|
1
|
Zhan T, Betge J, Schulte N, Dreikhausen L, Hirth M, Li M, Weidner P, Leipertz A, Teufel A, Ebert MP. Digestive cancers: mechanisms, therapeutics and management. Signal Transduct Target Ther 2025; 10:24. [PMID: 39809756 PMCID: PMC11733248 DOI: 10.1038/s41392-024-02097-4] [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: 06/29/2024] [Revised: 10/20/2024] [Accepted: 11/29/2024] [Indexed: 01/16/2025] Open
Abstract
Cancers of the digestive system are major contributors to global cancer-associated morbidity and mortality, accounting for 35% of annual cases of cancer deaths. The etiologies, molecular features, and therapeutic management of these cancer entities are highly heterogeneous and complex. Over the last decade, genomic and functional studies have provided unprecedented insights into the biology of digestive cancers, identifying genetic drivers of tumor progression and key interaction points of tumor cells with the immune system. This knowledge is continuously translated into novel treatment concepts and targets, which are dynamically reshaping the therapeutic landscape of these tumors. In this review, we provide a concise overview of the etiology and molecular pathology of the six most common cancers of the digestive system, including esophageal, gastric, biliary tract, pancreatic, hepatocellular, and colorectal cancers. We comprehensively describe the current stage-dependent pharmacological management of these malignancies, including chemo-, targeted, and immunotherapy. For each cancer entity, we provide an overview of recent therapeutic advancements and research progress. Finally, we describe how novel insights into tumor heterogeneity and immune evasion deepen our understanding of therapy resistance and provide an outlook on innovative therapeutic strategies that will shape the future management of digestive cancers, including CAR-T cell therapy, novel antibody-drug conjugates and targeted therapies.
Collapse
Affiliation(s)
- Tianzuo Zhan
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- DKFZ Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Johannes Betge
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- DKFZ Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Nadine Schulte
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Lena Dreikhausen
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Michael Hirth
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Moying Li
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Philip Weidner
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Antonia Leipertz
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Andreas Teufel
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Matthias P Ebert
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
- DKFZ Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany.
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
| |
Collapse
|
|
2
|
Lordick F, Rha SY, Muro K, Yong WP, Lordick Obermannová R. Systemic Therapy of Gastric Cancer-State of the Art and Future Perspectives. Cancers (Basel) 2024; 16:3337. [PMID: 39409957 PMCID: PMC11475804 DOI: 10.3390/cancers16193337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 09/27/2024] [Accepted: 09/27/2024] [Indexed: 10/20/2024] Open
Abstract
Background: The prognosis of patients diagnosed with locally advanced and metastatic gastric and esophago-gastric junction cancer is critical. The optimal choice of systemic therapy is essential to optimize survival outcomes. Methods: A comprehensive literature review via PubMed and analysis of major oncology congresses (European Society for Medical Oncology and American Society of Clinical Oncology websites) were conducted to ascertain the current status and latest developments in the systemic treatment of patients with localized or advanced gastric and esophago-gastric junction adenocarcinoma. Results: While neoadjuvant and perioperative chemotherapy for localized tumor stages is the preferred approach in the Western Hemisphere, adjuvant chemotherapy remains the preferred course of action in East Asia. The administration of chemotherapy, typically in the form of combinations comprising platinum and fluoropyrimidine compounds in combination with docetaxel, represents a standard of care. Investigations are underway into the potential of immunotherapy and other biologically targeted agents in the perioperative setting. To select the most appropriate therapy for advanced gastric cancer, including adenocarcinoma of the esophago-gastric junction, it is essential to determine biomarkers such as HER2 expression, PD-L1 combined positive score (CPS) (combined positive score), Claudin 18.2, and microsatellite instability (MSI). In the present clinical context, the standard first-line therapy is a combination of fluoropyrimidine and a platinum derivative. The selection of chemotherapy in combination with antibodies is contingent upon the specific biomarker under consideration. Conclusions: This article reviews the current state of the art based on recent clinical trial results and provides an outlook on the future of systemic therapy.
Collapse
Affiliation(s)
- Florian Lordick
- Department of Medicine (Oncology, Gastroenterology, Hepatology, Pulmonology), University of Leipzig Medical Center, Cancer Center Central Germany, 04103 Leipzig, Germany
| | - Sun Young Rha
- Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Kei Muro
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan
| | - Wei Peng Yong
- Department of Haematology-Oncology, National University Cancer Institute, Singapore 119074, Singapore
| | - Radka Lordick Obermannová
- Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Faculty of Medicine, Masaryk University, 656 53 Brno, Czech Republic
| |
Collapse
|
|
3
|
Wu L, Dong J, Fei D, Le T, Xiao L, Liu J, Yu Z. Fructose-1, 6-Bisphosphate Aldolase B Suppresses Glycolysis and Tumor Progression of Gastric Cancer. Dig Dis Sci 2024; 69:3290-3304. [PMID: 39068380 DOI: 10.1007/s10620-024-08568-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 07/15/2024] [Indexed: 07/30/2024]
Abstract
OBJECTIVE Gastric cancer (GC) is believed to be one of the most common digestive tract malignant tumors. However, mounting evidence indicates a link between the glycolysis and tumorigenesis, including gastric cancer. METHODS Our research identified 5508 differently expressed mRNAs in gastric cancer. Then, the genes highly associated with tumorigenesis were identified through weighted correlation network analysis (WGCNA). Bioinformatics analysis observed that these hub genes were significantly linked to the regulation of cell cycle, drug metabolism, and glycolysis. Among these hub genes, there is a critical gene involved in glycolysis regulation, namely fructose-bisphosphate B (ALDOB). RESULTS Analysis based on The Cancer Genome Atlas (TCGA) and three Gene Expression Omnibus (GEO) datasets revealed that ALDOB was significantly downregulated in GC compared with normal tissues. In addition, cell viability assay confirmed that ALDOB acted as a tumor suppressor. Finally, drug sensitivity analysis revealed that ALDOB increased the sensitivity of gastric cancer cells to most antitumor drugs, especially talazoparib, XAV939, and FTI-277. Our results showed that the expression of ALDOB was significantly lower in GC tissues than in normal tissues. And ALDOB significantly inhibited proliferation and migration, delayed glycolysis in GC cells. Consequently, our study suggests that ALDOB may be a potential target for the clinical treatment of gastric cancer.
Collapse
Affiliation(s)
- Liping Wu
- The Department of Science and Education, Zhoushan Hospital, Wenzhou Medical University, Zhoushan, Zhejiang, China
| | - Jinliang Dong
- Department of General Surgery, Zhoushan Hospital, Wenzhou Medical University, No. 739 Dingshen Road, Lincheng New District, Zhoushan, Zhejiang, China
| | - Dailiang Fei
- Department of General Surgery, Zhoushan Hospital, Wenzhou Medical University, No. 739 Dingshen Road, Lincheng New District, Zhoushan, Zhejiang, China
| | - Ting Le
- The Laboratory of Cytobiology and Molecular Biology, Zhoushan Hospital, Wenzhou Medical University, No. 739 Dingshen Road, Lincheng New District, Zhoushan, Zhejiang, China
| | - Liang Xiao
- The Department of Surgery and Oncology, Shenzhen Second People's Hospital, Shenzhen, Guangdong, China
| | - Jia Liu
- School of Agriculture, Sun Yat-Sen University, No. 66 Gongchang Road, Guangming District, Shenzhen, Guangdong, China
- Shenzhen Zhongjia Bio-Medical Technology Co., Ltd, No. 66 Gongchang Road, Guangming District, Shenzhen, Guangdong, China
| | - Ze Yu
- Department of General Surgery, Zhoushan Hospital, Wenzhou Medical University, No. 739 Dingshen Road, Lincheng New District, Zhoushan, Zhejiang, China.
- The Laboratory of Cytobiology and Molecular Biology, Zhoushan Hospital, Wenzhou Medical University, No. 739 Dingshen Road, Lincheng New District, Zhoushan, Zhejiang, China.
- The Second Affiliated Hospital of Zhejiang University, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
| |
Collapse
|
|
4
|
Lau DK, Collin JP, Mariadason JM. Clinical Developments and Challenges in Treating FGFR2-Driven Gastric Cancer. Biomedicines 2024; 12:1117. [PMID: 38791079 PMCID: PMC11118914 DOI: 10.3390/biomedicines12051117] [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: 03/21/2024] [Revised: 04/18/2024] [Accepted: 04/26/2024] [Indexed: 05/26/2024] Open
Abstract
Recent advances in the treatment of gastric cancer (GC) with chemotherapy, immunotherapy, anti-angiogenic therapy and targeted therapies have yielded some improvement in survival outcomes; however, metastatic GC remains a lethal malignancy and amongst the leading causes of cancer-related mortality worldwide. Importantly, the ongoing molecular characterisation of GCs continues to uncover potentially actionable molecular targets. Among these, aberrant FGFR2-driven signalling, predominantly arising from FGFR2 amplification, occurs in approximately 3-11% of GCs. However, whilst several inhibitors of FGFR have been clinically tested to-date, there are currently no approved FGFR-directed therapies for GC. In this review, we summarise the significance of FGFR2 as an actionable therapeutic target in GC, examine the recent pre-clinical and clinical data supporting the use of small-molecule inhibitors, antibody-based therapies, as well as novel approaches such as proteolysis-targeting chimeras (PROTACs) for targeting FGFR2 in these tumours, and discuss the ongoing challenges and opportunities associated with their clinical development.
Collapse
Affiliation(s)
- David K. Lau
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia;
- School of Cancer Medicine, La Trobe University, Heidelberg, VIC 3084, Australia
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
- Department of Oncology, Monash Health, Clayton, VIC 3168, Australia
| | - Jack P. Collin
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia;
- School of Cancer Medicine, La Trobe University, Heidelberg, VIC 3084, Australia
| | - John M. Mariadason
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia;
- School of Cancer Medicine, La Trobe University, Heidelberg, VIC 3084, Australia
| |
Collapse
|
|
5
|
Röcken C. Predictive biomarkers in gastric cancer. J Cancer Res Clin Oncol 2023; 149:467-481. [PMID: 36260159 PMCID: PMC9889517 DOI: 10.1007/s00432-022-04408-0] [Citation(s) in RCA: 52] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Accepted: 10/06/2022] [Indexed: 02/04/2023]
Abstract
Predictive biomarkers are the mainstay of precision medicine. This review summarizes the advancements in tissue-based diagnostic biomarkers for gastric cancer, which is considered the leading cause of cancer-related deaths worldwide. A disease seen in the elderly, it is often diagnosed at an advanced stage, thereby limiting therapeutic options. In Western countries, neoadjuvant/perioperative (radio-)chemotherapy is administered, and adjuvant chemotherapy is administered in the East. The morpho-molecular classification of gastric cancer has opened novel avenues identifying Epstein-Barr-Virus (EBV)-positive, microsatellite instable, genomically stable and chromosomal instable gastric cancers. In chromosomal instable tumors, receptor tyrosine kinases (RKTs) (e.g., EGFR, FGFR2, HER2, and MET) are frequently overexpressed. Gastric cancers such as microsatellite instable and EBV-positive types often express immune checkpoint molecules, such as PD-L1 and VISTA. Genomically stable tumors show alterations in claudin 18.2. Next-generation sequencing is increasingly being used to search for druggable targets in advanced palliative settings. However, most tissue-based biomarkers of gastric cancer carry the risk of a sampling error due to intratumoral heterogeneity, and adequate tissue sampling is of paramount importance.
