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Chen Y, Chen Y, Sun Q, Hou X, Fu S, Jin H, Tao X, Yang Y, Wang J, Cao Y, An X, Zhang Y. Adenocarcinoma of the rete testis: clinicopathological study of 18 cases with emphasis on MET amplification and a review of the literature. Histopathology 2025; 86:762-771. [PMID: 39628356 DOI: 10.1111/his.15383] [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: 08/06/2024] [Revised: 10/21/2024] [Accepted: 11/16/2024] [Indexed: 03/14/2025]
Abstract
BACKGROUND Knowledge regarding adenocarcinoma of the rete testis (ACRT) is extremely limited due to its scarcity. METHODS AND RESULTS This study enrolled 18 patients with ACRT from multiple institutions. Clinicopathological and immunohistochemical features were investigated, together with a comprehensive review of 95 previously reported cases. One case was assessed using next-generation sequencing (NGS). The median age of the patient cohort was 54 years (range = 20-69 years), with the majority presenting with a testicular mass (13 of 18); predominantly right-sided (11 of 18). Six patients died within the second year following diagnosis. The morphology of ACRT spans a wide spectrum, including newly identified mucinous carcinoid-like features, with mucous cells floating in mucus and signet-ring cells. Notably, transition from a benign to a malignant rete epithelium was noted in 38.9% of cases (seven of 18). Immunohistochemically, tumour cells most frequently showed strong positivity for CK7 (12 of 16) and CK20 (10 of 17), with occasionally positivity for calretinin (three of 16), WT-1 (two of 17) and PAX-8 (two of 15). According to NGS in a single case, MET was amplified, leading to the patient benefiting from mesenchymal-epidermal transition factor (MET) inhibitors. Furthermore, MET amplification was assessed in 13 cases using fluorescence in-situ hybridisation and detected in two cases (15.4%). No significant correlation between MET amplification and mesenchymal-epidermal transition factor (MET) levels was observed in the cases studied. CONCLUSIONS Primary ACRT is a rare malignant tumour which poses a diagnostic challenge, and is associated with poor prognosis. Cases of ACRT with MET amplification might represent promising candidates for the treatment with MET inhibitors.
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Affiliation(s)
- Ya Chen
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Department of Pathology, The Eighth Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Yanjun Chen
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Qi Sun
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Xinghua Hou
- Department of Pathology, Anshan Central Hospital, Anshan, China
| | - Sha Fu
- Department of Cellular and Molecular Diagnostics Center, Sun Yat-Sen Memorial Hospital, Guangzhou, China
| | - Hongtao Jin
- Department of Pathology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China
| | - Xuan Tao
- Department of Pathology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Yuanzhong Yang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Jiayu Wang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yun Cao
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Xin An
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Department of Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yijun Zhang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China
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Cui X, Chang M, Wang Y, Liu J, Sun Z, Sun Q, Sun Y, Ren J, Li W. Helicobacter pylori reduces METTL14-mediated VAMP3 m 6A modification and promotes the development of gastric cancer by regulating LC3C-mediated c-Met recycling. Cell Death Discov 2025; 11:13. [PMID: 39827141 PMCID: PMC11742886 DOI: 10.1038/s41420-025-02289-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 12/12/2024] [Accepted: 01/07/2025] [Indexed: 01/22/2025] Open
Abstract
Helicobacter pylori (H. pylori) plays an important role in the malignant transformation of the gastric mucosa from chronic inflammation to cancer. However, the mechanisms underlying the epigenetic regulation of gastric carcinogenesis mediated by H. pylori remain unclear. Here, we uncover that H. pylori inhibits METTL14 by upregulating ATF3. METTL14 inhibits gastric cancer (GC) cell proliferation and metastasis in vitro and in vivo. Downregulation of METTL14 inhibits Vesicle-associated membrane protein-3 (VAMP3) by reducing the m6A modification level of VAMP3 mRNA and the stability of IGF2BP2-dependent mRNA. H. pylori also accelerates the malignant progression of GC by regulating VAMP3/LC3C-mediated c-Met recycling. Moreover, the expression of METTL14 and VAMP3 in Hp+ chronic gastritis tissues is much lower than that in Hp- chronic gastritis tissues. METTL14 and VAMP3 expression levels are downregulated notably in cancerous tissues of patients with GC. Therefore, our results show a novel METTL14-VAMP3-LC3C-c-Met signalling axis in the GC development mediated by H. pylori infection, which reveals a novel m6A epigenetic modification mechanism for GC and provides potential prognostic biomarkers for GC progression.
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Affiliation(s)
- Xixi Cui
- Key Laboratory for Experimental Teratology of Chinese Ministry of Education, The Shandong Provincial Key Laboratory of Infection and Immunology, Department of Pathogenic biology, School of basic medical sciences, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Mingjie Chang
- Key Laboratory for Experimental Teratology of Chinese Ministry of Education, The Shandong Provincial Key Laboratory of Infection and Immunology, Department of Pathogenic biology, School of basic medical sciences, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Yuqiong Wang
- Key Laboratory for Experimental Teratology of Chinese Ministry of Education, The Shandong Provincial Key Laboratory of Infection and Immunology, Department of Pathogenic biology, School of basic medical sciences, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Jiayi Liu
- Key Laboratory for Experimental Teratology of Chinese Ministry of Education, The Shandong Provincial Key Laboratory of Infection and Immunology, Department of Pathogenic biology, School of basic medical sciences, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Zenghui Sun
- Key Laboratory for Experimental Teratology of Chinese Ministry of Education, The Shandong Provincial Key Laboratory of Infection and Immunology, Department of Pathogenic biology, School of basic medical sciences, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Qiyu Sun
- Key Laboratory for Experimental Teratology of Chinese Ministry of Education, The Shandong Provincial Key Laboratory of Infection and Immunology, Department of Pathogenic biology, School of basic medical sciences, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Yundong Sun
- Key Laboratory for Experimental Teratology of Chinese Ministry of Education, The Shandong Provincial Key Laboratory of Infection and Immunology, Department of Pathogenic biology, School of basic medical sciences, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Juchao Ren
- Department of Urology, Qilu Hospital, Shandong University, Jinan, PR China
| | - Wenjuan Li
- Key Laboratory for Experimental Teratology of Chinese Ministry of Education, The Shandong Provincial Key Laboratory of Infection and Immunology, Department of Pathogenic biology, School of basic medical sciences, Cheeloo College of Medicine, Shandong University, Jinan, PR China.
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Kawakami H. New therapeutic target molecules for gastric and gastroesophageal junction cancer. Int J Clin Oncol 2024; 29:1228-1236. [PMID: 38630383 DOI: 10.1007/s10147-024-02521-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Accepted: 03/18/2024] [Indexed: 08/27/2024]
Abstract
Molecularly targeted therapy for receptor tyrosine kinases (RTKs) has faced limitations in gastric and gastroesophageal junction (G/GEJ) cancer except for HER2-targeted agents, possibly due to inappropriate assay selection that has hindered identification of sensitive patients, in addition to coexisting genetic abnormalities as well as intratumoral heterogeneity. Immunohistochemistry of RTKs has, thus, proved largely unsuccessful for patient selection, and detection of RTK gene amplification as a true oncogenic driver is problematic given the small numbers of affected individuals. FGFR2 amplification is associated with poor prognosis in G/GEJ cancer, and immunohistochemistry of the FGFR2b protein isoform has proved effective for the detection of such FGFR2-dependent tumors. Phase III and Ib/III trials of the FGFR2-targeted antibody bemarituzumab for G/GEJ cancer overexpressing FGFR2b are ongoing based on the promising result in a phase II trial, especially in cases with an FGFR2b positivity of ≥ 10%. Challenges to EGFR- and MET-targeted therapies are being tackled with antibody-drug conjugates (ADCs) and bispecific antibodies. CLDN18.2 is expressed in some G/GEJ tumors but lacks oncogenic driver potential, and the CLDN18.2-targeted antibody zolbetuximab prolonged the survival of CLDN18.2-positive G/GEJ cancer patients in phase III trials. Antibody-drug conjugates and ADCs that target CLDN18.2 are also being pursued for treatment of such patients. Similarly, targeting of nondriver molecules such as DKK1, TROP2, and CEACAM5 is under investigation in early-stage clinical trials. This shift in focus from target molecules with driver potential to markers for precise drug delivery should increase the number of possible targets in G/GEJ cancer.
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Affiliation(s)
- Hisato Kawakami
- Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-sayama, 589-8511, Japan.
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Wei WJ, Hong YL, Deng Y, Wang GL, Qiu JT, Pan F. Research progress on the development of hepatocyte growth factor/c-Met signaling pathway in gastric cancer: A review. World J Gastrointest Oncol 2024; 16:3397-3409. [PMID: 39171189 PMCID: PMC11334049 DOI: 10.4251/wjgo.v16.i8.3397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 05/31/2024] [Accepted: 06/21/2024] [Indexed: 08/07/2024] Open
Abstract
Hepatocyte growth factor (HGF) and its receptor, c-Met, play important roles in the occurrence, development, and treatment of gastric cancer (GC). This review explored the function of the HGF/c-Met signaling pathway in GC and its potential targeted therapeutic mechanisms. As one of the most common malignant tumors worldwide, GC has a complex pathogenesis and limited therapeutic options. Therefore, a thorough understanding of the molecular mechanism of GC is very important for the development of new therapeutic methods. The HGF/c-Met signaling pathway plays an important role in the proliferation, migration, and invasion of GC cells and has become a new therapeutic target. This review summarizes the current research progress on the role of HGF/c-Met in GC and discusses targeted therapeutic strategies targeting this signaling pathway, providing new ideas and directions for the treatment of GC.
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Affiliation(s)
- Wu-Jie Wei
- Department of Oncology, People's Hospital of Chongqing Hechuan, Chongqing 401520, China
| | - Ya-Li Hong
- Department of Cardiovascular, People's Hospital of Chongqing Hechuan, Chongqing 401520, China
| | - Yi Deng
- Intensive Care Unit, People's Hospital of Chongqing Hechuan, Chongqing 401520, China
| | - Guan-Liang Wang
- Department of Oncology, People's Hospital of Chongqing Hechuan, Chongqing 401520, China
| | - Jiang-Tao Qiu
- Department of Gastrointestinal Surgery, Beijing Tsinghua Changgung Hospital, Beijing 100084, China
| | - Fang Pan
- Department of Oncology, People's Hospital of Chongqing Hechuan, Chongqing 401520, China
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Xu Y, Jin H, Chen Y, Yang Z, Xu D, Zhang X, Yang J, Wang Y. Comprehensive analysis of the expression, prognostic, and immune infiltration for COL4s in stomach adenocarcinoma. BMC Med Genomics 2024; 17:168. [PMID: 38907304 PMCID: PMC11191235 DOI: 10.1186/s12920-024-01934-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 06/14/2024] [Indexed: 06/23/2024] Open
Abstract
BACKGROUND Collagen (COL) genes, play a key role in tumor invasion and metastasis, are involved in tumor extracellular matrix (ECM)-receptor interactions and focal adhesion pathways. However, studies focusing on the diagnostic value of the COL4 family in stomach adenocarcinoma (STAD) are currently lacking. METHODS The TCGA database was employed to retrieve the clinical features and RNA sequencing expression profiles of patients with STAD. We conducted an investigation to examine the expression disparities between STAD and adjacent normal tissues. Kaplan-Meier survival analysis was utilized to assess their prognostic significance, while Spearman correlation analysis was employed to determine their association with immune checkpoint genes and immunomodulatory molecules. Furthermore, GO and KEGG analyses were performed on the COL4s-related genes, revealing potential biological pathways through gene set enrichment analysis (GSEA). Subsequently, we explored the extent of immune infiltration of the COL4 family in STAD using the TIMER database. Lastly, the expression levels of the COL4 family in STAD were further validated through quantitative PCR (qPCR) and western blot techniques. RESULTS The expression levels of COL4A1/2 were significantly upregulated, while COL4A5/6 were conspicuously downregulated in STAD. The survival analysis revealed that the upregulated COL4s indicated poorer overall survival, first progression and post-progression survival outcomes. Additionally, our findings demonstrated a positive correlation between the expressions of COL4A1/2/3/4 and the infiltration of immune cells, including CD8 + T cells, dendritic cells, macrophages, neutrophils and CD4 + T cells. Further correlation analysis uncovered a favorable association between the expression of COL4A1/2/3/4 and various crucial immunomodulatory molecules, immunological checkpoint molecules, and chemokines. Quantitative PCR analysis confirmed that the expression patterns of COL4A1/3/4/6 genes aligned with the finding from the TCGA database. However, gastric cancer cells exhibited downregulation of COL4A2. Consistently, the protein level of COL4A1 was elevated, whereas the protein level of COL4A2 was reduced in the gastric cancer cell lines. CONCLUSION COL4s could potentially serve as biomarkers for diagnosing and predicting the prognosis of STAD.
