsha, Hunan 410013, P.R. China
| | - Hanyi Zhang
- School of Life Science, Central South University, Changsha, Hunan 410013, P.R. China
| | - Lijun Tang
- School of Life Science, Central South University, Changsha, Hunan 410013, P.R. China
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47
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Link A, Bornschein J, Thon C. Helicobacter pylori induced gastric carcinogenesis - The best molecular model we have? Best Pract Res Clin Gastroenterol 2021; 50-51:101743. [PMID: 33975683 DOI: 10.1016/j.bpg.2021.101743] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/19/2021] [Accepted: 03/25/2021] [Indexed: 01/31/2023]
Abstract
Gastric carcinogenesis can be described as a consequence of multilevel molecular alterations that is triggered by a cascade of events. Historically, diet and environmental factors have been identified to substantially contribute to carcinogenesis before the discovery of Helicobacter pylori (H. pylori). But H. pylori infection has revolutionized the understanding of gastric carcinogenesis. Although the model of H. pylori-driven carcinogenesis remains valid, there is a continuous effort to precisely delineate the molecular pathways involved and to understand the interplay with additional risk factors including recent relevant knowledge on the stomach microbiota. In this review, we provide an updated view on the models of gastric carcinogenesis. This includes historically appreciated H. pylori-induced models and expands these taking recent molecular data into consideration. Based on the data provided, we conclude that indeed H. pylori-carcinogenesis remains one of the best-established models at least for a subset of gastric cancers. Implementation of the recently identified molecular subtypes in novel genetic animal models is required to expand our knowledge on H. pylori-independent carcinogenesis.
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Affiliation(s)
- Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Section of Molecular Gastroenterology and Microbiota-associated Diseases, Otto-von-Guericke University, Magdeburg, Germany.
| | - Jan Bornschein
- Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford University Hospitals, Headington, Oxford, UK
| | - Cosima Thon
- Department of Gastroenterology, Hepatology and Infectious Diseases, Section of Molecular Gastroenterology and Microbiota-associated Diseases, Otto-von-Guericke University, Magdeburg, Germany
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48
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Kim SR, Shin K, Park JM, Lee HH, Song KY, Lee SH, Kim B, Kim SY, Seo J, Kim JO, Roh SY, Kim IH. Clinical Significance of CLDN18.2 Expression in Metastatic Diffuse-Type Gastric Cancer. J Gastric Cancer 2020; 20:408-420. [PMID: 33425442 PMCID: PMC7781747 DOI: 10.5230/jgc.2020.20.e33] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 11/29/2020] [Accepted: 11/30/2020] [Indexed: 12/14/2022] Open
Abstract
Purpose Isoform 2 of tight junction protein claudin-18 (CLDN18.2) is a potential target for gastric cancer treatment. A treatment targeting CLDN18.2 has shown promising results in gastric cancer. We investigated the clinical significance of CLDN18.2 and other cell-adherens junction molecules (Rho GTPase-activating protein [RhoGAP] and E-cadherin) in metastatic diffuse-type gastric cancer (mDGC). Materials and Methods We evaluated CLDN18.2, RhoGAP, and E-cadherin expression using two-plex immunofluorescence and quantitative data analysis of H-scores of 77 consecutive mDGC patients who received first-line platinum-based chemotherapy between March 2015 and February 2017. Results CLDN18.2 and E-cadherin expression was significantly lower in patients with peritoneal metastasis (PM) than those without PM at the time of diagnosis (P=0.010 and 0.013, respectively), whereas it was significantly higher in patients who never developed PM from diagnosis to death than in those who did (P=0.001 and 0.003, respectively). Meanwhile, CLDN18.2 and E-cadherin expression levels were significantly higher in patients with bone metastasis than in those without bone metastasis (P=0.010 and 0.001, respectively). Moreover, we identified a positive correlation between the expression of CLDN18.2 and E-cadherin (P<0.001), RhoGAP and CLDN18.2 (P=0.004), and RhoGAP and E-cadherin (P=0.001). Conversely, CLDN18.2, RhoGAP, and E-cadherin expression was not associated with chemotherapy response and survival. Conclusions CLDN18.2 expression was reduced in patients with PM but significantly intact in those with bone metastasis. Furthermore, CLDN18.2 expression was positively correlated with other adherens junction molecules, which is clinically associated with mDGC and PM pathogenesis.