Collapse
Affiliation(s)
- C. Röcken
- Department of Pathology, Christian-Albrechts-University, Arnold-Heller-Str. 3, Haus 14, Haus U33, 24105 Kiel, Germany
| |
Collapse
|
|
6
|
Bogdan M, Meca AD, Turcu-Stiolica A, Oancea CN, Kostici R, Surlin MV, Florescu C. Insights into the Relationship between Pentraxin-3 and Cancer. Int J Mol Sci 2022; 23:15302. [PMID: 36499628 PMCID: PMC9739619 DOI: 10.3390/ijms232315302] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 11/21/2022] [Accepted: 11/29/2022] [Indexed: 12/11/2022] Open
Abstract
Although cancer can be cured if detected early and treated effectively, it is still a leading cause of death worldwide. Tumor development can be limited by an appropiate immune response, but it can be promoted by chronic extensive inflammation through metabolic dysregulation and angiogenesis. In the past decade, numerous efforts have been made in order to identify novel candidates with predictive values in cancer diagnostics. In line with this, researchers have investigated the involvement of pentraxin-3 (PTX-3) in cellular proliferation and immune escape in various types of cancers, although it has not been clearly elucidated. PTX-3 is a member of the long pentraxin subfamily which plays an important role in regulating inflammation, innate immunity response, angiogenesis, and tissue remodeling. Increased synthesis of inflammatory biomarkers and activation of different cellular mechanisms can induce PTX-3 expression in various types of cells (neutrophils, monocytes, lymphocytes, myeloid dendritic cells, fibroblasts, and epithelial cells). PTX-3 has both pro- and anti-tumor functions, thus dual functions in oncogenesis. This review elucidates the potential usefulness of PTX-3 as a serum biomarker in cancer. While future investigations are needed, PTX-3 is emerging as a promising tool for cancer's diagnosis and prognosis, and also treatment monitoring.
Collapse
Affiliation(s)
- Maria Bogdan
- Department of Pharmacology, Faculty of Pharmacy, University of Medicine and Pharmacy, 200349 Craiova, Romania
| | - Andreea-Daniela Meca
- Department of Pharmacology, Faculty of Pharmacy, University of Medicine and Pharmacy, 200349 Craiova, Romania
| | - Adina Turcu-Stiolica
- Department of Pharmacoeconomics, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Carmen Nicoleta Oancea
- Department of Biochemistry, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Roxana Kostici
- Department of Toxicology, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Marin Valeriu Surlin
- Department of General Surgery, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Cristina Florescu
- Department of Cardiology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| |
Collapse
|
|
7
|
Gordon A, Johnston E, Lau DK, Starling N. Targeting FGFR2 Positive Gastroesophageal Cancer: Current and Clinical Developments. Onco Targets Ther 2022; 15:1183-1196. [PMID: 36238135 PMCID: PMC9553429 DOI: 10.2147/ott.s282718] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 08/29/2022] [Indexed: 11/06/2022] Open
Abstract
Despite recent advances in the systemic treatment of gastroesophageal cancers, prognosis remains poor. Comprehensive molecular analyses have characterized the genomic landscape of gastroesophageal cancer that has established therapeutic targets such as human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor receptor (VEGFR) and programmed death ligand 1 (PD-L1). The aberrant fibroblast growth factor receptor 2 (FGFR2) pathway is attractive for targetable therapy with FGFR inhibition based on preclinical data showing a pivotal role in the progression of gastric cancer (GC). FGFR2 amplification is the most common FGFR2 gene aberration in gastroesophageal cancer, and most associated with diffuse GC, which is often linked to poorer prognostic outcomes. There has been considerable progress with drug development focused on FGFR inhibition. At present, there is no approved FGFR inhibitor for FGFR2 positive gastroesophageal cancer. A selective FGFR2b monoclonal antibody bemarituzumab is currently being investigated in the first phase III randomized trial for patients with first line advanced GC, which may change the treatment paradigm for FGFR2b positive GC. The role of FGFR signalling, specifically FGFR2, is less established in oesophageal squamous cell cancer (ESCC) with a paucity of evidence for clinical benefit in these patients. Precision medicine is part of the wider approach in gastrointestinal cancers; however, it can be challenging due to heterogeneity and here circulating tumour DNA (ctDNA) for patient selection may have future clinical utility. In our review, we outline the FGFR pathway and focus on the developments and challenges of targeting FGFR2 driven gastroesophageal cancers.
Collapse
Affiliation(s)
- Anderley Gordon
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation, London, UK
| | - Edwina Johnston
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation, London, UK
| | - David K Lau
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation, London, UK
| | - Naureen Starling
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation, London, UK,Correspondence: Naureen Starling, Gastrointestinal and Lymphoma Unit, The Royal Marsden Hospital, Downs Road, Sutton, Surrey, SM2 5PT, United Kingdom, Tel +44 2086426011, Email
| |
Collapse
|
|
8
|
Receptor Tyrosine Kinases Amplified in Diffuse-Type Gastric Carcinoma: Potential Targeted Therapies and Novel Downstream Effectors. Cancers (Basel) 2022; 14:cancers14153750. [PMID: 35954414 PMCID: PMC9367326 DOI: 10.3390/cancers14153750] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/28/2022] [Accepted: 07/28/2022] [Indexed: 11/28/2022] Open
Abstract
Simple Summary Diffuse-type gastric carcinoma (DGC) is an aggressive subtype of gastric carcinoma with an extremely poor prognosis due to frequent peritoneal metastasis and high probability of recurrence. Its pathogenesis is poorly understood, and consequently, no effective molecular targeted therapy is available. The importance of oncogenic receptor tyrosine kinase (RTK) signaling has been recently demonstrated in the malignant progression of DGC. In particular, RTK gene amplification appears to accelerate peritoneal metastasis. In this review, we provide an overview of RTK gene amplification in DGC and the potential of related targeted therapies. Abstract Gastric cancer (GC) is a major cause of cancer-related death worldwide. Patients with an aggressive subtype of GC, known as diffuse-type gastric carcinoma (DGC), have extremely poor prognoses. DGC is characterized by rapid infiltrative growth, massive desmoplastic stroma, frequent peritoneal metastasis, and high probability of recurrence. These clinical features and progression patterns of DGC substantially differ from those of other GC subtypes, suggesting the existence of specific oncogenic signals. The importance of gene amplification and the resulting aberrant activation of receptor tyrosine kinase (RTK) signaling in the malignant progression of DGC is becoming apparent. Here, we review the characteristics of RTK gene amplification in DGC and its importance in peritoneal metastasis. These insights may potentially lead to new targeted therapeutics.
Collapse
|
|
9
|
Schrumpf T, Behrens HM, Haag J, Krüger S, Röcken C. FGFR2 overexpression and compromised survival in diffuse-type gastric cancer in a large central European cohort. PLoS One 2022; 17:e0264011. [PMID: 35167603 PMCID: PMC8846517 DOI: 10.1371/journal.pone.0264011] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 02/01/2022] [Indexed: 12/24/2022] Open
Abstract
The significance of fibroblast growth factor receptor 2 (FGFR2) in gastric cancer (GC) has been studied predominantly in Asian patient cohorts. Data on White patients are scarce. Here, we aimed to independently validate the expression and putative tumor biological significance of FGFR2 in a large non-Asian GC cohort. Immunohistochemistry (IHC) was performed on large-area tissue sections from 493 patients with GC and evaluated using the HScore. GCs with moderate and strong FGFR2 expression were studied for Fgfr2 amplification using chromogenic in situ hybridization (CISH). Median overall survival was determined using the Kaplan–Meier method. The majority [240 (99.1%)] of FGFR2-positive GCs showed a variable combination of staining intensities with marked intratumoral heterogeneity, including weak [198 (40.2%) cases], moderate [145 (29.4%)], and strong [108 (21.9%)] staining in diverse combinations. 250 (50.9%) GCs expressed no FGFR2. Fgfr2 gene amplification was found in 40% of selected cases with high protein expression and was also heterogeneous at the cell level. FGFR2 protein expression did not correlate with patient survival in the entire cohort However, using different cutoff values, a negative correlation between FGFR2-expression and patient outcome was found for diffuse-type GC. FGFR2 expression was associated with a lower tumor grade and intestinal phenotype (p≤0.0001). FGFR2–positive diffuse-type GCs classify a small subset of patients with a poor tumor specific survival (5.29±1.3 vs. 14.67±1.9 months; p = 0.004).
Collapse
Affiliation(s)
- Thorben Schrumpf
- Dept. of Pathology, Christian-Albrechts-University, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Hans-Michael Behrens
- Dept. of Pathology, Christian-Albrechts-University, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Jochen Haag
- Dept. of Pathology, Christian-Albrechts-University, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Sandra Krüger
- Dept. of Pathology, Christian-Albrechts-University, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Christoph Röcken
- Dept. of Pathology, Christian-Albrechts-University, University Hospital Schleswig-Holstein, Kiel, Germany
- * E-mail:
| |
Collapse
|
|
10
|
Cheng X, Qian L, Wang B, Tan M, Li J. SPA: A Quantitation Strategy for MS Data in Patient-derived Xenograft Models. GENOMICS PROTEOMICS & BIOINFORMATICS 2021; 19:522-533. [PMID: 33631430 PMCID: PMC9040016 DOI: 10.1016/j.gpb.2019.11.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 09/12/2019] [Accepted: 11/11/2019] [Indexed: 11/29/2022]
Abstract
With the development of mass spectrometry (MS)-based proteomics technologies, patient-derived xenograft (PDX), which is generated from the primary tumor of a patient, is widely used for the proteome-wide analysis of cancer mechanism and biomarker identification of a drug. However, the proteomics data interpretation is still challenging due to complex data deconvolution from the PDX sample that is a cross-species mixture of human cancerous tissues and immunodeficient mouse tissues. In this study, by using the lab-assembled mixture of human and mouse cells with different mixing ratios as a benchmark, we developed and evaluated a new method, SPA (shared peptide allocation), for protein quantitation by considering the unique and shared peptides of both species. The results showed that SPA could provide more convenient and accurate protein quantitation in human–mouse mixed samples. Further validation on a pair of gastric PDX samples (one bearing FGFR2 amplification while the other one not) showed that our new method not only significantly improved the overall protein identification, but also detected the differential phosphorylation of FGFR2 and its downstream mediators (such as RAS and ERK) exclusively. The tool pdxSPA is freely available at https://github.com/Li-Lab-Proteomics/pdxSPA.