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Affiliation(s)
- Ying Xu
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, China
- Hangzhou Institute of Digestive Diseases, Hangzhou, China
- Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China
| | - Hangbin Jin
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, China
- Hangzhou Institute of Digestive Diseases, Hangzhou, China
- Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China
- Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Yan Chen
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, China
- Hangzhou Institute of Digestive Diseases, Hangzhou, China
- Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China
| | - Zhen Yang
- School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Dongchao Xu
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, China
- Hangzhou Institute of Digestive Diseases, Hangzhou, China
- Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China
| | - Xiaofeng Zhang
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, China.
- Hangzhou Institute of Digestive Diseases, Hangzhou, China.
- Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China.
- Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou, Zhejiang, China.
| | - Jianfeng Yang
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, China.
- Hangzhou Institute of Digestive Diseases, Hangzhou, China.
- Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China.
- Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou, Zhejiang, China.
| | - Yu Wang
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, China.
- Hangzhou Institute of Digestive Diseases, Hangzhou, China.
- Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China.
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Wang LM, Zhang WW, Qiu YY, Wang F. Ferroptosis regulating lipid peroxidation metabolism in the occurrence and development of gastric cancer. World J Gastrointest Oncol 2024; 16:2781-2792. [PMID: 38994139 PMCID: PMC11236228 DOI: 10.4251/wjgo.v16.i6.2781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 03/06/2024] [Accepted: 04/10/2024] [Indexed: 06/13/2024] Open
Abstract
BACKGROUND Gastric cancer is one of the most common malignant tumors in the world, and its occurrence and development involve complex biological processes. Iron death, as a new cell death mode, has attracted wide attention in recent years. However, the regulatory mechanism of iron death in gastric cancer and its effect on lipid peroxidation metabolism remain unclear. AIM To explore the role of iron death in the development of gastric cancer, reveal its relationship with lipid peroxidation, and provide a new theoretical basis for revealing the molecular mechanism of the occurrence and development of gastric cancer. METHODS The process of iron death in gastric cancer cells was simulated by cell culture model, and the occurrence of iron death was detected by fluorescence microscopy and flow cytometry. The changes of gene expression related to iron death and lipid peroxidation metabolism were analyzed by high-throughput sequencing technology. In addition, a mouse model of gastric cancer was established, and the role of iron death in vivo was studied by histology and immunohistochemistry, and the level of lipid peroxidation was detected. These methods comprehensively and deeply reveal the regulatory mechanism of iron death on lipid peroxidation metabolism in the occurrence and development of gastric cancer. RESULTS Iron death was significantly activated in gastric cancer cells, and at the same time, associated lipid peroxidation levels increased significantly. Through high-throughput sequencing analysis, it was found that iron death regulated the expression of several genes related to lipid metabolism. In vivo experiments demonstrated that increased iron death in gastric cancer mice was accompanied by a significant increase in lipid peroxidation. CONCLUSION This study confirmed the important role of iron death in regulating lipid peroxidation metabolism in the occurrence and development of gastric cancer. The activation of iron death significantly increased lipid peroxidation levels, revealing its regulatory mechanism inside the cell.
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Affiliation(s)
- Lan-Mei Wang
- Department of Clinical Laboratory, Anqiu People's Hospital, Weifang 262123, Shandong Province, China
| | - Wei-Wei Zhang
- Department of Gastroenterology, Feicheng People's Hospital, Tai’an 271600, Shandong Province, China
| | - Ying-Yang Qiu
- Yong Loo Lin School of Medicine, National University of Singapore, 119077, Singapore
| | - Fang Wang
- Department of Gastroenterology, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, Shandong Province, China
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Piper AK, Penney C, Holliday J, Tincknell G, Ma Y, Napaki S, Pantel K, Brungs D, Ranson M. EGFR and PI3K Signalling Pathways as Promising Targets on Circulating Tumour Cells from Patients with Metastatic Gastric Adenocarcinoma. Int J Mol Sci 2024; 25:5565. [PMID: 38791602 PMCID: PMC11122469 DOI: 10.3390/ijms25105565] [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: 04/17/2024] [Revised: 05/12/2024] [Accepted: 05/16/2024] [Indexed: 05/26/2024] Open
Abstract
The prognosis for metastatic gastric adenocarcinoma (mGAC) remains poor. Gene alterations in receptor tyrosine kinases (RTKs) such as epidermal growth factor receptor (EGFR) and their downstream effectors including catalytic subunit alpha of the phosphatidylinositol 3-kinase (PIK3CA) are common in mGAC. Targeted RTK and phosphatidylinositol-3-kinase (PI3K) treatments have demonstrated clinical benefits in other solid tumours and are key potential targets for clinical development against mGAC given the presence of recurrent alterations in these pathways. Furthermore, combination RTK/PI3K treatments may overcome compensatory mechanisms that arise using monotherapies, leading to improved patient outcomes. Herein, we investigated RTK/PI3K single and combination drug responses against our unique human mGAC-derived PIK3CA gain-of-function mutant, human epidermal growth factor receptor 2 (HER2)-negative, EGFR-expressing circulating tumour cell line, UWG02CTC, under two- and three-dimensional culture conditions to model different stages of metastasis. UWG02CTCs were highly responsive to the PI3K p110α-subunit targeted drugs PIK-75 (IC50 = 37.0 ± 11.1 nM) or alpelisib (7.05 ± 3.7 µM). Drug sensitivities were significantly increased in 3D conditions. Compensatory MAPK/ERK pathway upregulation by PI3K/Akt suppression was overcome by combination treatment with the EGFR inhibitor gefitinib, which was strongly synergistic. PIK-75 plus gefitinib significantly impaired UWG02CTC invasion in an organotypic assay. In conclusion, UWG02CTCs are a powerful ex vivo mGAC drug responsiveness model revealing EGFR/PI3K-targeted drugs as a promising combination treatment option for HER2-negative, RAS wild-type mGAC patients.
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Affiliation(s)
- Ann-Katrin Piper
- School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia
- Molecular Horizons, University of Wollongong, Wollongong, NSW 2522, Australia
| | - Chelsea Penney
- School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia
- Molecular Horizons, University of Wollongong, Wollongong, NSW 2522, Australia
| | - Jacqueline Holliday
- School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia
- Molecular Horizons, University of Wollongong, Wollongong, NSW 2522, Australia
| | - Gary Tincknell
- School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia
- Molecular Horizons, University of Wollongong, Wollongong, NSW 2522, Australia
- Illawarra Cancer Care Centre, Wollongong Hospital, Wollongong, NSW 2500, Australia
| | - Yafeng Ma
- Centre for Circulating Tumour Cell Diagnostics & Research at the Ingham Institute for Applied Medical Research, South-Western Clinical School, University of New South Wales, Liverpool, NSW 2170, Australia
| | - Sarbar Napaki
- Graduate School of Medicine, University of Wollongong, Wollongong, NSW 2522, Australia
- Department of Pathology, Wollongong Hospital, Wollongong, NSW 2500, Australia
| | - Klaus Pantel
- Institute for Tumor Biology, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Daniel Brungs
- Molecular Horizons, University of Wollongong, Wollongong, NSW 2522, Australia
- Illawarra Cancer Care Centre, Wollongong Hospital, Wollongong, NSW 2500, Australia
- Graduate School of Medicine, University of Wollongong, Wollongong, NSW 2522, Australia
- Department of Pathology, Wollongong Hospital, Wollongong, NSW 2500, Australia
| | - Marie Ranson
- School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia
- Molecular Horizons, University of Wollongong, Wollongong, NSW 2522, Australia
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Hashimoto T, Nakamura Y, Mishima S, Nakayama I, Kotani D, Kawazoe A, Kuboki Y, Bando H, Kojima T, Iida N, Shibuki T, Imai M, Fujisawa T, Nagamine M, Sakamoto N, Kuwata T, Yoshino T, Shitara K. Whole-transcriptome sequencing in advanced gastric or gastroesophageal cancer: A deep dive into its clinical potential. Cancer Sci 2024; 115:1622-1633. [PMID: 38429886 DOI: 10.1111/cas.16109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 01/22/2024] [Accepted: 01/31/2024] [Indexed: 03/03/2024] Open
Abstract
Advanced gastric and gastroesophageal junction cancers (GC/GEJCs) harbor diverse molecular signatures, highlighting the need for intricate evaluations to identify potential therapeutic targets. Although whole-transcriptome sequencing (WTS) has emerged as a useful tool for understanding these molecular intricacies, its clinical implications have yet to be fully elucidated. This study evaluated the correlation between immunohistochemistry (IHC) and WTS, compared their clinical significance, and identified potential therapeutic targets undetectable through IHC alone. We enrolled 140 patients with advanced GC/GEJC and assessed them using IHC for six pivotal biomarkers: claudin-18 (CLDN18), human epidermal growth factor receptor 2 (HER2), multiple receptor tyrosine kinases (RTKs), and programmed death ligand 1 (PD-L1). Concurrently, WTS was employed as part of the analyses in MONSTAR-SCREEN-2, a multicenter multiomics study. IHC analysis revealed 16.4% HER2, 39.3% CLDN18 (2+/3 + ≥75%), and 15.8% PD-L1 (combined positive score ≥ 10) positivity, among other molecular markers. Significant correlations were observed between IHC and WTS for all six pivotal biomarkers. Among nineteen HER2 IHC-positive patients treated with anti-HER2 therapeutics, ERBB2 status in WTS was significantly associated with progression-free survival (ERBB2-high vs. -low: median 9.0 vs. 5.6 months, log-rank p = 0.046). IHC-based molecular profiling revealed significantly high expression of CLDN18 in RTK-negative patients, with 78.4% positive for either CLDN18 or PD-L1. Additionally, WTS revealed elevated expression of pivotal biomarkers in patients displaying negative targetable biomarkers via IHC. Our findings highlighted the significant correlation between IHC and WTS, reinforcing the clinical utility of WTS. A subset with IHC-negative but WTS-positive status may benefit from specific biomarker-targeted therapies.
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Affiliation(s)
- Tadayoshi Hashimoto
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
| | - Yoshiaki Nakamura
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
| | - Saori Mishima
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Izuma Nakayama
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Daisuke Kotani
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Akihito Kawazoe
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Yasutoshi Kuboki
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Hideaki Bando
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
| | - Takashi Kojima
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Naoko Iida
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
| | - Taro Shibuki
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Mitsuho Imai
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
| | - Takao Fujisawa
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
- Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Michiko Nagamine
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Japan
| | - Naoya Sakamoto
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Japan
- Division of Pathology, Exploratory Oncology Research and Clinical Research Center, Kashiwa, Japan
| | - Takeshi Kuwata
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Japan
- Department of Genetic Medicine and Services, National Cancer Center Hospital East, Kashiwa, Japan
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Kohei Shitara
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
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Wei H, Zhang Y, Jia Y, Chen X, Niu T, Chatterjee A, He P, Hou G. Heat shock protein 90: biological functions, diseases, and therapeutic targets. MedComm (Beijing) 2024; 5:e470. [PMID: 38283176 PMCID: PMC10811298 DOI: 10.1002/mco2.470] [Citation(s) in RCA: 20] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 12/30/2023] [Accepted: 01/04/2024] [Indexed: 01/30/2024] Open
Abstract
Heat shock protein 90 (Hsp90) is a predominant member among Heat shock proteins (HSPs), playing a central role in cellular protection and maintenance by aiding in the folding, stabilization, and modification of diverse protein substrates. It collaborates with various co-chaperones to manage ATPase-driven conformational changes in its dimer during client protein processing. Hsp90 is critical in cellular function, supporting the proper operation of numerous proteins, many of which are linked to diseases such as cancer, Alzheimer's, neurodegenerative conditions, and infectious diseases. Recognizing the significance of these client proteins across diverse diseases, there is a growing interest in targeting Hsp90 and its co-chaperones for potential therapeutic strategies. This review described biological background of HSPs and the structural characteristics of HSP90. Additionally, it discusses the regulatory role of heat shock factor-1 (HSF-1) in modulating HSP90 and sheds light on the dynamic chaperone cycle of HSP90. Furthermore, the review discusses the specific contributions of HSP90 in various disease contexts, especially in cancer. It also summarizes HSP90 inhibitors for cancer treatment, offering a thoughtful analysis of their strengths and limitations. These advancements in research expand our understanding of HSP90 and open up new avenues for considering HSP90 as a promising target for therapeutic intervention in a range of diseases.