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Affiliation(s)
- Seo Ree Kim
- Division of Medical Oncology, Department of Internal Medicine, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Kabsoo Shin
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.,Department of Gastric Cancer Centre, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jae Myung Park
- Department of Gastric Cancer Centre, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.,Division of Gastroenterology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Han Hong Lee
- Department of Gastric Cancer Centre, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.,Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea,
| | - Kyo Yong Song
- Department of Gastric Cancer Centre, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.,Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea,
| | - Sung Hak Lee
- Department of Gastric Cancer Centre, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.,Department of Clinical Pathology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Bohyun Kim
- Department of Gastric Cancer Centre, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.,Department of Radiology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sang-Yeob Kim
- Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.,Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Junyoung Seo
- Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.,Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jeong-Oh Kim
- Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sang-Young Roh
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.,Department of Gastric Cancer Centre, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.,Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - In-Ho Kim
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.,Department of Gastric Cancer Centre, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.,Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea
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49
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Role of tight junctions in the epithelial-to-mesenchymal transition of cancer cells. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2020; 1863:183503. [PMID: 33189716 DOI: 10.1016/j.bbamem.2020.183503] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 10/20/2020] [Accepted: 10/21/2020] [Indexed: 12/15/2022]
Abstract
The epithelial-mesenchymal transition (EMT) is an essential step in cancer progression. Epithelial cells possess several types of cell-cell junctions, and tight junctions are known to play important roles in maintaining the epithelial program. EMT is characterized by a loss of epithelial markers, including E-cadherin and tight junction proteins. Somewhat surprisingly, the evidence is accumulating that upregulated expression of tight junction proteins plays an important role in the EMT of cancer cells. Tight junctions have distinct tissue-specific and cancer-specific regulatory mechanisms, enabling them to play different roles in EMT. Tight junctions and related signaling pathways are attractive targets for cancer treatments; signal transduction inhibitors and monoclonal antibodies for tight junction proteins may be used to suppress EMT, invasion, and metastasis. Here we review the role of bicellular and tricellular tight junction proteins during EMT. Further investigation of regulatory mechanisms of tight junctions during EMT in cancer cells will inform the development of biomarkers for predicting prognosis as well as novel therapies.
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50
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Zhang WH, Zhang SY, Hou QQ, Qin Y, Chen XZ, Zhou ZG, Shu Y, Xu H, Hu JK. The Significance of the CLDN18-ARHGAP Fusion Gene in Gastric Cancer: A Systematic Review and Meta-Analysis. Front Oncol 2020; 10:1214. [PMID: 32983960 PMCID: PMC7492548 DOI: 10.3389/fonc.2020.01214] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 06/15/2020] [Indexed: 02/05/2023] Open
Abstract
Objective: The objective of this study was to summarize the clinicopathological characteristics of the CLDN18-ARHGAP fusion gene in gastric cancer patients. Background: The CLDN18-ARHGAP26 fusion gene is one of the most frequent somatic genomic rearrangements in gastric cancer, especially in the genomically stable (GS) subtype. However, the clinical and prognostic meaning of the CLDN18-ARHGAP fusion in gastric cancer patients is unclear. Methods: Studies that investigated CLDN18-ARHGAP fusion gastric cancer patients were identified systematically from the PubMed, Cochrane, and Embase databases through the 28th of February 2020. A systematic review and meta-analysis were performed to estimate the clinical significance of CLDN18-ARHGAP fusion in patients. Results: A total of five eligible studies covering 1908 patients were selected for inclusion in the meta-analysis based on specified inclusion and exclusion criteria. Several fusion patterns were observed linking CLDN18 and ARHGAP26 or ARHGAP6, with the most common type being CLDN18/exon5-ARHGAP26/exon12. The survival outcome meta-analysis of the CLDN18-ARHGAP fusion gene showed that it was associated with overall survival outcomes in gastric cancer (HR, 2.03, 95% CI 1.26-3.26, P < 0.01, random-effects). In addition, diffuse gastric cancer had a greater proportion of CLDN18-ARHGAP fusions than intestinal gastric cancer (13.3%, 151/1,138 vs. 1.8%, 8/442; p < 0.001). Moreover, gastric cancer patients with the CLDN18-ARHGAP fusion gene are more likely to be female or have a younger age, lymph node metastasis and advanced TNM stages. Conclusion: The CLDN18-ARHGAP fusion is one of the molecular characteristics of diffuse gastric cancer and is also an independent prognostic risk factor for gastric cancer. In addition, it is also related to multiple clinical characteristics, including age, sex, lymph node metastasis and tumor stage. However, the mechanism of the CLDN18-ARHGAP fusion gene and potential targeted therapeutic strategies need further exploration.
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Affiliation(s)
- Wei-Han Zhang
- State Key Laboratory of Biotherapy, Department of Gastrointestinal Surgery and Laboratory of Gastric Cancer, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Shou-Yue Zhang
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China
| | - Qian-Qian Hou
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China
| | - Yun Qin
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
| | - Xin-Zu Chen
- State Key Laboratory of Biotherapy, Department of Gastrointestinal Surgery and Laboratory of Gastric Cancer, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Zong-Guang Zhou
- State Key Laboratory of Biotherapy, West China Hospital, Department of Gastrointestinal Surgery and Laboratory of Digestive Surgery, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Yang Shu
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China
| | - Heng Xu
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China
| | - Jian-Kun Hu
- State Key Laboratory of Biotherapy, Department of Gastrointestinal Surgery and Laboratory of Gastric Cancer, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
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