Collapse
Affiliation(s)
- Xi Cheng
- Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Lili Qian
- The Chemical Proteomics Center and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Bo Wang
- Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Minjia Tan
- The Chemical Proteomics Center and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
| | - Jing Li
- Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
| |
Collapse
|
|
11
|
Lau DK, Luk IY, Jenkins LJ, Martin A, Williams DS, Schoffer KL, Chionh F, Buchert M, Sjoquist K, Boussioutas A, Hayes SA, Ernst M, Weickhardt AJ, Pavlakis N, Tebbutt NC, Mariadason JM. Rapid Resistance of FGFR-driven Gastric Cancers to Regorafenib and Targeted FGFR Inhibitors can be Overcome by Parallel Inhibition of MEK. Mol Cancer Ther 2021; 20:704-715. [PMID: 33563752 DOI: 10.1158/1535-7163.mct-20-0836] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 11/16/2020] [Accepted: 02/02/2021] [Indexed: 11/16/2022]
Abstract
Amplification or overexpression of the FGFR family of receptor tyrosine kinases occurs in a significant proportion of gastric cancers. Regorafenib is a multikinase inhibitor of angiogenic and oncogenic kinases, including FGFR, which showed activity in the randomized phase II INTEGRATE clinical trial in advanced gastric cancer. There are currently no biomarkers that predict response to this agent, and whether regorafenib is preferentially active in FGFR-driven cancers is unknown. Through screening 25 gastric cancer cell lines, we identified five cell lines that were exquisitely sensitive to regorafenib, four of which harbored amplification or overexpression of FGFR family members. These four cell lines were also sensitive to the FGFR-specific inhibitors, BGJ398, erdafitinib, and TAS-120. Regorafenib inhibited FGFR-driven MAPK signaling in these cell lines, and knockdown studies confirmed their dependence on specific FGFRs for proliferation. In the INTEGRATE trial cohort, amplification or overexpression of FGFRs 1-4 was detected in 8%-19% of cases, however, this was not associated with improved progression-free survival and no objective responses were observed in these cases. Further preclinical analyses revealed FGFR-driven gastric cancer cell lines rapidly reactivate MAPK/ERK signaling in response to FGFR inhibition, which may underlie the limited clinical response to regorafenib. Importantly, combination treatment with an FGFR and MEK inhibitor delayed MAPK/ERK reactivation and synergistically inhibited proliferation of FGFR-driven gastric cancer cell lines. These findings suggest that upfront combinatorial inhibition of FGFR and MEK may represent a more effective treatment strategy for FGFR-driven gastric cancers.
Collapse
Affiliation(s)
- David K Lau
- Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.,School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia
| | - Ian Y Luk
- Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.,School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia
| | - Laura J Jenkins
- Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.,School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia
| | - Andrew Martin
- NHMRC Clinical trials Centre, Sydney University, Sydney, New South Wales, Australia.,Cancer Care Centre, St. George Hospital, Kogarah, New South Wales, Australia
| | - David S Williams
- Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia
| | - Kael L Schoffer
- Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia
| | - Fiona Chionh
- Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.,School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia
| | - Michael Buchert
- Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.,School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia
| | - Katrin Sjoquist
- NHMRC Clinical trials Centre, Sydney University, Sydney, New South Wales, Australia.,Cancer Care Centre, St. George Hospital, Kogarah, New South Wales, Australia
| | - Alex Boussioutas
- Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Department of Medicine, University of Melbourne, Parkville, Victoria, Australia
| | - Sarah A Hayes
- Kolling Institute for Medical Research, Royal North Shore Hospital, Sydney, New South Wales, Australia
| | - Matthias Ernst
- Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.,School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia
| | - Andrew J Weickhardt
- Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.,School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia
| | - Nick Pavlakis
- Kolling Institute for Medical Research, Royal North Shore Hospital, Sydney, New South Wales, Australia
| | - Niall C Tebbutt
- Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia. .,Department of Medical Oncology, Austin Health, Heidelberg, Victoria, Australia.,Department of Surgery, University of Melbourne, Melbourne, Victoria, Australia
| | - John M Mariadason
- Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia. .,School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia.,Cancer Care Centre, St. George Hospital, Kogarah, New South Wales, Australia
| |
Collapse
|
|
12
|
[Intratumoral heterogeneity of gastric cancer-impact on biomarker evaluation]. DER PATHOLOGE 2021; 41:76-82. [PMID: 33427920 DOI: 10.1007/s00292-020-00881-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 11/23/2020] [Indexed: 12/23/2022]
Abstract
BACKGROUND Gastric carcinomas often measure more than 5 cm at primary diagnosis. Predictive biomarker testing is usually carried out on tissue biopsies, which do not represent the entire tumor biology and intratumoral heterogeneity. OBJECTIVES The aim of this study was to explore gastric cancer's intratumoral heterogeneity and its impact on the evaluation of predictive and prognostic biomarkers. MATERIALS AND METHODS The study cohort consisted of approximately 500 patients with therapy-naive adenocarcinomas of the stomach or the esophagogastric junction. The following biomarkers were determined: HER2, MET, Ki67, PD-L1/PD‑1, VISTA, EBV-status, and PIK3CA. RESULTS All examined biomarkers were influenced by gastric cancer's intratumoral heterogeneity. Tissue biopsies might carry the risk of sampling errors, which may significantly hamper adequate tumor classification in a clinical setting. CONCLUSIONS Our findings unravel issues of tumor heterogeneity in gastric cancer. Biomarker diagnostics on tissue biopsies should be carried out on at least five biopsies of different tumor areas. If possible, biomarker diagnostics should be repeated on resection specimens. Tissue microarrays should no longer be used for research studies of gastric cancer.
Collapse
|
|
13
|
Bonelli P, Borrelli A, Tuccillo FM, Silvestro L, Palaia R, Buonaguro FM. Precision medicine in gastric cancer. World J Gastrointest Oncol 2019; 11:804-829. [PMID: 31662821 PMCID: PMC6815928 DOI: 10.4251/wjgo.v11.i10.804] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 07/11/2019] [Accepted: 09/05/2019] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer (GC) is a complex disease linked to a series of environmental factors and unhealthy lifestyle habits, and especially to genetic alterations. GC represents the second leading cause of cancer-related deaths worldwide. Its onset is subtle, and the majority of patients are diagnosed once the cancer is already advanced. In recent years, there have been innovations in the management of advanced GC including the introduction of new classifications based on its molecular characteristics. Thanks to new technologies such as next-generation sequencing and microarray, the Cancer Genome Atlas and Asian Cancer Research Group classifications have also paved the way for precision medicine in GC, making it possible to integrate diagnostic and therapeutic methods. Among the objectives of the subdivision of GC into subtypes is to select patients in whom molecular targeted drugs can achieve the best results; many lines of research have been initiated to this end. After phase III clinical trials, trastuzumab, anti-Erb-B2 receptor tyrosine kinase 2 (commonly known as ERBB2) and ramucirumab, anti-vascular endothelial growth factor receptor 2 (commonly known as VEGFR2) monoclonal antibodies, were approved and introduced into first- and second-line therapies for patients with advanced/metastatic GC. However, the heterogeneity of this neoplasia makes the practical application of such approaches difficult. Unfortunately, scientific progress has not been matched by progress in clinical practice in terms of significant improvements in prognosis. Survival continues to be low in contrast to the reduction in deaths from many common cancers such as colorectal, lung, breast, and prostate cancers. Although several target molecules have been identified on which targeted drugs can act and novel products have been introduced into experimental therapeutic protocols, the overall approach to treating advanced stage GC has not substantially changed. Currently, surgical resection with adjuvant or neoadjuvant radiotherapy and chemotherapy are the most effective treatments for this disease. Future research should not underestimate the heterogeneity of GC when developing diagnostic and therapeutic strategies aimed toward improving patient survival.
Collapse
Affiliation(s)
- Patrizia Bonelli
- Molecular Biology and Viral Oncology, Istituto Nazionale Tumori - IRCCS - Fondazione G Pascale, Napoli 80131, Italy
| | - Antonella Borrelli
- Molecular Biology and Viral Oncology, Istituto Nazionale Tumori - IRCCS - Fondazione G Pascale, Napoli 80131, Italy
| | - Franca Maria Tuccillo
- Molecular Biology and Viral Oncology, Istituto Nazionale Tumori - IRCCS - Fondazione G Pascale, Napoli 80131, Italy
| | - Lucrezia Silvestro
- Abdominal Medical Oncology, Istituto Nazionale Tumori - IRCCS - Fondazione G Pascale, Napoli 80131, Italy
| | - Raffaele Palaia
- Gastro-pancreatic Surgery Division, Istituto Nazionale Tumori - IRCCS - Fondazione G Pascale, Napoli 80131, Italy
| | - Franco Maria Buonaguro
- Molecular Biology and Viral Oncology, Istituto Nazionale Tumori - IRCCS - Fondazione G Pascale, Napoli 80131, Italy
| |
Collapse
|
|
14
|
Sun GK, Tang LJ, Zhou JD, Xu ZJ, Yang L, Yuan Q, Ma JC, Liu XH, Lin J, Qian J, Yao DM. DOK6 promoter methylation serves as a potential biomarker affecting prognosis in de novo acute myeloid leukemia. Cancer Med 2019; 8:6393-6402. [PMID: 31486300 PMCID: PMC6797566 DOI: 10.1002/cam4.2540] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Revised: 08/14/2019] [Accepted: 08/22/2019] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND Downstream of tyrosine kinase 6 (DOK6), which is specifically expressed in the nervous system, was previously recognized as an adapter only in neurite outgrowth. Recent studies also demonstrated the potential role of DOK6 in solid tumors such as gastric cancer and breast cancer. However, previous studies of DOK6 have not dealt with its roles in myeloid malignancies. Herein, we verified the promoter methylation status of DOK6 and further explored its clinical implication in de novo acute myeloid leukemia (AML). METHODS A total of 100 newly diagnosed adult AML patients were involved in the current study. DOK6 expression and methylation were detected by real-time qPCR and methylation-specific PCR (MSP), respectively. Bisulfite sequencing PCR (BSP) was performed to assess the methylation density of the DOK6 promoter. RESULTS Downstream of tyrosine kinase 6 promoter methylation was significantly increased in AML patients compared to controls (P = .037), whereas DOK6 expression significantly decreased in AML patients (P < .001). The expression of DOK6 was markedly up-regulated after treated by 5-aza-2'-deoxycytidine (5-aza-dC) in THP-1 cell lines. The methylation status of the DOK6 promoter was associated with French-American-British classifications (P = .037). There was no significant correlation existed between DOK6 expression and its promoter methylation (R = .077, P = .635). Interestingly, of whole-AML and non-APL AML patients, both have a tendency pertaining to the DOK6 methylation group and a significantly longer overall survival (OS) than the DOK6 unmethylation group (P = .042 and .036, respectively). CONCLUSION Our study suggested that DOK6 promoter hypermethylation was a common molecular event in de novo AML patients. Remarkably, DOK6 promoter methylation could serve as an independent and integrated prognostic biomarker not only in non-APL AML patients but also in AML patients who are less than 60 years old.