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Affiliation(s)
- Huiyun Wei
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of EducationSchool of Pharmaceutical SciencesZhengzhou UniversityZhengzhouChina
| | - Yingying Zhang
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of EducationSchool of Pharmaceutical SciencesZhengzhou UniversityZhengzhouChina
| | - Yilin Jia
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of EducationSchool of Pharmaceutical SciencesZhengzhou UniversityZhengzhouChina
| | - Xunan Chen
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of EducationSchool of Pharmaceutical SciencesZhengzhou UniversityZhengzhouChina
| | - Tengda Niu
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of EducationSchool of Pharmaceutical SciencesZhengzhou UniversityZhengzhouChina
| | - Aniruddha Chatterjee
- Department of PathologyDunedin School of MedicineUniversity of OtagoDunedinNew Zealand
| | - Pengxing He
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of EducationSchool of Pharmaceutical SciencesZhengzhou UniversityZhengzhouChina
| | - Guiqin Hou
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of EducationSchool of Pharmaceutical SciencesZhengzhou UniversityZhengzhouChina
- Department of PathologyDunedin School of MedicineUniversity of OtagoDunedinNew Zealand
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Yu S, Chen C, Chen M, Liang J, Jiang K, Lou B, Lu J, Zhu X, Zhou D. MAGOH promotes gastric cancer progression via hnRNPA1 expression inhibition-mediated RONΔ160/PI3K/AKT signaling pathway activation. J Exp Clin Cancer Res 2024; 43:32. [PMID: 38268030 PMCID: PMC10809607 DOI: 10.1186/s13046-024-02946-8] [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: 10/05/2023] [Accepted: 01/05/2024] [Indexed: 01/26/2024] Open
Abstract
BACKGROUND Gastric cancer (GC) is associated with high mortality and heterogeneity and poses a great threat to humans. Gene therapies for the receptor tyrosine kinase RON and its spliceosomes are attracting increasing amounts of attention due to their unique characteristics. However, little is known about the mechanism involved in the formation of the RON mRNA alternative spliceosome RONΔ160. METHODS Fourteen human GC tissue samples and six normal gastric tissue samples were subjected to label-free relative quantitative proteomics analysis, and MAGOH was identified as a candidate protein for subsequent studies. The expression of MAGOH in clinical specimens was verified by quantitative real-time PCR and western blotting. We then determined the biological function of MAGOH in GC through in vitro and in vivo experiments. RNA pulldown, RNA sequencing and RNA immunoprecipitation (RIP) were subsequently conducted to uncover the underlying mechanism by which MAGOH regulated the formation of RONΔ160. RESULTS Proteomic analysis revealed that MAGOH, which is located at key nodes and participates in RNA processing and mRNA splicing, was upregulated in GC tissue and GC cell lines and was associated with poor prognosis. Functional analysis showed that MAGOH promoted the proliferation, migration and invasion of GC cells in vitro and in vivo. Mechanistically, MAGOH inhibited the expression of hnRNPA1 and reduced the binding of hnRNPA1 to RON mRNA, thereby promoting the formation of RONΔ160 to activate the PI3K/AKT signaling pathway and consequently facilitating GC progression. CONCLUSIONS Our study revealed that MAGOH could promote the formation of RONΔ160 and activate the PI3K/AKT signaling pathway through the inhibition of hnRNPA1 expression. We elucidate a novel mechanism and potential therapeutic targets for the growth and metastasis of GC based on the MAGOH-RONΔ160 axis, and these findings have important guiding significance and clinical value for the future development of effective therapeutic strategies for GC.
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Affiliation(s)
- Shanshan Yu
- Department of Surgical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Cheng Chen
- Department of Surgical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ming Chen
- Department of Surgical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jinxiao Liang
- Department of Surgical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Kecheng Jiang
- Department of Surgical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Bin Lou
- Department of Laboratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jun Lu
- Department of Surgical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaohua Zhu
- Department of Oncology, Shaoxing People's Hospital, Shaoxing, China
| | - Donghui Zhou
- Department of Surgical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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De Marco K, Lepore Signorile M, Di Nicola E, Sanese P, Fasano C, Forte G, Disciglio V, Pantaleo A, Varchi G, Del Rio A, Grossi V, Simone C. SMYD3 Modulates the HGF/MET Signaling Pathway in Gastric Cancer. Cells 2023; 12:2481. [PMID: 37887325 PMCID: PMC10605494 DOI: 10.3390/cells12202481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 10/11/2023] [Accepted: 10/13/2023] [Indexed: 10/28/2023] Open
Abstract
Gastric cancer (GC) is the third most deadly cancer worldwide. Considerable efforts have been made to find targetable drivers in order to improve patient outcomes. MET is one of the most important factors involved in GC initiation and progression as it plays a major role in GC invasiveness and is related to cancer stemness. Unfortunately, treatment strategies targeting MET are still limited, with a proportion of patients responding to therapy but later developing resistance. Here, we showed that MET is a molecular partner of the SMYD3 methyltransferase in GC cells. Moreover, we found that SMYD3 pharmacological inhibition affects the HGF/MET downstream signaling pathway. Extensive cellular analyses in GC models indicated that EM127, a novel active site-selective covalent SMYD3 inhibitor, can be used as part of a synergistic approach with MET inhibitors in order to enhance the targeting of the HGF/MET pathway. Importantly, our data were confirmed in a 3D GC cell culture system, which was used as a surrogate to evaluate stemness characteristics. Our findings identify SMYD3 as a promising therapeutic target to impair the HGF/MET pathway for the treatment of GC.
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Affiliation(s)
- Katia De Marco
- Medical Genetics, National Institute for Gastroenterology—IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (K.D.M.); (M.L.S.); (E.D.N.); (P.S.); (C.F.); (G.F.); (V.D.); (A.P.)
| | - Martina Lepore Signorile
- Medical Genetics, National Institute for Gastroenterology—IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (K.D.M.); (M.L.S.); (E.D.N.); (P.S.); (C.F.); (G.F.); (V.D.); (A.P.)
| | - Elisabetta Di Nicola
- Medical Genetics, National Institute for Gastroenterology—IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (K.D.M.); (M.L.S.); (E.D.N.); (P.S.); (C.F.); (G.F.); (V.D.); (A.P.)
| | - Paola Sanese
- Medical Genetics, National Institute for Gastroenterology—IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (K.D.M.); (M.L.S.); (E.D.N.); (P.S.); (C.F.); (G.F.); (V.D.); (A.P.)
| | - Candida Fasano
- Medical Genetics, National Institute for Gastroenterology—IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (K.D.M.); (M.L.S.); (E.D.N.); (P.S.); (C.F.); (G.F.); (V.D.); (A.P.)
| | - Giovanna Forte
- Medical Genetics, National Institute for Gastroenterology—IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (K.D.M.); (M.L.S.); (E.D.N.); (P.S.); (C.F.); (G.F.); (V.D.); (A.P.)
| | - Vittoria Disciglio
- Medical Genetics, National Institute for Gastroenterology—IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (K.D.M.); (M.L.S.); (E.D.N.); (P.S.); (C.F.); (G.F.); (V.D.); (A.P.)
| | - Antonino Pantaleo
- Medical Genetics, National Institute for Gastroenterology—IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (K.D.M.); (M.L.S.); (E.D.N.); (P.S.); (C.F.); (G.F.); (V.D.); (A.P.)
| | - Greta Varchi
- Institute for Organic Synthesis and Photoreactivity (ISOF), National Research Council of Italy (CNR), 40129 Bologna, Italy; (G.V.); (A.D.R.)
| | - Alberto Del Rio
- Institute for Organic Synthesis and Photoreactivity (ISOF), National Research Council of Italy (CNR), 40129 Bologna, Italy; (G.V.); (A.D.R.)
- Innovamol Consulting Srl, 41126 Modena, Italy
| | - Valentina Grossi
- Medical Genetics, National Institute for Gastroenterology—IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (K.D.M.); (M.L.S.); (E.D.N.); (P.S.); (C.F.); (G.F.); (V.D.); (A.P.)
| | - Cristiano Simone
- Medical Genetics, National Institute for Gastroenterology—IRCCS “Saverio de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (K.D.M.); (M.L.S.); (E.D.N.); (P.S.); (C.F.); (G.F.); (V.D.); (A.P.)
- Medical Genetics, Department of Precision and Regenerative Medicine and Jonic Area (DiMePRe-J), University of Bari Aldo Moro, 70124 Bari, Italy
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Kumaki Y, Oda G, Ikeda S. Targeting MET Amplification: Opportunities and Obstacles in Therapeutic Approaches. Cancers (Basel) 2023; 15:4552. [PMID: 37760522 PMCID: PMC10526812 DOI: 10.3390/cancers15184552] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 09/01/2023] [Accepted: 09/11/2023] [Indexed: 09/29/2023] Open
Abstract
The MET gene plays a vital role in cellular proliferation, earning it recognition as a principal oncogene. Therapies that target MET amplification have demonstrated promising results both in preclinical models and in specific clinical cases. A significant obstacle to these therapies is the ability to distinguish between focal amplification and polysomy, a task for which simple MET copy number measurement proves insufficient. To effectively differentiate between the two, it is crucial to utilize comparative measures, including in situ hybridization (ISH) with the centromere or next generation sequencing (NGS) with adjacent genes. Despite the promising potential of MET amplification treatment, the judicious selection of patients is paramount to maximize therapeutic efficacy. The effectiveness of MET inhibitors can fluctuate depending on the extent of MET amplification. Future research must seek to establish the ideal threshold value for MET amplification, identify the most efficacious combination therapies, and innovate new targeted treatments for patients exhibiting MET amplification.
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Affiliation(s)
- Yuichi Kumaki
- Department of Specialized Surgery, Tokyo Medical and Dental University, Tokyo 113-8519, Japan;
| | - Goshi Oda
- Department of Specialized Surgery, Tokyo Medical and Dental University, Tokyo 113-8519, Japan;
| | - Sadakatsu Ikeda
- Center for Innovative Cancer Treatment, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
- Moores Cancer Center, University of California San Diego, La Jolla, CA 92037, USA
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13
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Ding Y, Wang Z, Chen C, Wang C, Li D, Qin Y. The gene regulatory molecule GLIS3 in gastric cancer as a prognostic marker and be involved in the immune infiltration mechanism. Front Oncol 2023; 13:1091733. [PMID: 36923439 PMCID: PMC10009178 DOI: 10.3389/fonc.2023.1091733] [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: 12/01/2022] [Accepted: 02/14/2023] [Indexed: 03/02/2023] Open
Abstract
Background Gastric cancer is the most prevalent solid tumor form. Even after standard treatment, recurrence and malignant progression are nearly unavoidable in some cases of stomach cancer. GLIS Family Zinc Finger 3 (GLIS3) has received scant attention in gastric cancer research. Therefore, we sought to examine the prognostic significance of GLIS3 and its association with immune infiltration in gastric cancer. Method Using public data from The Cancer Genome Atlas (TCGA), we investigated whether GLIS3 gene expression was linked with prognosis in patients with stomach cancer (STAD). The following analyses were performed: functional enrichment analysis (GSEA), quantitative real-time PCR, immune infiltration analysis, immunological checkpoint analysis, and clinicopathological analysis. We performed functional validation of GLIS3 in vitro by plate cloning and CCK8 assay. Using univariate and multivariate Cox regression analyses, independent prognostic variables were identified. Additionally, a nomogram model was built. The link between OS and subgroup with GLIS3 expression was estimated using Kaplan-Meier survival analysis. Gene set enrichment analysis utilized the TCGA dataset. Result GLIS3 was significantly upregulated in STAD. An examination of functional enrichment revealed that GLIS3 is related to immunological responses. The majority of immune cells and immunological checkpoints had a positive correlation with GLIS3 expression. According to a Kaplan-Meier analysis, greater GLIS3 expression was related to adverse outcomes in STAD. GLIS3 was an independent predictive factor in STAD patients, as determined by Cox regression (HR = 1.478, 95%CI = 1.478 (1.062-2.055), P=0.02). Conclusion GLIS3 is considered a novel STAD patient predictive biomarker. In addition, our research identifies possible genetic regulatory loci in the therapy of STAD.