Collapse
Affiliation(s)
- Guo-Kang Sun
- Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China.,The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China
| | - Li-Juan Tang
- Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China.,The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China
| | - Jing-Dong Zhou
- Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China.,The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China
| | - Zi-Jun Xu
- Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China.,The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China
| | - Lan Yang
- Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China.,The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China
| | - Qian Yuan
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China.,The Key Lab of Precision Diagnosis and Treatment in Hematologic Malignancies of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China
| | - Ji-Chun Ma
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China.,The Key Lab of Precision Diagnosis and Treatment in Hematologic Malignancies of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China
| | - Xing-Hui Liu
- Department of Clinical Laboratory, Shanghai Gongli Hospital, The Second Military Medical University, Shanghai, China
| | - Jiang Lin
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China.,The Key Lab of Precision Diagnosis and Treatment in Hematologic Malignancies of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China
| | - Jun Qian
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China.,The Key Lab of Precision Diagnosis and Treatment in Hematologic Malignancies of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China.,Department of Hematology, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
| | - Dong-Ming Yao
- Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China.,The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China
| |
Collapse
|
|
15
|
Evaluation of Intratumoral and Intertumoral Heterogeneity of MET Protein Expression in Gastric Cancer. Appl Immunohistochem Mol Morphol 2019; 26:445-453. [PMID: 28968267 DOI: 10.1097/pai.0000000000000448] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Tumor heterogeneity of a target molecule could contribute to failure of the targeted therapy. We investigated the heterogeneity of MET expression within same primary gastric cancer (GC) and between primary and corresponding secondary GC lesions using immunohistochemistry (IHC). Intratumoral heterogeneity was defined as discordant MET status among 3 tissue microarray cores (3 different areas of same tumor). IHC 3+ was considered positive for MET overexpression. MET overexpression was observed in 2.7% (50/1869) of all examined cores and 5.3% (33/623) of primary GCs. When we compared MET IHC results between 3 cores from each tumor, intratumoral heterogeneity was identified (65.0% in total 623 cases; 84.4% in 480 cases with any staining intensity; 84.9% in 251 cases with moderate to strong intensity; 90.9% in 33 cases with strong intensity). Of 33 MET-overexpressed GCs, the average proportion of strongly stained area was 19.6% in the whole sections. Of 269 cases with primary GC and regional lymph node metastasis, 17 (6.3%) showed MET positivity in which 9 (52.9%) were discordant (negative conversion). In 123 cases with primary and corresponding local recurrent/distant metastatic GC, 3 (2.4%) showed MET positivity in which 2 (66.7%) were discordant (positive conversion). In the survival analysis, MET IHC 3+ in lymph node metastases was an independent negative prognostic factor for overall survival. We found that MET overexpression is uncommon and highly heterogeneous in GC. This severe heterogeneity of MET status should be considered in tissue sampling and development of biomarkers for anti-MET therapy.
Collapse
|
|
16
|
Kim HS, Kim JH, Jang HJ. Pathologic and prognostic impacts of FGFR2 amplification in gastric cancer: a meta-analysis and systemic review. J Cancer 2019; 10:2560-2567. [PMID: 31258762 PMCID: PMC6584337 DOI: 10.7150/jca.29184] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Accepted: 04/12/2019] [Indexed: 01/10/2023] Open
Abstract
Fibroblast growth factor receptor-2 (FGFR2) gene is amplified in up to 15% of patients with gastric cancer (GC). However, the prognostic significance of FGFR2 amplification has been controversial. This meta-analysis was conducted to evaluate the clinicopathological impacts of FGFR2 amplification in patients with GC. We performed a systematic computerized search of the electronic databases of PubMed, PMC, EMBASE, Web of Science, and Google Scholar and selected studies assessing the correlation of FGFR2 amplification with pathologic features and/or prognosis in gastric adenocarcinoma. From eight studies, 2,377 patients were included in the pooled analysis of odds ratios (ORs) with 95% confidence intervals (CIs) for pathologic findings and hazard ratios (HRs) with 95% CIs for overall survival. FGFR2 amplification was significantly associated with LN metastasis (OR = 3.93, 95% CI: 2.22-6.96, p < 0.00001) and poorly differentiated adenocarcinoma (OR = 2.36, 95% CI: 1.03-5.39, p = 0.04). In addition, patients with GC harboring FGFR2 amplification showed significantly worse survival (HR = 2.09, 95% CI: 1.68-2.59, p < 0.00001), compared with patients with FGFR2-unamplified GC. In conclusion, this meta-analysis indicates that FGFR2 amplification is an adverse prognostic factor in patients with GC.
Collapse
Affiliation(s)
- Hyeong Su Kim
- Division of Hemato-Oncology, Department of Internal Medicine, Kangnam Sacred-Heart Hospital, Hallym University Medical Center, Hallym University College of Medicine, Seoul, Republic of Korea
| | - Jung Han Kim
- Division of Hemato-Oncology, Department of Internal Medicine, Kangnam Sacred-Heart Hospital, Hallym University Medical Center, Hallym University College of Medicine, Seoul, Republic of Korea
| | - Hyun Joo Jang
- Division of Gastroenterology, Department of Internal Medicine, Dongtan Sacred-Heart Hospital, Hallym University Medical Center, Hallym University College of Medicine, Hwasung, Republic of Korea
| |
Collapse
|
|
17
|
Tokumaru Y, Tajirika T, Sugito N, Kuranaga Y, Shinohara H, Tsujino T, Matsuhashi N, Futamura M, Akao Y, Yoshida K. Synthetic miR-143 Inhibits Growth of HER2-Positive Gastric Cancer Cells by Suppressing KRAS Networks Including DDX6 RNA Helicase. Int J Mol Sci 2019; 20:ijms20071697. [PMID: 30959742 PMCID: PMC6479539 DOI: 10.3390/ijms20071697] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2019] [Accepted: 04/03/2019] [Indexed: 12/14/2022] Open
Abstract
Gastric cancer (GC) is one of the most common cancers worldwide. In the clinical setting, the identification of HER2 overexpression in GC was a significant finding, as trastuzumab, an anti-HER2 drug, provides a survival advantage to HER2-positive GC patients. In HER2-postive GC, the dysregulation of PI3K/AKT and MAPK/ERK signaling pathways has been reported, and inhibition of these pathways is an important therapeutic strategy. MiR-143 is known to act as a tumor suppressor in several cancers, such as bladder cancer, breast cancer, colorectal cancer, and gastric cancer. In the current study, we developed a novel chemically-modified miR-143 and explored the functions of this synthetic miR-143 (syn-miR-143) in HER2-positive gastric cancer. The expression level of miR-143 was down-regulated in GC cell lines, including HER2-positive GC cell lines, MKN7, and KATO-III. The ectopic expression of miR-143 in those cell lines suppressed cell growth through systemic silencing of KRAS and its effector signaling molecules, AKT and ERK. Furthermore, syn-miR-143 indirectly down-regulated the expression of HER2, an upstream molecule of KRAS, through silencing DEAD/H-box RNA helicase 6 (DDX6), RNA helicase, which enhanced HER2 protein expression at the translational step in HER2-positive GC cells. These findings suggested that syn-miR-143 acted as a tumor suppressor through the impairment of KRAS networks including the DDX6.
Collapse
Affiliation(s)
- Yoshihisa Tokumaru
- United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan.
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan.
| | - Toshihiro Tajirika
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan.
| | - Nobuhiko Sugito
- United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan.
| | - Yuki Kuranaga
- United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan.
| | - Haruka Shinohara
- United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan.
| | - Takuya Tsujino
- United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan.
- Department of Urology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan.
| | - Nobuhisa Matsuhashi
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan.
| | - Manabu Futamura
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan.
| | - Yukihiro Akao
- United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan.
| | - Kazuhiro Yoshida
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan.
| |
Collapse
|
|
18
|
Creemers A, Ebbing EA, Pelgrim TC, Lagarde SM, van Etten-Jamaludin FS, van Berge Henegouwen MI, Hulshof MCCM, Krishnadath KK, Meijer SL, Bijlsma MF, van Oijen MGH, van Laarhoven HWM. A systematic review and meta-analysis of prognostic biomarkers in resectable esophageal adenocarcinomas. Sci Rep 2018; 8:13281. [PMID: 30185893 PMCID: PMC6125467 DOI: 10.1038/s41598-018-31548-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Accepted: 08/20/2018] [Indexed: 02/07/2023] Open
Abstract
Targeted therapy is lagging behind in esophageal adenocarcinoma (EAC). To guide the development of new treatment strategies, we provide an overview of the prognostic biomarkers in resectable EAC treated with curative intent. The Medline, Cochrane and EMBASE databases were systematically searched, focusing on overall survival (OS). The quality of the studies was assessed using a scoring system ranging from 0-7 points based on modified REMARK criteria. To evaluate all identified prognostic biomarkers, the hallmarks of cancer were adapted to fit all biomarkers based on their biological function in EAC, resulting in the features angiogenesis, cell adhesion and extra-cellular matrix remodeling, cell cycle, immune, invasion and metastasis, proliferation, and self-renewal. Pooled hazard ratios (HR) and 95% confidence intervals (CI) were derived by random effects meta-analyses performed on each hallmarks of cancer feature. Of the 3298 unique articles identified, 84 were included, with a mean quality of 5.9 points (range 3.5-7). The hallmarks of cancer feature 'immune' was most significantly associated with worse OS (HR 1.88, (95%CI 1.20-2.93)). Of the 82 unique prognostic biomarkers identified, meta-analyses showed prominent biomarkers, including COX-2, PAK-1, p14ARF, PD-L1, MET, LC3B, IGFBP7 and LGR5, associated to each hallmark of cancer.
Collapse
Affiliation(s)
- Aafke Creemers
- Laboratory of Experimental Oncology and Radiobiology, Amsterdam UMC, Univ of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands.
- Department of Medical Oncology, Amsterdam UMC, Univ of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands.
| | - Eva A Ebbing
- Laboratory of Experimental Oncology and Radiobiology, Amsterdam UMC, Univ of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
- Department of Medical Oncology, Amsterdam UMC, Univ of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Thomas C Pelgrim
- Department of Medical Oncology, Amsterdam UMC, Univ of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Sjoerd M Lagarde
- Department of Surgery, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Faridi S van Etten-Jamaludin
- Department of Medical Library Science, Amsterdam UMC, Univ of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | | | - Maarten C C M Hulshof
- Department of Radiotherapy, Amsterdam UMC, Univ of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Kausilia K Krishnadath
- Laboratory of Experimental Oncology and Radiobiology, Amsterdam UMC, Univ of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
- Department of Gastroenterology, Amsterdam UMC, Univ of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Sybren L Meijer
- Department of Pathology, Amsterdam UMC, Univ of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Maarten F Bijlsma
- Laboratory of Experimental Oncology and Radiobiology, Amsterdam UMC, Univ of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Martijn G H van Oijen
- Department of Medical Oncology, Amsterdam UMC, Univ of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Hanneke W M van Laarhoven
- Laboratory of Experimental Oncology and Radiobiology, Amsterdam UMC, Univ of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
- Department of Medical Oncology, Amsterdam UMC, Univ of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
| |
Collapse
|
|
19
|
Lee SY, Na YJ, Jeong YA, Kim JL, Oh SC, Lee DH. Upregulation of EphB3 in gastric cancer with acquired resistance to a FGFR inhibitor. Int J Biochem Cell Biol 2018; 102:128-137. [PMID: 30044964 DOI: 10.1016/j.biocel.2018.07.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Revised: 07/20/2018] [Accepted: 07/21/2018] [Indexed: 11/16/2022]
Abstract
Amplification of fibroblast growth factor receptor2 (FGFR2) has been regarded as a druggable target in gastric cancer (GC). Despite known potential of AZD4547, a selective inhibitor of FGFR 1-3, to suppress tumorigenic effects of activated FGFR2, resistance to the targeted agent has been an unresolved issue. This study was performed to elucidate the mechanism of AZD4547 resistance in GC cells. SNU-16 cells were used to establish an AZD4547-resistant GC cell line, SNU-16R. Elevated phosphorylation of EphB3 was confirmed using the Human Phospho-Receptor Tyrosine Kinase Array kit. A tyrosine kinase inhibitor (TKI) of EphB3 was used to investigate the effects of suppressed EphB3 activity in the SNU-16R cell line. SNU-16R cells exhibited upregulated phosphorylation of EphB3. Treatment of SNU-16R cells with the EphB3 TKI resulted in induction of apoptosis, decreased cellular viability, and cell cycle arrest at sub-G1 phase. SNU-16R cells expressed upregulated levels of N-cadherin, vimentin, Snail, matrix metalloproteinase 2 (MMP-2), and MMP-9, and reduced levels of E-cadherin, characteristic of epithelial to mesenchymal transition (EMT). Matrigel invasion assay also demonstrated the increased invasiveness of SNU-16R cells. EphB3 TKI treatment inhibited EMT of SNU-16R cells. Activation of mammalian target of rapamycin (mTOR) through the Ras-ERK1/2 pathway was suggested as the signal transduction mechanism downstream EphB3 by showing enhanced phosphorylation of Raf-1, MEK1/2, ERK1/2, mTOR and its downstream substrates in SNU-16R cells. As expected, EphB3 TKI decreased phosphorylation of these proteins. Our data suggest phosphorylation of mTOR through signaling by EphB3 is a potential mechanism of AZD4547 resistance in GC cells.
Collapse
Affiliation(s)
- Suk-Young Lee
- Division of Oncology/Hematology, Department of Internal Medicine, College of Medicine, Korea University, 148 Gurodong-ro, Guro-gu, Seoul 08308, Republic of Korea.
| | - Yoo Jin Na
- Division of Oncology/Hematology, Department of Internal Medicine, College of Medicine, Korea University, 148 Gurodong-ro, Guro-gu, Seoul 08308, Republic of Korea.
| | - Yoon A Jeong
- Division of Oncology/Hematology, Department of Internal Medicine, College of Medicine, Korea University, 148 Gurodong-ro, Guro-gu, Seoul 08308, Republic of Korea.
| | - Jung Lim Kim
- Division of Oncology/Hematology, Department of Internal Medicine, College of Medicine, Korea University, 148 Gurodong-ro, Guro-gu, Seoul 08308, Republic of Korea.
| | - Sang Cheul Oh
- Division of Oncology/Hematology, Department of Internal Medicine, College of Medicine, Korea University, 148 Gurodong-ro, Guro-gu, Seoul 08308, Republic of Korea.
| | - Dae-Hee Lee
- Division of Oncology/Hematology, Department of Internal Medicine, College of Medicine, Korea University, 148 Gurodong-ro, Guro-gu, Seoul 08308, Republic of Korea; Brain Korea 21 Program for Biomedicine Science, College of Medicine, Korea University, 148 Gurodong-ro, Guro-gu, Seoul 08308, Republic of Korea.
| |
Collapse
|
|
20
|
Matsuoka T, Yashiro M. Biomarkers of gastric cancer: Current topics and future perspective. World J Gastroenterol 2018; 24:2818-2832. [PMID: 30018477 PMCID: PMC6048430 DOI: 10.3748/wjg.v24.i26.2818] [Citation(s) in RCA: 302] [Impact Index Per Article: 43.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 05/19/2018] [Accepted: 06/01/2018] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is one of the most prevalent malignant types in the world and an aggressive disease with a poor 5-year survival. This cancer is biologically and genetically heterogeneous with a poorly understood carcinogenesis at the molecular level. Although the incidence is declining, the outcome of patients with GC remains dismal. Thus, the detection at an early stage utilizing useful screening approaches, selection of an appropriate treatment plan, and effective monitoring is pivotal to reduce GC mortalities. Identification of biomarkers in a basis of clinical information and comprehensive genome analysis could improve diagnosis, prognosis, prediction of recurrence and treatment response. This review summarized the current status and approaches in GC biomarker, which could be potentially used for early diagnosis, accurate prediction of therapeutic approaches and discussed the future perspective based on the molecular classification and profiling.
Collapse
Affiliation(s)
- Tasuku Matsuoka
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Masakazu Yashiro
- Oncology Institute of Geriatrics and Medical Science, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| |
Collapse
|
|
21
|
Neves Filho EHC, Pires APB, de Sant'Ana RO, Rabenhorst SHB, Hirth CG, da Cunha MDPSS. The association among HER2, MET and FOXP3 expression and tumor regression grading in gastric adenocarcinoma. APMIS 2018; 126:389-395. [PMID: 29696715 DOI: 10.1111/apm.12840] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 03/06/2018] [Indexed: 12/13/2022]
Abstract
Although the introduction of the perioperative chemotherapy on the management of gastric cancer has improved patients survival, heterogeneity of clinical outcomes has been evidenced in parallel to different histopathological regression pattern of gastric cancer cells. Thus, this study evaluated the tumor regression grading (TRG) in a series of post-treatment gastric tumors and its associations with HER2, MET, and FOXP3 expression. Material of 54 gastric cancer samples was available for TRG evaluation and immunohistochemistry. We found that total and subtotal pathologic response were significantly associated to the intestinal subtype (p = 0.04) and that well-differentiated tumors were significantly correlated with total or partial response (p = 0.019). Although not associated with the TRG, FOXP3 expression in gastric tumors was associated to poorly differentiated tumors (p = 0.03), to the diffuse and mixed subtypes together (p = 0.04) and to the presence of vascular infiltration (p = 0.04), while HER2 overexpression was associated to better differentiated cases (p = 0.04) and to the absence of vascular infiltration (p = 0.02). MET expression, however, showed no association with the analyzed clinicopathological factors. This study highlights the role of tissue differentiation on pathological response to neoadjuvant chemotherapy in gastric cancer and shows no impact between FOXP3, HER2 and MET expression in terms of TRG.
Collapse
|
|
22
|
Park CK, Park JS, Kim HS, Rha SY, Hyung WJ, Cheong JH, Noh SH, Lee SK, Lee YC, Huh YM, Kim H. Receptor tyrosine kinase amplified gastric cancer: Clinicopathologic characteristics and proposed screening algorithm. Oncotarget 2018; 7:72099-72112. [PMID: 27765925 PMCID: PMC5342148 DOI: 10.18632/oncotarget.12291] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Accepted: 09/17/2016] [Indexed: 12/12/2022] Open
Abstract
Although targeted therapy for receptor tyrosine kinases (RTKs) of advanced gastric cancers (AGCs) has been in the spotlight, guidelines for the identification of RTK-amplified gastric cancers (RA-GCs) have not been established. In this study, we investigate clinicopathologic characteristics of RA-GCs and propose a screening algorithm for their identification. We performed immunohistochemistry (IHC) for MLH1, MSH2, PMS2, MSH6, key RTKs (EGFR, HER2, MET), and p53, in situ hybridization for Epstein-Barr virus encoding RNA, and silver in situ hybridization (SISH) for EGFR, HER2, and MET using tissue microarrays of 993 AGCs. On IHC, 157 (15.8%) 61, (6.15%), and 85 (8.56%) out of 993 cases scored 2+ or 3+ for EGFR, HER2, and MET, respectively. On SISH, 31.2% (49/157), 80.3% (49/61), and 30.6% (26/85) of 2+ or 3+ cases on IHC showed amplification of the corresponding genes. Of the 993 cases, 104 were classified as RA-GCs. RA-GC status correlated with older age (P < 0.001), differentiated histology (P = 0.001), intestinal or mixed type by Lauren classification (P < 0.001), lymphovascular invasion (P = 0.026), and mutant-pattern of p53 (P < 0.001). The cases were divided into four subgroups using two classification systems, putative molecular classification and histologic-molecular classification, based on Lauren classification, IHC, and SISH results. The histologic-molecular classification showed higher sensitivity for identification of RA-GCs and predicted patient prognosis better than the putative molecular classification. In conclusion, RA-GCs show unique clinicopathologic features. The proposed algorithm based on histologic-molecular classification can be applied to select candidates for genetic examination and targeted therapy.