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Affiliation(s)
- Yi Ding
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zehua Wang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chen Chen
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chenxu Wang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Dongyu Li
- School of Pharmacy, Macau University of Science and Technology, Macao, Macao SAR, China
| | - Yanru Qin
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Harrold E, Corrigan L, Barry S, Lowery M. Targeting MET amplification in Gastro-oesophageal (GO) malignancies and overcoming MET inhibitor resistance: challenges and opportunities. Expert Rev Gastroenterol Hepatol 2022; 16:601-624. [PMID: 35757852 DOI: 10.1080/17474124.2022.2093185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION MET, the hepatocyte growth factor receptor is amplified in 8% of gastroesophageal (GO) malignancies and associated with poor prognosis. Therapeutic targeting of MET amplification and MET mutations has the potential to improve outcomes for patients with GO cancers (GOC). AREAS COVERED The efficacy of MET inhibition (METi) in preclinical studies has yet to translate into meaningful improvements in the treatment paradigm for unselected GOC. MET amplification has been proposed as a superior modality for patient selection; however even if confirmed, frequency and duration of response to METi are limited by rapid activation of primary and secondary resistance pathways. These observations illustrate the challenges inherent in the application of precision oncology predicated on the theory of oncogenic addiction. EXPERT OPINION A standardized definition of MET positivity is critical to enhance patient selection. Early successes targeting the METex14 skipping mutation demonstrate the potent therapeutic effects of METi in a clearly molecularly defined cohort. There is robust preclinical rationale and early-phase data supporting exploitation of immune system interaction with MET. Pragmatic investigation of rational therapeutic combinations based on molecular profiling of both primary and metastatic disease sites with sequential circulating tumor DNA analysis can inform successful clinical development of METi agents in GOC.
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Affiliation(s)
- Emily Harrold
- Medical Oncology Department, Mater Private Hospital Dublin, Leinster, Ireland.,Trinity St James Cancer Institute, Trinity College Dublin, Leinster, Ireland
| | - Lynda Corrigan
- Trinity St James Cancer Institute, Trinity College Dublin, Leinster, Ireland.,Medical Oncology Department, Tallaght/AMNCH Hospital Dublin, Leinster, Ireland
| | - Simon Barry
- Medical Oncology Department, St James University Hospital Dublin, Leinster, Ireland
| | - Maeve Lowery
- Trinity St James Cancer Institute, Trinity College Dublin, Leinster, Ireland.,Medical Oncology Department, St James University Hospital Dublin, Leinster, Ireland
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15
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Xu Y, Lu J, Tang Y, Xie W, Zhang H, Wang B, Zhang S, Hou W, Zou C, Jiang P, Zhang W. RETRACTED: PINK1 deficiency in gastric cancer compromises mitophagy, promotes the Warburg effect, and facilitates M2 polarization of macrophages. Cancer Lett 2022; 529:19-36. [PMID: 34979165 DOI: 10.1016/j.canlet.2021.12.032] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 12/25/2021] [Accepted: 12/28/2021] [Indexed: 12/16/2022]
Abstract
This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief and authors. Following the publication of the above article, the Editor was notified by a concerned reader that the authors supplied duplicated images. Specifically, that in Fig. 5A, both FACS panels are identical and in Fig. 5E, two different proteins (HK2 and PDK1) have the same western blot. After checking the data in relation with Fig. 5A and Fig. 5E, the authors have confirmed that the two pictures indeed have the problems of duplication. The authors reported that this problem came from the authors’ unintentional behavior, which may be due to a copy and paste error in the manner of image processing. The authors sincerely apologize for the inconvenience caused to our Editors and readers. Due to this duplication error, the authors and Editor have made the decision to retract this paper.
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Affiliation(s)
- Ying Xu
- Department of Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Jiawei Lu
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Yinbing Tang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Wenjie Xie
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Heteng Zhang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Beibei Wang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Shouliang Zhang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Wenji Hou
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Chen Zou
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Pengcheng Jiang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China.
| | - Wenbo Zhang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China.
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Dong Y, Xu J, Sun B, Wang J, Wang Z. MET-Targeted Therapies and Clinical Outcomes: A Systematic Literature Review. Mol Diagn Ther 2022; 26:203-227. [PMID: 35266116 PMCID: PMC8942886 DOI: 10.1007/s40291-021-00568-w] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/21/2021] [Indexed: 12/17/2022]
Abstract
Introduction Numerous therapeutic agents specifically targeting the mesenchymal-epithelial transition (MET) oncogene are being developed. Objective The aim of the current review was to systematically identify and analyze clinical trials that have evaluated MET inhibitors in various cancer types and to provide an overview of their clinical outcomes. Methods An electronic literature search was carried out in the PubMed and Embase databases to identify published clinical trials related to MET inhibitors. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement was followed for the systematic appraisal of the literature. Data related to clinical outcomes, including progression-free survival, overall survival, objective response rate, and overall tumor response, were extracted. Results In total, 49 publications were included. Among these, 51.02% were phase II studies, 14.28% were randomized controlled trials, three were phase III studies, two were prospective observational studies, and the remainder were either phase I or Ib studies. The majority (44.89%) of articles reported the clinical outcomes of MET inhibitors, including small molecules, monoclonal antibodies, and other agents, in patients with non-small-cell lung cancer (NSCLC) harboring MET alterations. MET amplification, overexpression, and MET exon 14 skipping mutations were the major MET alteration types reported across the included studies. Clinical responses/outcomes varied considerably. Conclusion This systematic literature review provides an overview of the literature available in Embase and PubMed regarding MET-targeted therapies. MET-selective tyrosine kinase inhibitors (TKIs) (capmatinib, tepotinib, and savolitinib) may become a new standard of care in NSCLC, specifically with MET exon 14 skipping mutations. A combination of MET TKIs with epidermal growth factor receptor (EGFR) TKIs (osimertinib + savolitinib, tepotinib + gefitinib) may be a potential solution for MET-driven EGFR TKI resistance. Further, MET alteration (MET amplification/overexpression) may be an actionable target in gastric cancer and papillary renal cell carcinoma.
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Affiliation(s)
- Yiting Dong
- State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Pan-jia-yuan South Lane, Chaoyang District, Beijing, 100021, China
| | - Jiachen Xu
- State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Pan-jia-yuan South Lane, Chaoyang District, Beijing, 100021, China
| | - Boyang Sun
- State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Pan-jia-yuan South Lane, Chaoyang District, Beijing, 100021, China
| | - Jie Wang
- State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Pan-jia-yuan South Lane, Chaoyang District, Beijing, 100021, China.
| | - Zhijie Wang
- State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Pan-jia-yuan South Lane, Chaoyang District, Beijing, 100021, China.
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Pereira MA, Ramos MFKP, Dias AR, Cardili L, Ribeiro RRE, de Castria TB, Zilberstein B, Nahas SC, Ribeiro U, de Mello ES. RhoA, Claudin 18, and c-MET in Gastric Cancer: Clinicopathological Characteristics and Prognostic Significance in Curative Resected Patients. Med Sci (Basel) 2021; 10:4. [PMID: 35076580 PMCID: PMC8788521 DOI: 10.3390/medsci10010004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 12/23/2021] [Accepted: 12/27/2021] [Indexed: 12/26/2022] Open
Abstract
Background: Recently, markers related to molecular classification were suggested as promising therapeutic targets for treatment and prediction of prognosis in gastric cancer (GC), including c-MET, RhoA, and Claudin-18 (CLDN18). This study aimed to investigate their expression in GC and its correlation with clinicopathological characteristics and survival. Methods: We retrospectively evaluated GC patients who underwent curative gastrectomy. c-MET, RhoA, and CLDN18 were analyzed through immunohistochemistry (IHC), and groups for analysis were determined according to the median values obtained for each marker. Results: Among the 349 GC evaluated, 180 (51.6%), 59 (16.9%), and 61 (17.5%) patients were completely negative for c-MET, RhoA, and CLDN18, respectively. Total gastrectomy, D1 lymphadenectomy, poorly differentiated histology, and greater inflammatory infiltrate were more frequent in the c-MET-negative group. Diffuse type, greater inflammatory infiltrate, and advanced pT and pTNM stage were associated with low-RhoA GC. The venous invasion was more frequent in the low-CLDN18 group. Furthermore, c-MET was positively correlated with RhoA and negatively with CLDN18. HER2 expression was associated with c-MET-positive and high-CLDN18 GC; and loss of E-cadherin expression in c-MET-negative and low-RhoA GC. c-MET-negative and Low-RhoA were significantly associated with worse disease-free survival. Conclusions: c-MET, RhoA, and CLD18 expression occurred frequently in GC. RhoA GC had distinct clinicopathological characteristics related to prognosis. c-MET and RhoA were associated with survival but were not independent predictors of prognosis.
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Affiliation(s)
- Marina Alessandra Pereira
- Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 01246-000, Brazil; (M.F.K.P.R.); (A.R.D.); (L.C.); (R.R.e.R.); (T.B.d.C.); (B.Z.); (S.C.N.); (U.R.J.); (E.S.d.M.)
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Chen Z, Xie Y, Chen W, Li T, Chen X, Liu B. RETRACTED: microRNA-6785-5p-loaded human umbilical cord mesenchymal stem cells-derived exosomes suppress angiogenesis and metastasis in gastric cancer via INHBA. Life Sci 2021; 284:119222. [PMID: 33609542 DOI: 10.1016/j.lfs.2021.119222] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 02/04/2021] [Accepted: 02/09/2021] [Indexed: 01/18/2023]
Abstract
This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. Concern was raised about the reliability of the Western blot results in Figs. 1D+F, 2G, 3C, 4C and 6C, which appear to have the same eyebrow shaped phenotype as many other publications tabulated here (https://docs.google.com/spreadsheets/d/149EjFXVxpwkBXYJOnOHb6RhAqT4a2llhj9LM60MBffM/edit#gid=0). The journal requested the corresponding author comment on these concerns and provide the raw data. However the authors were not able to satisfactorily fulfil this request and therefore the Editor-in-Chief decided to retract the article.
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Affiliation(s)
- Zonglin Chen
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Yong Xie
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Weidong Chen
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Tiegang Li
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Xianyu Chen
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.
| | - Bo Liu
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
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Inhibited HDAC3 promotes microRNA-376c-3p to suppress malignant phenotypes of gastric cancer cells by reducing WNT2b. Genomics 2021; 113:3512-3522. [PMID: 34284078 DOI: 10.1016/j.ygeno.2021.07.018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 05/31/2021] [Accepted: 07/14/2021] [Indexed: 11/20/2022]
Abstract
OBJECTIVE Our study aims to identify the impact of histone deacetylase 3 (HDAC3) and microRNA-376c-3p (miR-376c-3p) on gastric cancer (GC) by targeting wingless-type MMTV integration site family member 2b (WNT2b). METHODS Levels of miR-376c-3p, HDAC3 and WNT2b were assessed. GC cells were treated with altered HDAC3 or miR-376c-3p to evaluate their biological functions, and rescue experiment was performed to assess the effect of WNT2b on GC cells. The tumor growth in vivo was observed. RESULTS HDAC3 and WNT2b were up-regulated while miR-376c-3p was reduced in GC tissues and cell lines. The inhibited HDAC3 or elevated miR-376c-3p could restrain malignant behaviors of GC cells in vitro, and also suppress the xenograft growth. WNT2b silencing reduced the effect of miR-376c-3p inhibition while WNT2b overexpression mitigated that of miR-376c-3p promotion on GC cell growth. CONCLUSION Inhibiting HDAC3 promotes miR-376c-3p to suppress malignant phenotypes of GC cells via reducing WNT2b, thereby restricting GC development.