Collapse
Affiliation(s)
- Cheol Keun Park
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Ji Soo Park
- Division of Medical Oncology, Yonsei Cancer Center, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyo Song Kim
- Division of Medical Oncology, Yonsei Cancer Center, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sun Young Rha
- Division of Medical Oncology, Yonsei Cancer Center, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Woo Jin Hyung
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jae-Ho Cheong
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sung Hoon Noh
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sang Kil Lee
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yong Chan Lee
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yong-Min Huh
- YUMS-KRIBB Medical Convergence Research Institute, Department of Radiology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyunki Kim
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
| |
Collapse
|
|
23
|
Zhang J, Guo L, Liu X, Li W, Ying J. MET overexpression, gene amplification and relevant clinicopathological features in gastric adenocarcinoma. Oncotarget 2018; 8:10264-10273. [PMID: 28052014 PMCID: PMC5354657 DOI: 10.18632/oncotarget.14382] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Accepted: 12/13/2016] [Indexed: 12/21/2022] Open
Abstract
This study was conducted to investigate the expression of MET in Chinese gastric adenocarcinoma cohort, the correlation between MET overexpression and clinical pathological features, HER2 expression and MET gene amplification. A total of 816 gastric adenocarcinoma patients were included and MET and HER2 immunohistochemical (IHC) staining were performed. IHC and dual-color silver in situ hybridization analysis were performed in the tissue microarrays, constructed from the 240 patients who were randomly selected. MET overexpression (IHC 3+) was observed in 6.0% (49/816) of the cohort. MET overexpression rate was higher in patients with poor prognostic factors, such as clinical stages III/IV (p =0.012) and pathologic stages T3/T4 (p =0.027). The HER2 overexpression (IHC 3+) rate was 8.8% (72/816) and MET overexpression rate was higher in HER2 positive patients (9.7%, 7/72). A high concordance rate (94.6%) between MET overexpression and gene amplification was demonstrated. Therefore, MET overexpression could serve as a prognostic biomarker and a potential therapeutic target for gastric cancer.
Collapse
Affiliation(s)
- Jing Zhang
- Department of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Lei Guo
- Department of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xiuyun Liu
- Department of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Wenbin Li
- Department of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Jianming Ying
- Department of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| |
Collapse
|
|
24
|
[Effect of basic fibroblast growth factor antibody combined with irinotecan on proliferation and apoptosis of small cell lung cancer H223 cells in vitro]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2017; 37. [PMID: 29180337 PMCID: PMC6779646 DOI: 10.3969/j.issn.1673-4254.2017.11.18] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
OBJECTIVE To study the synergistic inhibitory effects of basic fibroblast growth factor (bFGF) monoclonal antibody (bFGF mAb) and irinotecan on the proliferation of small cell lung cancer H223 cells. METHODS CCK-8 assay and flow cytometry were used to assess the effects of bFGF mAb combined with irinotecan on the proliferation and apoptosis of H223 cells, respectively. Western blotting was performed to analyze the effect of bFGF-mAb combined with irinotecan on AKT and ERK1/2 phosphorylation in the cells. RESULTS Both bFGF mAb and irinotecan alone inhibited H223 cell proliferation in a dose-dependent manner (P<0.05). The inhibitory rate was significantly higher in H223 cells treated with bFGF mAb + irinotecan (54.30%) than in cell treated with bFGF mAb (18.73%) or irinotecan (21.96%) alone (P<0.05). Both bFGF mAb and irinotecan induced H223 cell apoptosis in a dose-dependent manner (P<0.05), and the combined treatment resulted in a significantly higher early apoptosis rates (6.5%) than treatment with bFGF mAb (2.7%) or irinotecan (4.3%) alone (P<0.05). bFGF mAb and irinotecan, either alone or in combination, significantly inhibited the levels of p-AKT protein and p-ERK1/2 protein without obviously affecting AKT and ERK1/2 protein levels. CONCLUSION bFGF mAb and irinotecan produce synergistic inhibitory effects on small cell lung cancer H223 cells by suppressing proliferation and promoting apoptosis of the cells, and can effectively block the MAPK/ERK and PI3K/AKT signaling pathways associated with bFGF.
Collapse
|
|
25
|
Baraniskin A, Van Laethem JL, Wyrwicz L, Guller U, Wasan HS, Matysiak-Budnik T, Gruenberger T, Ducreux M, Carneiro F, Van Cutsem E, Seufferlein T, Schmiegel W. Clinical relevance of molecular diagnostics in gastrointestinal (GI) cancer: European Society of Digestive Oncology (ESDO) expert discussion and recommendations from the 17th European Society for Medical Oncology (ESMO)/World Congress on Gastrointestinal Cancer, Barcelona. Eur J Cancer 2017; 86:305-317. [DOI: 10.1016/j.ejca.2017.09.021] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 09/12/2017] [Indexed: 02/06/2023]
|
|
26
|
Comparison of Clinicopathologic Parameters and Survivals Between Epstein-Barr Virus–positive and Her2-positive Gastric Cancers. Appl Immunohistochem Mol Morphol 2017; 25:609-614. [DOI: 10.1097/pai.0000000000000353] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
|
|
27
|
Hierro C, Alsina M, Sánchez M, Serra V, Rodon J, Tabernero J. Targeting the fibroblast growth factor receptor 2 in gastric cancer: promise or pitfall? Ann Oncol 2017; 28:1207-1216. [DOI: 10.1093/annonc/mdx081] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
|
|
28
|
Moran-Jones K. The Therapeutic Potential of Targeting the HGF/cMET Axis in Ovarian Cancer. Mol Diagn Ther 2017; 20:199-212. [PMID: 27139908 DOI: 10.1007/s40291-016-0201-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Survival rates for ovarian cancer have remained relatively stable for the past 2 decades despite advances in surgical techniques and cytotoxic chemotherapeutics, indicating a requirement for better therapies. One pathway currently proposed for targeting is the HGF/cMET pathway. Upregulated in a number of tumour types, cMET is a tyrosine kinase receptor expressed on epithelial cells. In ovarian cancer, it has been identified as highly expressed in the four major subtypes, with expression estimates ranging from 11 to 68 % of cases. HGF, the only known ligand for cMET, is found at high levels in both serum and ascites in women with ovarian cancer, and is proposed to induce both migration and metastasis. However, clinically validated biomarkers are not yet available for either HGF or cMET, preventing a clear understanding of the true rate of overexpression, or its correlation with prognosis. Despite this, a number of agents against HGF and cMET are currently being investigated in clinical trials for multiple tumour types, including ovarian. However, a lack of patient selection, biomarker usage, and post hoc analysis correlating response with expression has resulted in the majority of these trials showing little beneficial effect from these agents, indicating that additional research is required to determine their usefulness in patients with ovarian cancer.
Collapse
Affiliation(s)
- Kim Moran-Jones
- Wolfson Wohl Cancer Research Centre, University of Glasgow, Switchback Rd, Glasgow, G61 1QH, UK. .,The Kinghorn Cancer Centre, Garvan Institute of Medical Research, 370 Victoria St, Sydney, NSW, 2010, Australia.
| |
Collapse
|
|
29
|
Leong SH, Lwin KM, Lee SS, Ng WH, Ng KM, Tan SY, Ng BL, Carter NP, Tang C, Lian Kon O. Chromosomal breaks at FRA18C: association with reduced DOK6 expression, altered oncogenic signaling and increased gastric cancer survival. NPJ Precis Oncol 2017; 1:9. [PMID: 29872697 PMCID: PMC5859466 DOI: 10.1038/s41698-017-0012-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Revised: 02/16/2017] [Accepted: 02/21/2017] [Indexed: 12/13/2022] Open
Abstract
Chromosomal rearrangements are common in cancer. More than 50% occur in common fragile sites and disrupt tumor suppressors. However, such rearrangements are not known in gastric cancer. Here we report recurrent 18q2 breakpoints in 6 of 17 gastric cancer cell lines. The rearranged chromosome 18, t(9;18), in MKN7 cells was flow sorted and identified by reverse chromosome painting. High-resolution tiling array hybridization mapped breakpoints to DOK6 (docking protein 6) intron 4 in FRA18C (18q22.2) and an intergenic region in 9q22.2. The same rearrangement was detected by FISH in 22% of 99 primary gastric cancers. Intron 4 truncation was associated with reduced DOK6 transcription. Analysis of The Cancer Genome Atlas stomach adenocarcinoma cohort showed significant correlation of DOK6 expression with histological and molecular phenotypes. Multiple oncogenic signaling pathways (gastrin-CREB, NGF-neurotrophin, PDGF, EGFR, ERK, ERBB4, FGFR1, RAS, VEGFR2 and RAF/MAP kinase) known to be active in aggressive gastric cancers were strikingly diminished in gastric cancers with low DOK6 expression. Median survival of patients with low DOK6-expressing tumors was 2100 days compared with 533 days in patients with high DOK6-expressing tumors (log-rank P = 0.0027). The level of DOK6 expression in tumors predicted patient survival independent of TNM stage. These findings point to new functions of human DOK6 as an adaptor that interacts with diverse molecular components of signaling pathways. Our data suggest that DOK6 expression is an integrated biomarker of multiple oncogenic signals in gastric cancer and identify FRA18C as a new cancer-associated fragile site.