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20
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Hum M, Tan HJ, Yang Y, Srivastava S, Teh M, Lim YP. WBP2 promotes gastric cancer cell migration via novel targeting of LATS2 kinase in the Hippo tumor suppressor pathway. FASEB J 2021; 35:e21290. [PMID: 33475198 DOI: 10.1096/fj.202000393r] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 11/04/2020] [Accepted: 12/03/2020] [Indexed: 01/07/2023]
Abstract
Dysregulation of signaling pathways is responsible for many human diseases. The lack of understanding of the molecular etiology of gastric cancer (GC) poses a substantial challenge to the development of effective cancer therapy. To better understand the molecular mechanisms underlying the pathogenesis of GC, which will facilitate the identification and development of effective therapeutic approaches to improve patient outcomes, mass spectrometry-based phosphoproteomics analysis was performed to map the global molecular changes in GC. A total of 530 proteins with altered phosphorylation levels were detected across a panel of 15 normal and GC cell lines. WW domain-binding protein 2 (WBP2) was validated to be upregulated in a subset of GC cell lines. WBP2 is overexpressed in 61% cases of GC compared to non-cancer tissues and high WBP2 expression correlates with poor clinical outcomes. WBP2 was found to be required for GC cell migration but is dispensable for cell growth and proliferation. WBP2 knockdown increased p-LATS2 with a concomitant increase in p-YAP, resulting in the cytoplasmic retention of YAP and ultimately the inhibition of YAP/TEAD activity and downregulation of TEAD target genes--CTGF and CYR61. Importantly, the loss of LATS2 reversed the activation of Hippo pathway caused by WBP2 knockdown, indicating that WBP2 acts through LATS2 to exert its function on the Hippo pathway. Moreover, WBP2 interacted with LATS2 to inhibit its phosphorylation and activity. In conclusion, our study established a pivotal role for WBP2 in the promotion of GC cell migration via a novel mechanism that inactivates the Hippo pathway transducer LATS2.
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Affiliation(s)
- Melissa Hum
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Hock Jin Tan
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Yixuan Yang
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Supriya Srivastava
- Department of Medicine, Yong Loo Lin School of Medicine, National University Health System, Singapore, Singapore
| | - Ming Teh
- Department of Pathology, National University Health System, Singapore, Singapore
| | - Yoon Pin Lim
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,National University Cancer Institute, Singapore, Singapore.,NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore
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21
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Weidle UH, Birzele F, Brinkmann U, Auslaender S. Gastric Cancer: Identification of microRNAs Inhibiting Druggable Targets and Mediating Efficacy in Preclinical In Vivo Models. Cancer Genomics Proteomics 2021; 18:497-514. [PMID: 34183383 DOI: 10.21873/cgp.20275] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/30/2021] [Accepted: 05/05/2021] [Indexed: 01/06/2023] Open
Abstract
In addition to chemotherapy, targeted therapies have been approved for treatment of locally advanced and metastatic gastric cancer. The therapeutic benefit is significant but more durable responses and improvement of survival should be achieved. Therefore, the identification of new targets and new approaches for clinical treatment are of paramount importance. In this review, we searched the literature for down-regulated microRNAs which interfere with druggable targets and exhibit efficacy in preclinical in vivo efficacy models. As druggable targets, we selected transmembrane receptors, secreted factors and enzymes. We identified 38 microRNAs corresponding to the criteria as outlined. A total of 13 miRs target transmembrane receptors, nine inhibit secreted proteins and 16 attenuate enzymes. These microRNAs are targets for reconstitution therapy of gastric cancer. Further target validation experiments are mandatory for all of the identified microRNAs.
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Affiliation(s)
- Ulrich H Weidle
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany;
| | - Fabian Birzele
- Pharmaceutical Sciences, Roche Pharma Research and Early Development (pRed), Roche Innovation Center Basel, Basel, Switzerland
| | - Ulrich Brinkmann
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany;
| | - Simon Auslaender
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
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22
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Kim S, Ahn JM, Bae WJ, Han JH, Lee D. Quantitation of ligand is critical for ligand-dependent MET signalling activation and determines MET-targeted therapeutic response in gastric cancer. Gastric Cancer 2021; 24:577-588. [PMID: 33164142 DOI: 10.1007/s10120-020-01139-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 10/26/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Despite the promising preclinical antitumor activity of MET-targeting therapies, most clinical trials have failed. We introduced a new concept of quantitation of stroma-induced hepatocyte growth factor (HGF) to assess the actual MET signalling activity in gastric cancer (GC). METHODS We treated serially diluted HGF and conditioned media (CM) from cancer-associated fibroblasts (CAFs) on low MET-expressing cancer cells and investigated the phenotypical and signalling changes. Stromal proportion and MET expression in GC samples were assessed, and gene set enrichment analysis (GSEA) from the public database was performed. The antitumor effect of anti-MET treatment was examined, especially when cancer cells were activated in a ligand-dependent manner. RESULTS Relatively high doses of HGF or high-concentrated CM fully activated MET signalling cascades and promoted cell proliferation/invasion. High stromal proportion denoted worse patient survival in MET-positive GCs than in MET-negative ones. GSEA showed that the gene sets regarding proliferation, migration, and CAF as well as MET pathway signature were enriched in simultaneously MET- and HGF-positive samples. Sufficient ligand-dependent MET signalling activation increased the sensitivity to crizotinib. CONCLUSIONS We conclude that patients whose tumours have a high stromal proportion and at least low MET expression may benefit more from MET-targeted therapies.
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Affiliation(s)
- Seokhwi Kim
- Department of Pathology, Ajou University School of Medicine, 164, Worldcup-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do, 16499, Republic of Korea
| | - Ji Mi Ahn
- Department of Pathology, Ajou University School of Medicine, 164, Worldcup-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do, 16499, Republic of Korea
| | - Won Jung Bae
- Department of Pathology, Ajou University School of Medicine, 164, Worldcup-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do, 16499, Republic of Korea
| | - Jae Ho Han
- Department of Pathology, Ajou University School of Medicine, 164, Worldcup-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do, 16499, Republic of Korea
| | - Dakeun Lee
- Department of Pathology, Ajou University School of Medicine, 164, Worldcup-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do, 16499, Republic of Korea.
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23
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Yang Y, Wang C, Dai C, Liu X, Li W, Huang M, Zhao X, Ji D, Li J, Guo W. Amplification and expression of c-MET correlate with poor prognosis of patients with gastric cancer and upregulate the expression of PDL1. Acta Biochim Biophys Sin (Shanghai) 2021; 53:547-557. [PMID: 33693450 DOI: 10.1093/abbs/gmab026] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Indexed: 12/22/2022] Open
Abstract
The prognostic significance of c-MET in gastric cancer (GC) remains uncertain. In the present study, we examined the amplification, expression, and the prognostic value of c-MET, human epidermal growth factor receptor 2 (HER2), and programmed cell death 1 ligand 1 (PDL1), together with the correlations among them in a large cohort of Chinese samples. A total of 444 patients were included. The immunohistochemistry (IHC) and the dual-color silver in situ hybridization (SISH) were performed to examine their expression and amplification. Univariate and multivariate analyses were performed by the Cox proportional hazard regression model, and survival curves were estimated by the Kaplan-Meier method. The positivity determined by IHC of c-MET was 24.8%, and the MET amplification rate was 2.3%. The positivity rates of HER2 and PDL1 were 8% and 34.7%, respectively. PDL1 expression had a significantly positive association with c-MET expression. c-MET positivity played a significant prognostic role in disease-free survival (DFS) (P = 0.032). Patients with mesenchymal-epithelial transition (MET) amplification had significantly poorer prognosis on both DFS and overall survival (OS). Subgroup analysis showed that in HER2-negative patients, but not in HER2-positive patients, MET-positive patients had significantly worse DFS (P = 0.000) and OS (P = 0.006). c-MET regulated the expression of PDL1 through an AKT-dependent pathway. c-MET inhibitor enhanced the T-cell killing ability and increased the efficacy of PD1 antibody. c-MET was found to be an independent prognostic factor for DFS of GC patients. A combination of c-MET inhibitors and PD1 antibodies could enhance the killing capacity of T cells, providing a preliminary basis for the clinical research on the same combination in GC treatment.
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Affiliation(s)
- Ya’nan Yang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Chenchen Wang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Congqi Dai
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Xinyang Liu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Wenhua Li
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Mingzhu Huang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Xiaoying Zhao
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Dongmei Ji
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Jin Li
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Medical Oncology, Tongji University Shanghai East Hospital, Shanghai 200120, China
| | - Weijian Guo
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
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Jørgensen JT, Mollerup J, Yang H, Go N, Nielsen KB. MET deletion is a frequent event in gastric/gastroesophageal junction/esophageal cancer: a cross-sectional analysis of gene status and signal distribution in 1,580 patients. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:225. [PMID: 33708852 PMCID: PMC7940901 DOI: 10.21037/atm-20-4081] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 11/01/2020] [Indexed: 12/22/2022]
Abstract
BACKGROUND MET gene aberrations are found in several human cancers including gastric, ovarian and lung. In a large multinational cohort of patients with gastric/gastroesophageal junction/esophageal (G/GEJ/E) adenocarcinoma we assessed the MET status with respect to amplification and deletion and correlate the results with the phenotypical gene signal distribution pattern. METHODS Tissue specimens from 1,580 patients were analyzed using a novel fluorescence in situ hybridization (FISH) assay employing a MET/CEN-7 IQFISH Probe Mix. MET amplification and deletions were defined as a MET/CEN-7 ratio ≥2.0 and a MET/CEN-7 ratio <0.8, respectively. Furthermore, the link between the MET gene status and the phenotypical signal distribution was investigated. RESULTS The prevalence of MET amplification and deletions was found to be 7.2% and 8.7%, respectively. Significant differences were observed with regard to geographic regions and sex. The Asian population had the highest percentage of MET amplification (9.4%) and the lowest percentage of deletions (3.2%). MET deletions was found more frequently among males (10.1%) compared to females (5.3%) and in esophagus (17.6%) compared to the stomach (5.7%). More than 50% of the patients who harbored MET gene amplification had a heterogeneous distribution of the FISH signals. Patients with a focal signal distribution were solely to be found among the MET amplified population. MET deletion were mainly observed in the group of patients with a homogenous signal distribution. CONCLUSIONS The screening data from this cross-sectional study showed that MET deletion and amplification are frequent events in G/GEJ/E cancer, which are linked to different phenotypical signal distribution patterns. The role of MET deletion in relation to tumor development is not fully understood but it is likely to play a role in the oncogenic transformation of the cells.
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Affiliation(s)
| | - Jens Mollerup
- Pathology Division, Agilent Technologies, Glostrup, Denmark
| | - Hui Yang
- Medical Sciences, Amgen Inc., Thousand Oaks, USA
| | - Ning Go
- Medical Sciences, Amgen Inc., Thousand Oaks, USA
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25
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Gu ML, Zhou XX, Ren MT, Shi KD, Yu MS, Jiao WR, Wang YM, Zhong WX, Ji F. Blockage of ETS homologous factor inhibits the proliferation and invasion of gastric cancer cells through the c-Met pathway. World J Gastroenterol 2020; 26:7497-7512. [PMID: 33384550 PMCID: PMC7754554 DOI: 10.3748/wjg.v26.i47.7497] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 10/13/2020] [Accepted: 11/02/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is one of the most common and deadliest types of cancer worldwide due to its delayed diagnosis and high metastatic frequency, but its exact pathogenesis has not been fully elucidated. ETS homologous factor (EHF) is an important member of the ETS family and contributes to the pathogenesis of multiple malignant tumors. To date, whether EHF participates in the development of GC via the c-Met signaling pathway remains unclear.
AIM To investigate the role and mechanism of EHF in the occurrence and development of GC.
METHODS The expression of EHF mRNA in GC tissues and cell lines was measured by quantitative PCR. Western blotting was performed to determine the protein expression of EHF, c-Met, and its downstream signal molecules. The EHF expression in GC tissues was further detected by immunohistochemical staining. To investigate the role of EHF in GC oncogenesis, small interfering RNA (siRNA) against EHF was transfected into GC cells. The cell proliferation of GC cells was determined by Cell Counting Kit-8 and colony formation assays. Flow cytometry was performed following Annexin V/propidium iodide (PI) to identify apoptotic cells and PI staining to analyze the cell cycle. Cell migration and invasion were assessed by transwell assays.
RESULTS The data showed that EHF was upregulated in GC tissues and cell lines in which increased expression of c-Met was also observed. Silencing of EHF by siRNA reduced the proliferation of GC cells. Inhibition of EHF induced significant apoptosis and cell cycle arrest in GC cells. Cell migration and invasion were significantly inhibited. EHF silencing led to c-Met downregulation and further blocked the Ras/c-Raf/extracellular signal-related kinase 1/2 (Erk1/2) pathway. Additionally, phosphatase and tensin homolog was upregulated and glycogen synthase kinase 3 beta was deactivated. Moreover, inactivation of signal transducer and activator of transcription 3 was detected following EHF inhibition, leading to inhibition of the epithelial-to-mesenchymal transition (EMT).
CONCLUSION These results suggest that EHF plays a key role in cell proliferation, invasion, apoptosis, the cell cycle and EMT via the c-Met pathway. Therefore, EHF may serve as an antineoplastic target for the diagnosis and treatment of GC.
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Affiliation(s)
- Meng-Li Gu
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Xin-Xin Zhou
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Meng-Ting Ren
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Ke-Da Shi
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Mo-Sang Yu
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Wen-Rui Jiao
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Ya-Mei Wang
- Department of Gastroenterology, The Fourth Affiliated Hospital, College of Medicine, Zhejiang University, Yiwu 322000, Zhejiang Province, China
| | - Wei-Xiang Zhong
- Department of Pathology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Feng Ji
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
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M2 macrophage-derived extracellular vesicles promote gastric cancer progression via a microRNA-130b-3p/MLL3/GRHL2 signaling cascade. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:134. [PMID: 32660626 PMCID: PMC7359233 DOI: 10.1186/s13046-020-01626-7] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 06/21/2020] [Indexed: 01/25/2023]
Abstract
BACKGROUND Transfer of noncoding microRNAs (miRNAs) by extracellular vesicles (EVs) promotes the development of chemoresistance in many tumor types. Additionally, restoration or depletion of several miRNAs has been observed in multiple cancer types including gastric cancer (GC). In this present study, we aimed to investigate the mechanism of miR-130b-3p in M2 macrophage-derived EVs in the development of GC through regulation of mixed lineage leukemia 3 (MLL3) and grainyhead-like 2 (GRHL2). METHODS Expression of miR-130b-3p and GRHL2 was quantified in 63 pairs of cancerous and noncancerous gastric tissues. The predicted binding between miR-130b-3p and MLL3, together with the enrichment of MLL3, H3K4me1, and H3K27ac in gene enhancer region, was verified by luciferase activity assay and chromatin immunoprecipitation. Effects of miR-130b-3p on GC cell proliferation, apoptosis, migration and invasion, as well as tube formation of human umbilical endothelial vein cells (HUEVCs) were further determined by gain- and loss-of function assays in vitro. RESULTS miR-130b-3p was upregulated in GC tissues, and miR-130b-3p promoted survival, metastasis and angiogenesis of GC cells as well as enhanced tumor formation and angiogenesis in GC in vivo. Additionally, miR-130b-3p delivered in M2 macrophage-derived EVs promoted survival, migration, invasion, and angiogenesis of GC cells. Notably, MLL3 inhibited GC cell proliferation, migration, invasion, and vessel-like tube formation of HUEVCs by increasing GRHL2. Furthermore, downregulation of miR-130b-3p in M2 macrophage-derived EVs or upregulation of GRHL2 inhibited tumor formation and angiogenesis in GC. CONCLUSION This study highlights that EVs loaded with the specific miRNA cargo miR-130b-3p mediate communication between M2 macrophages and cancer cells in the tumor microenvironment through the modulation of MLL3 and GRHL2 in GC.
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27
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Zhu C, Shi H, Wu M, Wei X. A dual MET/AXL small-molecule inhibitor exerts efficacy against gastric carcinoma through killing cancer cells as well as modulating tumor microenvironment. MedComm (Beijing) 2020; 1:103-118. [PMID: 34766112 PMCID: PMC8489669 DOI: 10.1002/mco2.11] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 05/26/2020] [Accepted: 05/26/2020] [Indexed: 02/05/2023] Open
Abstract
The receptor tyrosine kinases MET and AXL have been implicated in tumorigenesis and aggressiveness of multiple malignancies. We performed this study to evaluate the antitumor impact of LY2801653, a dual MET and AXL inhibitor on gastric cancer and to elucidate the underlying mechanisms. In the present study, tissue microarrays containing gastric cancer tissues were stained with MET and AXL antibodies, which showed the prognostic values of MET and AXL. Administration of LY2801653 inhibited cell proliferation, migration, epithelial‐mesenchymal transition, induced apoptosis, and cell cycle arrest. Xenograft mouse models showed suppressed cell proliferation of tumors in high MET and AXL expression cells. LY2801653 also inhibited the growth of MET and AXL‐independent cells at higher but clinically relevant doses through decreased angiogenesis and M2 macrophages in the tumor microenvironment. In conclusion, our study provides evidence for MET and AXL as prognostic biomarkers and potential therapeutic targets in gastric cancer. The dual MET/AXL inhibitor LY2801653 represents a promising therapeutic strategy for the treatment of patients with gastric carcinoma.
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Affiliation(s)
- Chenjing Zhu
- Laboratory of Aging Research and Cancer Drug Target State Key Laboratory of Biotherapy and Cancer Center National Clinical Research Center for Geriatrics West China Hospital Sichuan University Chengdu Sichuan China.,Department of Radiation Oncology Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University Nanjing Jiangsu China
| | - Huashan Shi
- Laboratory of Aging Research and Cancer Drug Target State Key Laboratory of Biotherapy and Cancer Center National Clinical Research Center for Geriatrics West China Hospital Sichuan University Chengdu Sichuan China
| | - Min Wu
- Department of Biomedical Sciences School of Medicine and Health Sciences University of North Dakota Grand Forks North Dakota USA
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Drug Target State Key Laboratory of Biotherapy and Cancer Center National Clinical Research Center for Geriatrics West China Hospital Sichuan University Chengdu Sichuan China
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Lu J, Li X, Tu K, Guan Y, Fung KP, Liu F. Verticillin A suppresses HGF-induced migration and invasion via repression of the c-Met/FAK/Src pathway in human gastric and cervical cancer cells. Onco Targets Ther 2019; 12:5823-5833. [PMID: 31440058 PMCID: PMC6668566 DOI: 10.2147/ott.s208683] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 06/12/2019] [Indexed: 01/06/2023] Open
Abstract
Background and purpose: Verticillin A is a fungal epipolythiodioxopiperazine (ETP) metabolite that was isolated from Amanita flavorubescens Alk infected by Verticillium sp. It was previously proven to possess potent anti-tumor cell growth activity, and we have recently determined that verticillin A is a selective inhibitor of H3K9me3-specific histone methyltransferase. The objective of this study was to find out whether verticillin A is an effective agent for suppression of gastric and cervical tumor progression. Materials and methods: Wound healing and transwell assays was performed to evaluate the effect of verticillin A on hepatocyte growth factor (HGF)-induced AGS and HeLa cells migration and invasion in vitro. Western blot was used to detect signaling proteins verticillin A affected. Results: We determined that verticillin A effectively suppressed hepatocyte growth factor (HGF)-induced AGS and HeLa cells migration and invasion in vitro. At the molecular level, we demonstrated that verticillin A inhibited HGF-induced c-Met phosphorylation and repressed the expression of total c-Met protein in AGS and HeLa cells, resulting from reduced expression of fatty acid synthase. In addition, verticillin A could suppress c-Met downstream FAK/Src signaling pathways by impairing c-Met phosphorylation induced by HGF. Conclusion: Our study demonstrated verticillin A inhibits the migration ability of human gastric cancer (AGS) cells and cervical cancer (HeLa) cells by targeting c-Met and its downstream FAK/Src signaling pathways, and suggested that verticillin A acts as a novel HGF/c-Met inhibitor by reducing expression of this receptor.
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Affiliation(s)
- Jingxin Lu
- Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zhejiang University, Hangzhou310058, People’s Republic of China
- Joint Centre of Zhejiang University and the Chinese University of Hong Kong on Natural Products and Toxicology Research, Zhejiang University, Hangzhou, People’s Republic of China
| | - Xia Li
- Joint Centre of Zhejiang University and the Chinese University of Hong Kong on Natural Products and Toxicology Research, Zhejiang University, Hangzhou, People’s Republic of China
- Zhejiang Cancer Research Institute, Zhejiang Cancer Hospital, Hangzhou 310022, People’s Republic of China
| | - Kai Tu
- Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zhejiang University, Hangzhou310058, People’s Republic of China
- Joint Centre of Zhejiang University and the Chinese University of Hong Kong on Natural Products and Toxicology Research, Zhejiang University, Hangzhou, People’s Republic of China
| | - Yuelin Guan
- Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zhejiang University, Hangzhou310058, People’s Republic of China
- Joint Centre of Zhejiang University and the Chinese University of Hong Kong on Natural Products and Toxicology Research, Zhejiang University, Hangzhou, People’s Republic of China
| | - Kwok-Pui Fung
- Joint Centre of Zhejiang University and the Chinese University of Hong Kong on Natural Products and Toxicology Research, Zhejiang University, Hangzhou, People’s Republic of China
- School of Biomedical Sciences (SBS), The Chinese University of Hong Kong, Shatin, Hong Kong SAR, People’s Republic of China
| | - Feiyan Liu
- Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zhejiang University, Hangzhou310058, People’s Republic of China
- Joint Centre of Zhejiang University and the Chinese University of Hong Kong on Natural Products and Toxicology Research, Zhejiang University, Hangzhou, People’s Republic of China
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Liu J, Li S, Chen S, Chen S, Geng Q, Xu D. c‐Met‐dependent phosphorylation of RhoA plays a key role in gastric cancer tumorigenesis. J Pathol 2019; 249:126-136. [DOI: 10.1002/path.5287] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2018] [Revised: 03/24/2019] [Accepted: 04/29/2019] [Indexed: 02/06/2023]
Affiliation(s)
- Jianjun Liu
- State Key Laboratory of Oncology in South PR China Collaborative Innovation Center for Cancer Medicine Guangzhou PR China
- Department of Gastric Surgery Sun Yat‐Sen University Cancer Center Guangzhou PR China
| | - Shun Li
- State Key Laboratory of Oncology in South PR China Collaborative Innovation Center for Cancer Medicine Guangzhou PR China
- Department of Gastric Surgery Sun Yat‐Sen University Cancer Center Guangzhou PR China
| | - Shangxiang Chen
- State Key Laboratory of Oncology in South PR China Collaborative Innovation Center for Cancer Medicine Guangzhou PR China
- Department of Gastric Surgery Sun Yat‐Sen University Cancer Center Guangzhou PR China
| | - Shuai Chen
- State Key Laboratory of Oncology in South PR China Collaborative Innovation Center for Cancer Medicine Guangzhou PR China
| | - Qirong Geng
- Department of Medical Oncology Fudan University Shanghai Cancer Center Shanghai PR China
| | - Dazhi Xu
- State Key Laboratory of Oncology in South PR China Collaborative Innovation Center for Cancer Medicine Guangzhou PR China
- Department of Gastric Surgery Sun Yat‐Sen University Cancer Center Guangzhou PR China
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Lin X, Peng Z, Wang X, Zou J, Chen D, Chen Z, Li Z, Dong B, Gao J, Shen L. Targeting autophagy potentiates antitumor activity of Met-TKIs against Met-amplified gastric cancer. Cell Death Dis 2019; 10:139. [PMID: 30760701 PMCID: PMC6374362 DOI: 10.1038/s41419-019-1314-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2018] [Revised: 12/05/2018] [Accepted: 12/20/2018] [Indexed: 12/19/2022]
Abstract
Met tyrosine kinase inhibitors (Met-TKIs) subjected to ongoing clinical trials are a promising option for Met-amplified gastric cancer (GC), but how to optimize their antitumor activity especially with combination schemes remains unclear. Since autophagy is known to be initiated by Met-TKIs, we investigated its underlying mechanisms and therapeutic potentials of Met-TKIs combined with autophagy inhibitors against Met-amplified GC. As expected, four Met-TKIs induced autophagy in Met-amplified GC cells marked by p62 degradation, LC3-II accumulation and increased LC3-positive puncta. Autophagy flux activation by Met-TKIs was further validated with combined lysosomal inhibitors, bafilomycin A1 (Baf A1) and hydroxychloroquine (HCQ). Molecular investigations reveal that autophagy induction along with mTOR and ULK1 de-phosphorylation upon Met-TKI treatment could be relieved by hepatocyte growth factor (HGF) and mTOR agonist MHY1485 (MHY), suggesting that autophagy was initiated by Met-TKIs via Met/mTOR/ULK1 cascade. Intriguingly, Met-TKIs further suppressed cell survival and tumor growth in the presence of autophagy blockade in Met-amplified GC preclinical models. Thus, these findings indicate Met/mTOR/ULK1 cascade responsible for Met-TKI-mediated autophagy and Met-TKIs combined with autophagy inhibitors as a promising choice to treat Met-amplified GC.