Collapse
Affiliation(s)
- Siew Hong Leong
- 1Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610 Singapore.,2Department of Biochemistry, National University of Singapore, 8 Medical Drive, Singapore, 117596 Singapore
| | - Kyaw Myo Lwin
- 1Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610 Singapore
| | - Sze Sing Lee
- 1Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610 Singapore
| | - Wai Har Ng
- 1Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610 Singapore
| | - Kia Min Ng
- 1Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610 Singapore
| | - Soo Yong Tan
- 3Department of Pathology, Singapore General Hospital, Outram Road, Singapore, 169608 Singapore
| | - Bee Ling Ng
- 4Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA UK
| | - Nigel P Carter
- 4Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA UK
| | - Carol Tang
- 5National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore, 308433 Singapore
| | - Oi Lian Kon
- 1Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610 Singapore.,2Department of Biochemistry, National University of Singapore, 8 Medical Drive, Singapore, 117596 Singapore
| |
Collapse
|
|
30
|
Inokuchi M, Murase H, Otsuki S, Kawano T, Kojima K. Different clinical significance of FGFR1-4 expression between diffuse-type and intestinal-type gastric cancer. World J Surg Oncol 2017; 15:2. [PMID: 28056982 PMCID: PMC5217622 DOI: 10.1186/s12957-016-1081-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Accepted: 12/22/2016] [Indexed: 12/18/2022] Open
Abstract
Background Receptor tyrosine kinases promote tumor progression in many cancers, although oncologic activation differs between diffuse-type gastric cancer (DGC) and intestinal-type gastric cancer (IGC). Fibroblast growth factor receptor (FGFR) is one RTK, and we previously reported the clinical significance of FGFR1, 2, 3, and 4 in gastric cancer. The aim of the present study was to reevaluate the clinical significance of FGFR1–4 expression separately in DGC and IGC. Methods Tumor samples, including 109 DGCs and 100 IGCs, were obtained from patients who underwent gastrectomy between 2003 and 2007 in our institution. The expression levels of FGFR1, 2, 3, and 4 were measured in the tumors by immunohistochemical analysis. Results In DGC, high expression of FGFR1, FGFR2, or FGFR4 was significantly associated with the depth of invasion, lymph-node metastasis, pathological stage, and distant metastasis or recurrent disease. Patients with high expression of FGFR1, FGFR2, or FGFR4 had significantly poorer disease-specific survival (DSS) (p = 0.009, p = 0.001, and p = 0.023, respectively). In IGC, only FGFR4 expression was significantly associated with factors relative to tumor progression and with shorter DSS (p = 0.012). Conclusion In conclusion, high FGFR4 expression correlated with tumor progression and survival in both DGC and IGC, whereas high expression of FGFR1 and 2 correlated with tumor progression and survival in only DGC.
Collapse
Affiliation(s)
- Mikito Inokuchi
- Department of Gastrointestinal Surgery, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo, Tokyo, 113-8519, Japan.
| | - Hideaki Murase
- Department of Gastrointestinal Surgery, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo, Tokyo, 113-8519, Japan
| | - Sho Otsuki
- Department of Gastrointestinal Surgery, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo, Tokyo, 113-8519, Japan
| | - Tatsuyuki Kawano
- Department of Gastrointestinal Surgery, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo, Tokyo, 113-8519, Japan
| | - Kazuyuki Kojima
- Department of Minimally Invasive Surgery, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo, Tokyo, 113-8519, Japan
| |
Collapse
|
|
31
|
Fuchs CS, Tabernero J, Tomášek J, Chau I, Melichar B, Safran H, Tehfe MA, Filip D, Topuzov E, Schlittler L, Udrea AA, Campbell W, Brincat S, Emig M, Melemed SA, Hozak RR, Ferry D, Caldwell CW, Ajani JA. Biomarker analyses in REGARD gastric/GEJ carcinoma patients treated with VEGFR2-targeted antibody ramucirumab. Br J Cancer 2016; 115:974-982. [PMID: 27623234 PMCID: PMC5061911 DOI: 10.1038/bjc.2016.293] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Revised: 08/12/2016] [Accepted: 08/16/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Angiogenesis inhibition is an important strategy for cancer treatment. Ramucirumab, a human IgG1 monoclonal antibody that targets VEGF receptor 2 (VEGFR2), inhibits VEGF-A, -C, -D binding and endothelial cell proliferation. To attempt to identify prognostic and predictive biomarkers, retrospective analyses were used to assess tumour (HER2, VEGFR2) and serum (VEGF-C and -D, and soluble (s) VEGFR1 and 3) biomarkers in phase 3 REGARD patients with metastatic gastric/gastroesophageal junction carcinoma. METHODS A total of 152 out of 355 (43%) patients randomised to ramucirumab or placebo had ⩾1 evaluable biomarker result using VEGFR2 immunohistochemistry or HER2, immunohistochemistry or FISH, of blinded baseline tumour tissue samples. Serum samples (32 patients, 9%) were assayed for VEGF-C and -D, and sVEGFR1 and 3. RESULTS None of the biomarkers tested were associated with ramucirumab efficacy at a level of statistical significance. High VEGFR2 endothelial expression was associated with a non-significant prognostic trend toward shorter progression-free survival (high vs low HR=1.65, 95% CI=0.84,3.23). Treatment with ramucirumab was associated with a trend toward improved survival in both high (HR=0.69, 95% CI=0.38, 1.22) and low (HR=0.73, 95% CI=0.42, 1.26) VEGFR2 subgroups. The benefit associated with ramucirumab did not appear to differ by tumoural HER2 expression. CONCLUSIONS REGARD exploratory analyses did not identify a strong potentially predictive biomarker of ramucirumab efficacy; however, statistical power was limited.
Collapse
Affiliation(s)
- Charles S Fuchs
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA
| | - Josep Tabernero
- Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - Jiří Tomášek
- Masaryk Memorial Cancer Institute, Faculty of Medicine, Masaryk University, Brno 656 53, Czech Republic
| | - Ian Chau
- Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK
| | - Bohuslav Melichar
- Onkologicka klinika, Lekarska fakulta Univerzity Palackeho a Fakultni nemocnice, I.P. Pavlova, 6, Olomouc 779 00, Czech Republic
| | - Howard Safran
- Brown University Oncology Research Group, 164 Summit Avenue, Fain 3, Providence, Rhode Island 02906, USA
| | - Mustapha A Tehfe
- Centre Hospitalier de Montréal, 1560 Sherbrooke East St, Montreal, Quebec H2L4M1, Canada
| | - Dumitru Filip
- Spitalul Judetean de Urgenta, Strada George Coşbuc 31, Baia Mare 430031, Romania
| | - Eldar Topuzov
- State Budgetary Educational Institution of Higher Professional Education (SBEIHPE), Northwest State Medical University na II Mechnikov, Ministry of Healthcare of the Russian Federation, Russia
| | - Luis Schlittler
- Hospital da Cida de Passo Fundo, Rua Tiradentes, 295 Centro, Passo Fundo, 99010-260, Brazil
| | | | | | | | - Michael Emig
- Lilly Deutschland GmbH, Werner-Reimers-Straße 2, Bad Homburg vor der Höhe 61352, Germany
| | - Symantha A Melemed
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA
| | - Rebecca R Hozak
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA
| | - David Ferry
- Eli Lilly and Company, 440 Route 22 East, Bridgewater, New Jersey 08807, USA
| | - C William Caldwell
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA
| | - Jaffer A Ajani
- The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 426, Houston, Texas 77030, USA
| |
Collapse
|
|
32
|
Pyo JS, Kang G, Cho H. Clinicopathological Significance and Diagnostic Accuracy of c-MET Expression by Immunohistochemistry in Gastric Cancer: A Meta-Analysis. J Gastric Cancer 2016; 16:141-151. [PMID: 27752391 PMCID: PMC5065943 DOI: 10.5230/jgc.2016.16.3.141] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Revised: 06/09/2016] [Accepted: 06/10/2016] [Indexed: 12/20/2022] Open
Abstract
PURPOSE The aim of the present study was to elucidate the clinicopathological significance and diagnostic accuracy of immunohistochemistry (IHC) for determining the mesenchymal epidermal transition (c-MET) expression in patients with gastric cancer (GC). MATERIALS AND METHODS The present meta-analysis investigated the correlation between c-MET expression as determined by IHC and the clinicopathological parameters in 8,395 GC patients from 37 studies that satisfied the eligibility criteria. In addition, a concordance analysis was performed between c-MET expression as determined by IHC and c-MET amplification, and the diagnostic test accuracy was reviewed. RESULTS The estimated rate of c-MET overexpression was 0.403 (95% confidence interval [CI], 0.327~0.484) and it was significantly correlated with male patients, poor differentiation, lymph node metastasis, higher TNM stage, and human epidermal growth factor receptor 2 (HER2) positivity in IHC analysis. There was a significant correlation between c-MET expression and worse overall survival rate (hazard ratio, 1.588; 95% CI, 1.266~1.992). The concordance rates between c-MET expression and c-MET amplification were 0.967 (95% CI, 0.916~0.987) and 0.270 (95% CI, 0.173~0.395) for cases with non-overexpressed and overexpressed c-MET, respectively. In the diagnostic test accuracy review, the pooled sensitivity and specificity were 0.56 (95% CI, 0.50~0.63) and 0.79 (95% CI, 0.77~0.81), respectively. CONCLUSIONS The c-MET overexpression as determined by IHC was significantly correlated with aggressive tumor behavior and positive IHC status for HER2 in patients with GC. In addition, the c-MET expression status could be useful in the screening of c-MET amplification in patients with GC.
Collapse
Affiliation(s)
- Jung-Soo Pyo
- Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Guhyun Kang
- Department of Pathology, Inje University Sanggye Paik Hospital, Seoul, Korea
| | - Hyunjin Cho
- Department of Surgery, Inje University Sanggye Paik Hospital, Seoul, Korea
| |
Collapse
|
|
33
|
Jia YX, Li TF, Zhang DD, Fan ZM, Fan HJ, Yan J, Chen LJ, Tang H, Qin YR, Li XY. The coexpression and prognostic significance of c-MET, fibroblast growth factor receptor 2, and human epidermal growth factor receptor 2 in resected gastric cancer: a retrospective study. Onco Targets Ther 2016; 9:5919-5929. [PMID: 27729801 PMCID: PMC5045911 DOI: 10.2147/ott.s111778] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Molecular-targeted therapy against tyrosine kinase receptors (RTKs) plays an important role in gastric cancer (GC) treatment. Understanding the correlation between RTK coexpression could better guide clinical drug use. In the present study, the coexpression status of c-MET, fibroblast growth factor receptor 2 (FGFR2), and human epidermal growth factor receptor 2 (HER2) in human GC and their clinical significance in clinical therapy were explored. Immunohistochemical (IHC) staining, quantitative real-time polymerase chain reaction and fluorescent in situ hybridization were performed in 143 cases of GC who had undergone gastrectomy without preoperative chemoradiotherapy. Their association with clinicopathological features and clinical prognosis was analyzed. The frequencies of c-MET, FGFR2, and HER2 overexpression were 47.6% (68/143), 34.3% (49/143), and 10.5% (15/143), respectively. In the RTK coexpression study, 30.1% of patients (43/143) were positive for only one RTK, 25.8% (37/143) were positive for two RTKs, 3.5% (5/143) had triple-positive status, and 40.6% (58/143) had triple-negative status. In survival analysis, the overexpression of c-MET, FGFR2, and HER2 were significantly associated with overall survival (OS) (P=0.018, 0.004, and 0.049, respectively). In coexpression analysis, patients with triple-positive GC had the poorest OS (P=0.013). In conclusion, RTK coexpression is significantly associated with poor clinical outcome in GC.