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Affiliation(s)
- Xiaoting Lin
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Zhi Peng
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Xiaojuan Wang
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Jianling Zou
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Dongshao Chen
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Zuhua Chen
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Zhongwu Li
- Department of Pathology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Bin Dong
- Department of Pathology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Jing Gao
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
| | - Lin Shen
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
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31
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Jalilzadeh-Razin S, Mantegi M, Tohidkia MR, Pazhang Y, Pourseif MM, Barar J, Omidi Y. Phage antibody library screening for the selection of novel high-affinity human single-chain variable fragment against gastrin receptor: an in silico and in vitro study. ACTA ACUST UNITED AC 2019; 27:21-34. [PMID: 30607886 DOI: 10.1007/s40199-018-0233-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Accepted: 12/03/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND As a membrane G protein coupled receptors (GPCRs) family, gastrin/cholecystokinin-2 receptor (CCK2R) plays a key role in the initiation and development of gastric cancer. OBJECTIVES Targeting CCK2R by immunotherapeutics such as single-chain variable fragments (scFvs) may provide an effective treatment modality against gastric cancer. Thus, the main objective of this study was to isolate scFvs specific to CCK2R. METHODS To isolate scFvs specific to the CCK2R, we capitalized on a semi-synthetic diverse phage antibody library (PAL) and a solution-phase biopanning process. The library was panned against a biotinylated peptide of the second extracellular loop (ECL2) of CCK2R. After four rounds of biopanning, the selected soluble scFv clones were screened by enzyme-linked immunosorbent assay (ELISA) and examined for specific binding to the peptide. The selected scFvs were purified using immobilized metal affinity chromatography (IMAC). The binding affinity and specificity of the scFvs were examined by the surface plasmon resonance (SPR), immunoblotting and flow cytometry assays and molecular docking using ZDOCK v3.0.2. RESULTS Ten different scFvs were isolated, which displayed binding affinity ranging from 0.68 to 8.0 (nM). Immunoblotting and molecular docking analysis revealed that eight scFvs were able to detect the denatured form of CCK2R protein. Of the isolated scFvs, two scFvs showed high-binding affinity to the human gastric adenocarcinoma AGS cells. CONCLUSIONS Based on our findings, a couple of the selected scFvs showed markedly high-binding affinity to immobilized CCK2R peptide and CCK2R-overexpressing AGS cells. Therefore, these scFvs are proposed to serve as targeting and/or treatment agents in the diagnosis and immunotherapy of CCK2R-positive tumors. Graphical abstract ᅟ.
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Affiliation(s)
- Sepideh Jalilzadeh-Razin
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Malihe Mantegi
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.,Islamic Azad University of Urmia, Urmia, Iran
| | - Mohammad R Tohidkia
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Yaghub Pazhang
- Department of Biochemistry, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran
| | - Mohammad M Pourseif
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Jaleh Barar
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Yadollah Omidi
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran. .,Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
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Li D, Yang M, Liao A, Zeng B, Liu D, Yao Y, Hu G, Chen X, Feng Z, Du Y, Zhou Y, He J, Nie Y. Linc00483 as ceRNA regulates proliferation and apoptosis through activating MAPKs in gastric cancer. J Cell Mol Med 2018; 22:3875-3886. [PMID: 29761936 PMCID: PMC6050491 DOI: 10.1111/jcmm.13661] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2017] [Accepted: 03/28/2018] [Indexed: 12/20/2022] Open
Abstract
Long non‐coding RNAs (lncRNAs) are important regulators of many cellular processes, and their aberrant expression and/or function is associated with many different diseases, including cancer. However, the identification of functional lncRNAs in gastric cancer is still a challenge. In this study, we describe a novel functional lncRNA, linc00483, that is upregulated and associated with tumorigenesis, tumour size, metastasis and poor prognosis in gastric cancer. In our study, linc00483 promoted gastric cancer cell proliferation, invasiveness and metastasis in vitro and in vivo. Mechanistically, upregulated expression of linc00483 in gastric cancer acts as a sponge to absorb endogenous tumour suppressor miR‐30a‐3p. Furthermore, it restores SPAG9 expression, which is negatively regulated by miR‐30a‐3p, and actives MAPK signaling pathway in gastric cancer cells. Thus, linc00483 is an oncogenic lncRNA in gastric cancer and targeting linc00483 or its pathway can potentially be useful in development of targeted therapies for patients with gastric cancer. Our results show that linc00483 is an important regulator in carcinogenesis and may be a useful biomarker to predict prognosis of gastric cancer patients. We believe our findings are novel and will be of interest to scientists working in many areas related to biomarkers in cancer.
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Affiliation(s)
- Defeng Li
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China.,Guangzhou Key Laboratory of Digestive Disease, Guangzhou First People's Hospital, Guangzhou, China.,Department of Gastroenterology, The Second Affiliated Hospital, Medical School, South China University of Technology, Guangzhou, China.,Department of Gastroenterology, The First Affiliated Hospital of South China of University, South China of University, Hengyang, China
| | - Meifeng Yang
- Department of Hematology, The First Affiliated Hospital of South China of University, South China of University, Hengyang, China
| | - Aijun Liao
- Department of Gastroenterology, The First Affiliated Hospital of South China of University, South China of University, Hengyang, China
| | - Bing Zeng
- Department of Gastroenterology, The First Affiliated Hospital of South China of University, South China of University, Hengyang, China
| | - Diqun Liu
- Department of Gastroenterology, The First Affiliated Hospital of South China of University, South China of University, Hengyang, China
| | - Yuhong Yao
- Department of Gastroenterology, The First Affiliated Hospital of South China of University, South China of University, Hengyang, China
| | - Guangsheng Hu
- Department of Gastroenterology, The First Affiliated Hospital of South China of University, South China of University, Hengyang, China
| | - Xuanmin Chen
- Department of Gastroenterology, The First Affiliated Hospital of South China of University, South China of University, Hengyang, China
| | - Zhiqiang Feng
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China.,Guangzhou Key Laboratory of Digestive Disease, Guangzhou First People's Hospital, Guangzhou, China.,Department of Gastroenterology, The Second Affiliated Hospital, Medical School, South China University of Technology, Guangzhou, China
| | - Yanlei Du
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China.,Guangzhou Key Laboratory of Digestive Disease, Guangzhou First People's Hospital, Guangzhou, China.,Department of Gastroenterology, The Second Affiliated Hospital, Medical School, South China University of Technology, Guangzhou, China
| | - Youlian Zhou
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China.,Guangzhou Key Laboratory of Digestive Disease, Guangzhou First People's Hospital, Guangzhou, China.,Department of Gastroenterology, The Second Affiliated Hospital, Medical School, South China University of Technology, Guangzhou, China
| | - Jie He
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China.,Guangzhou Key Laboratory of Digestive Disease, Guangzhou First People's Hospital, Guangzhou, China.,Department of Gastroenterology, The Second Affiliated Hospital, Medical School, South China University of Technology, Guangzhou, China
| | - Yuqiang Nie
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China.,Guangzhou Key Laboratory of Digestive Disease, Guangzhou First People's Hospital, Guangzhou, China.,Department of Gastroenterology, The Second Affiliated Hospital, Medical School, South China University of Technology, Guangzhou, China
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Wang X, Liu Y, Diao Y, Gao N, Wan Y, Zhong J, Zheng H, Wang Z, Jin G. Gastric cancer vaccines synthesized using a TLR7 agonist and their synergistic antitumor effects with 5-fluorouracil. J Transl Med 2018; 16:120. [PMID: 29739434 PMCID: PMC5941430 DOI: 10.1186/s12967-018-1501-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2018] [Accepted: 04/30/2018] [Indexed: 12/19/2022] Open
Abstract
Background Vaccines play increasingly important roles in cancer treatment due to their advantages of effective targeting and few side effects. Our laboratory has attempted to construct vaccines by conjugating TLR7 agonists with tumor-associated antigens. Furthermore, immunochemotherapy has recently become an appealing approach to cancer therapy. 5-fluorouracil (5-FU), a commonly used chemotherapeutic agent, can reportedly potently and selectively kill tumor-associated MDSCs in vivo. Methods Gastric cancer vaccines were synthesized by the covalent attachment of our TLR7 agonist with the gastric cancer antigen MG7-Ag tetra-epitope, leading to T7 − ML (linear tetra-epitope) and T7 − MB (branched tetra-epitope). Cytokines induced by the vaccines in vitro were assessed by ELISA. A tumor challenge model was created by treating BALB/c mice on either a prophylactic or therapeutic vaccination schedule. 5-FU was simultaneously applied to mice in the combination treatment group. CTL and ADCC activities were determined by the LDH method, while CD3+/CD8+, CD3+/CD4+ T cells and MDSCs were evaluated by flow cytometry. Results In vitro, rapid TNF-α and IL-12 inductions occurred in BMDCs treated with the vaccines. In vivo, among all the vaccines tested, T7 − MB most effectively reduced EAC tumor burdens and induced CTLs, antibodies and ADCC activity in BALB/c mice. Immunization with T7 − MB in combination with 5-FU chemotherapy reduced tumor sizes and extended long-term survival rates, mainly by improving T cell responses, including CTLs, CD3+/CD8+ and CD3+/CD4+ T cells. 5-FU also enhanced the T7 − MB efficiency by reversing immunosuppressive factors, i.e., MDSCs, which could not be validly inhibited by the vaccines alone. In addition, T7 − MB repressed tumor growth and immune tolerance when the therapeutic schedule was used, although the effects were weaker than those achieved with either T7 − MB alone or in combination with 5-FU on the prophylactic schedule. Conclusions A novel effective gastric cancer vaccine was constructed, and the importance of branched multiple antigen peptides and chemical conjugation to vaccine design were confirmed. The synergistic effects and mechanisms of T7 − MB and 5-FU were also established, observing mainly T cell activation and MDSC inhibition. Electronic supplementary material The online version of this article (10.1186/s12967-018-1501-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Xiaodong Wang
- School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen, 518060, Guangdong, China
| | - Yu Liu
- The 3rd Affiliated Hospital of Shenzhen University, Shenzhen, 518001, Guangdong, China
| | - Yuwen Diao
- Department of Biology and School of Medicine, Southern University of Science and Technology, Shenzhen, 518055, Guangdong, China
| | - Ningning Gao
- School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen, 518060, Guangdong, China
| | - Yanyan Wan
- The 3rd Affiliated Hospital of Shenzhen University, Shenzhen, 518001, Guangdong, China
| | - Jingjing Zhong
- School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen, 518060, Guangdong, China
| | - Huali Zheng
- School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen, 518060, Guangdong, China
| | - Zhulin Wang
- School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen, 518060, Guangdong, China
| | - Guangyi Jin
- School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen, 518060, Guangdong, China. .,Cancer Research Center, Shenzhen University Health Science Center, Shenzhen, 518060, Guangdong, China.
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Backert S, Haas R, Gerhard M, Naumann M. The Helicobacter pylori Type IV Secretion System Encoded by the cag Pathogenicity Island: Architecture, Function, and Signaling. Curr Top Microbiol Immunol 2018. [DOI: 10.1007/978-3-319-75241-9_8] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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35
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Ma L, Zhou Y, Luo X, Gao H, Deng X, Jiang Y. Long non-coding RNA XIST promotes cell growth and invasion through regulating miR-497/MACC1 axis in gastric cancer. Oncotarget 2018; 8:4125-4135. [PMID: 27911852 PMCID: PMC5354817 DOI: 10.18632/oncotarget.13670] [Citation(s) in RCA: 94] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Accepted: 10/19/2016] [Indexed: 01/23/2023] Open
Abstract
Abnormal expression of long non-coding RNA (lncRNAs) often contributes to unrestricted growth and invasion of cancer cells. LncRNA XIST expression is up-regulated in several cancers, however, its modulatory mechanism in gastric cancer (GC) has not been elucidated. In the present study, we found that XIST expression was significantly increased in GC tissues and cell lines. LncRNA XIST promoted cell cycle progression from the G1 phase to the S phase and protected cells from apoptosis, which contributed to GC cell growth. LncRNA XIST also contributed to GC cell invasion both in vitro and in vivo. We revealed that XIST functioned as competing endogenous RNA to repress miR-497, which controlled its down-stream target MACC1. We proposed that XIST was responsible for GC cell proliferation and invasion and XIST exerted its function through the miR-497/MACC1 axis. Our findings suggested that lncRNA XIST may be a candidate prognostic biomarker and a target for new therapies in GC patients.
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Affiliation(s)
- Lei Ma
- Cancer Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Gastroenterology, Guangzhou Medical University, Guangzhou, China
| | - Yongjian Zhou
- Department of Gastroenterology, The First Hospital of Guangzhou, Guangzhou, China
| | - Xiaojun Luo
- Cancer Center, TCM-Integrated Hospital, Southern Medical University, Guangzhou, China
| | - Hai Gao
- Xiamen Hospital of Traditional Chinese Medicine, Xiamen, China.,Xiamen Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Xiamen, China
| | - Xubin Deng
- Cancer Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yingjie Jiang
- Department of Gastroenterology, The First Hospital of Guangzhou, Guangzhou, China
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A non-randomized, open-label, single-arm, Phase 2 study of emibetuzumab in Asian patients with MET diagnostic positive, advanced gastric cancer. Cancer Chemother Pharmacol 2017; 80:1197-1207. [PMID: 29071414 PMCID: PMC5686250 DOI: 10.1007/s00280-017-3445-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Accepted: 09/22/2017] [Indexed: 12/14/2022]
Abstract
Purpose Mesenchymal–epithelial transition factor (MET) is expressed in gastric cancer and associated with poor clinical outcomes. We assessed activity, safety, and pharmacokinetics of emibetuzumab, a bivalent monoclonal anti-MET antibody that blocks ligand-dependent and ligand-independent MET signaling. Methods This non-randomized, single-arm, Phase 2 study enrolled Asian patients with MET diagnostic positive advanced gastric adenocarcinoma. Emibetuzumab (2000 mg, intravenous) was given on days 1 and 15 (28-day cycle). The primary endpoint was 8-week progression-free survival rate. Secondary objectives included safety, pharmacokinetics, overall survival, and change in tumor size. Results Tumors from 65 patients were immunohistochemically screened to enroll 15 MET diagnostic positive patients (23% positivity; 8 Japanese, 7 Korean; 10 male). Eight-week progression-free survival rate was 0.47 (70% CI, 0.33–0.59). Disease control rate was 40% (target lesion decreases, three patients; no complete/partial responses according to RECIST). Median overall survival was 17.1 weeks (95% CI, 6.3–not achievable). No serious emibetuzumab-related adverse events or new safety signals emerged. Grade ≥ 3 possibly drug-related adverse events were hyperkalemia, hyponatremia, and hyperuricemia (one each). Emibetuzumab’s pharmacokinetics profile was similar to that observed previously. MET expression and clinical outcomes were not obviously associated. Conclusion Emibetuzumab was well tolerated with limited single-agent activity in advanced gastric adenocarcinoma.
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Catenacci DVT, Tebbutt NC, Davidenko I, Murad AM, Al-Batran SE, Ilson DH, Tjulandin S, Gotovkin E, Karaszewska B, Bondarenko I, Tejani MA, Udrea AA, Tehfe M, De Vita F, Turkington C, Tang R, Ang A, Zhang Y, Hoang T, Sidhu R, Cunningham D. Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2017; 18:1467-1482. [PMID: 28958504 DOI: 10.1016/s1470-2045(17)30566-1] [Citation(s) in RCA: 281] [Impact Index Per Article: 35.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Revised: 07/13/2017] [Accepted: 07/17/2017] [Indexed: 12/27/2022]
Abstract
BACKGROUND Rilotumumab is a fully human monoclonal antibody that selectively targets the ligand of the MET receptor, hepatocyte growth factor (HGF). We aimed to assess the efficacy, safety, and pharmacokinetics of rilotumumab combined with epirubicin, cisplatin, and capecitabine, and to assess potential biomarkers, in patients with advanced MET-positive gastric or gastro-oesophageal junction adenocarcinoma. METHODS This multicentre, randomised, double-blind, placebo-controlled, phase 3 study was done at 152 centres in 27 countries. We recruited adults (aged ≥18 years) with unresectable locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, MET-positive tumours (≥25% of tumour cells with membrane staining of ≥1+ staining intensity), and evaluable disease, who had not received previous systemic therapy. Eligible patients were randomly assigned (1:1) via a computerised voice response system to receive rilotumumab 15 mg/kg intravenously or placebo in combination with open-label chemotherapy (epirubicin 50 mg/m2 intravenously; cisplatin 60 mg/m2 intravenously; capecitabine 625 mg/m2 orally twice daily) in 21-day cycles for up to ten cycles. After completion of chemotherapy, patients continued to receive rilotumumab or placebo monotherapy until disease progression, intolerability, withdrawal of consent, or study termination. Randomisation was stratified by disease extent and ECOG performance status. Both patients and physicians were masked to study treatment assignment. The primary endpoint was overall survival, analysed by intention to treat. We report the final analysis. This study is registered with ClinicalTrials.gov, number NCT01697072. FINDINGS Between Nov 7, 2012, and Nov 21, 2014, 609 patients were randomly assigned to rilotumumab plus epirubicin, cisplatin, and capecitabine (rilotumumab group; n=304) or placebo plus epirubicin, cisplatin, and capecitabine (placebo group; n=305). Study treatment was stopped early after an independent data monitoring committee found a higher number of deaths in the rilotumumab group than in the placebo group; all patients in the rilotumumab group subsequently discontinued all study treatment. Median follow-up was 7·7 months (IQR 3·6-12·0) for patients in the rilotumumab group and 9·4 months (5·3-13·1) for patients in the placebo group. Median overall survival was 8·8 months (95% CI 7·7-10·2) in the rilotumumab group compared with 10·7 months (9·6-12·4) in the placebo group (stratified hazard ratio 1·34, 95% CI 1·10-1·63; p=0·003). The most common grade 3 or worse adverse events in the rilotumumab and placebo groups were neutropenia (86 [29%] of 298 patients vs 97 [32%] of 299 patients), anaemia (37 [12%] vs 43 [14%]), and fatigue (30 [10%] vs 35 [12%]). The frequency of serious adverse events was similar in the rilotumumab and placebo groups (142 [48%] vs 149 [50%]). More deaths due to adverse events occurred in the rilotumumab group than the placebo group (42 [14%] vs 31 [10%]). In the rilotumumab group, 33 (11%) of 298 patients had fatal adverse events due to disease progression, and nine (3%) had fatal events not due to disease progression. In the placebo group, 23 (8%) of 299 patients had fatal adverse events due to disease progression, and eight (3%) had fatal events not due to disease progression. INTERPRETATION Ligand-blocking inhibition of the MET pathway with rilotumumab is not effective in improving clinical outcomes in patients with MET-positive gastric or gastro-oesophageal adenocarcinoma. FUNDING Amgen.
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Affiliation(s)
| | | | - Irina Davidenko
- State Budgetary Healthcare Institution, Clinical Oncology Dispensary #1, Krasnodar Region Ministry of Healthcare, Krasnodar, Russia
| | - André M Murad
- Hospital das Clínicas da Universidade Federal de Minas Gerais, Horizonte, Brazil
| | - Salah-Eddin Al-Batran
- Institute of Clinical Cancer Research, Krankenhaus Nordwest, University Cancer Center, Frankfurt, Germany
| | - David H Ilson
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Evengy Gotovkin
- Regional Budgetary Institution of Public Health Ivanovo Regional Oncology Dispensary, Ivanovo, Russia
| | | | - Igor Bondarenko
- Dnipropetrovsk Medical Academy, City Multifield Clinical Hospital 4, Dnipropetrovsk, Ukraine
| | - Mohamedtaki A Tejani
- University of Rochester Medical Center, James P Wilmot Cancer Center, Rochester, NY, USA
| | | | - Mustapha Tehfe
- Centre Hospitalier de L'Universite de Montreal Notre-Dame, Montreal, QC, Canada
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Schmid E, Klotz M, Steiner-Hahn K, Konen T, Frisk AL, Schatz C, Krahn T, von Ahsen O. Detection of MET mRNA in gastric cancer in situ. Comparison with immunohistochemistry and sandwich immunoassays. Biotech Histochem 2017; 92:425-435. [PMID: 28836864 DOI: 10.1080/10520295.2017.1339913] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Determination of predictive biomarkers by immunohistochemistry (IHC) relies on antibodies with high selectivity. RNA in situ hybridization (RNA ISH) may be used to confirm IHC and may potentially replace it if suitable antibodies are not available or are insufficiently selective to discriminate closely related protein isoforms. We validated RNA ISH as specificity control for IHC and as a potential alternative method for selecting patients for treatment with MET inhibitors. MET, the HGF receptor, is encoded by the MET proto-oncogene that may be activated by mutation or amplification. MET expression and activity were tested in a panel of control cell lines. MET could be detected in formalin fixed paraffin, embedded (FFPE) samples by IHC and RNA ISH, and this was confirmed by sandwich immunoassays of fresh frozen samples. Gastric cancer cell lines with high MET expression and phosphorylation of tyrosine-1349 respond to the MET inhibitor, BAY-853474. High expression and phosphorylation of MET is a predictive biomarker for response to MET inhibitors. We then analyzed MET expression and activity in a matched set of FFPE vs. fresh frozen tumor samples consisting of 20 cases of gastric cancer. Two of 20 clinical samples investigated exhibited high MET expression with RNA ISH and IHC. Both cases were shown by sandwich immunoassays to exhibits strong functional activity. Expression levels and functional activity in these two cases were in a range that predicted response to treatment. Our findings indicate that owing to its high selectivity, RNA ISH can be used to confirm findings obtained by IHC and potentially may replace IHC for certain targets if no suitable antibodies are available. RNA ISH is a valid platform for testing predictive biomarkers for patient selection.
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Affiliation(s)
- E Schmid
- a Biomarker Research , Bayer AG , Berlin
| | - M Klotz
- a Biomarker Research , Bayer AG , Berlin
| | | | - T Konen
- a Biomarker Research , Bayer AG , Berlin.,b Department of NanoBiophotonics , Max Planck Institute for Biophysical Chemistry , Göttingen , Germany
| | - A L Frisk
- a Biomarker Research , Bayer AG , Berlin
| | - C Schatz
- a Biomarker Research , Bayer AG , Berlin
| | - T Krahn
- a Biomarker Research , Bayer AG , Berlin
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