Collapse
Affiliation(s)
- Yong-Xu Jia
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Esophageal and Gastric Cancer Center of Henan Province
| | | | | | - Zong-Min Fan
- Henan Key Laboratory for Esophageal Cancer Research, The First Affiliated Hospital of Zhengzhou University
| | - Hui-Jie Fan
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Esophageal and Gastric Cancer Center of Henan Province
| | - Jie Yan
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Esophageal and Gastric Cancer Center of Henan Province
| | - Li-Juan Chen
- Department of Oncology, Tumor Hospital of Henan Province, Zhengzhou, Henan, People's Republic of China
| | - Hong Tang
- Department of Oncology, Tumor Hospital of Henan Province, Zhengzhou, Henan, People's Republic of China
| | - Yan-Ru Qin
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Esophageal and Gastric Cancer Center of Henan Province
| | - Xing-Ya Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University
| |
Collapse
|
|
34
|
Profiling of cMET and HER Family Receptor Expression in Pancreatic Ductal Adenocarcinomas and Corresponding Lymph Node Metastasis to Assess Relevant Pathways for Targeted Therapies: Looking at the Soil Before Planting the Seed. Pancreas 2016; 45:1167-74. [PMID: 26825865 DOI: 10.1097/mpa.0000000000000604] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
OBJECTIVES Comprehensive assessment of cMET and HER family receptor tyrosine kinases expression, changes of expression during metastatic progression, amplification status of the MET gene, and correlations with patient characteristics in pancreatic ductal adenocarcinoma (PDAC) was conducted. METHODS We investigated 56 PDACs and corresponding lymph node metastases for HER1 to HER4 and cMET expression by immunohistochemistry, as well as cMET gene copy numbers by chromogenic in situ hybridization. RESULTS Of all receptor tyrosine kinases evaluated, cMET expression was highest with 46.5% of tumors showing moderate or strong expression and a weak correlation with gene copy number status (P = 0.04; Spearman ρ = 0.28). cMET expression was increased in metastases. In contrast, expression levels of HER family receptors were generally low both in primaries and metastases. A weak yet significant correlation of HER1 and cMET expression levels was observed (P < 0.001; Spearman ρ = 0.44) and HER1 was often present in poorly differentiated tumors (G3, P = 0.049). CONCLUSIONS Our data suggest that cMET might constitute an interesting molecule for combining targeted and chemotherapeutic approaches in PDAC, because expression is frequent and increased during metastatic progression. In PDAC, cMET protein expression might be a more useful stratification biomarker than cMET gene amplification, which does not seem to be its primary regulator.
Collapse
|
|
35
|
Khandelwal AR, Ma X, Egan P, Kaskas NM, Moore-Medlin T, Caldito G, Abreo F, Gu X, Aubrey L, Milligan E, Nathan CAO. Biomarker and Pathologic Predictors of Cutaneous Squamous Cell Carcinoma Aggressiveness. Otolaryngol Head Neck Surg 2016; 155:281-8. [PMID: 27095050 DOI: 10.1177/0194599816641913] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2014] [Accepted: 03/09/2016] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Aggressive cutaneous squamous cell carcinoma (cSCC) patients are at increased risk of metastasis. Currently, there are no accepted criteria or biomarkers for reliably predicting individuals at risk for recurrence and metastasis. Our objective is to determine if pS6 and pERK can predict cSCC aggressiveness and to identify primary tumor characteristics that may predict parotid metastasis. STUDY DESIGN Retrospective case series. SETTINGS Tertiary care center. SUBJECTS AND METHODS An Institutional Review Board-approved retrospective review was performed for patients with facial cSCC, with and without metastasis to the parotids. Subjects for the study were identified through the Louisiana Tumor Registry, Veterans Medical Records, and LSU Health-Shreveport pathology database. Tumor specimens from patients with cSCC and cSCC with parotid metastasis were analyzed for pERK and pS6 expression through immunohistochemistry. To identify risk factors for tumor aggressiveness, multiple logistic regression analysis was used to evaluate patients with cSCC that was metastatic to the parotid and managed surgically. RESULTS cSCC with parotid metastasis specimens exhibited significantly higher average pS6 but not pERK positivity than those from cSCC without metastasis (P < .05). Primary lesion-positive margins (P < .01), size of the skin tumor (P < .01) and degree of tumor differentiation (P < .01) were significantly associated with parotid metastasis. CONCLUSION Surgical history of cSCC, primary lesion-positive margins, degree of differentiation, and lesion size together with pS6 positivity appear to be predictors of cSCC aggressiveness and should prompt increased monitoring or elective parotidectomy.
Collapse
Affiliation(s)
- Alok R Khandelwal
- Department of Otolaryngology-Head and Neck Surgery, LSU-Health Shreveport, Shreveport, Louisiana, USA
| | - Xiaohui Ma
- Department of Otolaryngology-Head and Neck Surgery, LSU-Health Shreveport, Shreveport, Louisiana, USA
| | - Paige Egan
- Department of Otolaryngology-Head and Neck Surgery, LSU-Health Shreveport, Shreveport, Louisiana, USA Department of Surgery, Overton Brooks Veterans Medical Center, Shreveport, Louisiana, USA
| | - Nadine M Kaskas
- School of Medicine, LSU Health-Shreveport, Shreveport, Louisiana, USA
| | - Tara Moore-Medlin
- Department of Otolaryngology-Head and Neck Surgery, LSU-Health Shreveport, Shreveport, Louisiana, USA
| | - Gloria Caldito
- Department of Neurology and Biometry, LSU-Health Shreveport, Shreveport, Louisiana, USA
| | - Fleurette Abreo
- Department of Pathology, LSU-Health Shreveport, Shreveport, Louisiana, USA
| | - Xin Gu
- Department of Pathology, LSU-Health Shreveport, Shreveport, Louisiana, USA
| | - Lurie Aubrey
- Department of Surgery, Overton Brooks Veterans Medical Center, Shreveport, Louisiana, USA
| | - Edward Milligan
- Department of Surgery, Overton Brooks Veterans Medical Center, Shreveport, Louisiana, USA
| | - Cherie-Ann O Nathan
- Department of Otolaryngology-Head and Neck Surgery, LSU-Health Shreveport, Shreveport, Louisiana, USA Department of Surgery, Overton Brooks Veterans Medical Center, Shreveport, Louisiana, USA
| |
Collapse
|
|
36
|
Xu YP, Lin G, Sun XJ, Yan MH, Zhang G, Hu JL, Sun WY, Yu JM. C-Met as a Molecular Marker for Esophageal Squamous Cell Carcinoma and Its Association with Clinical Outcome. J Cancer 2016; 7:587-94. [PMID: 27053957 PMCID: PMC4820735 DOI: 10.7150/jca.13687] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2015] [Accepted: 01/09/2016] [Indexed: 12/12/2022] Open
Abstract
Background: Epidermal growth factor receptor (EGFR), c-Met, and human epidermal growth factor receptor 2 (HER2) are overexpressed in a variety of human cancers, and may serve as biomarkers for disease prognosis. We examined whether high expression of these molecular markers correlates with poor disease prognosis in esophageal squamous cell cancer (ESCC). Materials and Methods: Expression of EGFR, c-Met, and HER2 protein was detected by immunohistochemistry (IHC) in 180 paraffin-embedded tissue samples from stage IIB-IIIC ESCC patients. The overall survival (OS) rates were calculated according to the Kaplan-Meier method, and the log-rank test was used to evaluate differences between survival curves. The Cox proportional hazards model was used for univariate and multivariate analyses. Results: The median survival of all patients was 46 months. There was no significant difference in OS in terms of HER2 and EGFR status (P = 0.177 and P=0.061, respectively). However, there was a significant difference in OS between c-Met high expression patients and c-Met low expression or negative patients (median: 41.9 months vs. 56.7 months; P = 0.001). Multivariate analysis also showed that, of the covariates analyzed, c-Met high expression was the only prognostic factor for OS (HR: 0.459 [95 % confidence interval: 0.287-0.733]; P = 0.001). Patients with ESCC that had concurrent overexpression of EGFR and c-Met had significantly worse survival than ESCC that displayed overexpression of either EGFR or c-Met individually or that did not have overexpression of either protein (P=0.000). Conclusions: Overexpression of HER2 and EGFR individually is not significantly associated with poor prognosis in ESCC. High expression of c-Met may be indicative of a poorer prognosis in ESCC. In order to promote efficient and rapid development of therapeutic methods in ESCC, further studies are necessary to explore the role of c-Met.
Collapse
Affiliation(s)
- Ya-Ping Xu
- 1. School of Medicine, Shandong University, Jinan, China;; 2. Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, China
| | - Gang Lin
- 3. First Clinical Medical School, Wenzhou Medical University, Wenzhou, China
| | - Xiao-Jiang Sun
- 2. Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, China
| | - Mao-Hui Yan
- 2. Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, China
| | - Gu Zhang
- 4. Department of Pathology, Zhejiang Cancer Hospital, Hangzhou, China
| | - Jin-Lin Hu
- 4. Department of Pathology, Zhejiang Cancer Hospital, Hangzhou, China
| | - Wen-Yong Sun
- 4. Department of Pathology, Zhejiang Cancer Hospital, Hangzhou, China
| | - Jin-Ming Yu
- 5. Department of Radiation Oncology, Shandong University Affiliated Shandong Cancer Hospital and Institute, Jinan, Shandong, China
| |
Collapse
|
|
37
|
Warford A. In situ hybridisation: Technologies and their application to understanding disease. ACTA ACUST UNITED AC 2015; 50:37-48. [PMID: 26797255 DOI: 10.1016/j.proghi.2015.12.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Revised: 12/17/2015] [Accepted: 12/22/2015] [Indexed: 12/23/2022]
Abstract
In situ hybridisation (ISH) is unique amongst molecular analysis methods in providing for the precise microscopic localisation of genes, mRNA and microRNA in metaphase spreads, cell and tissue preparations. The method is well established as a tool to guide appropriate therapeutic intervention in breast, gastric and lung cancer. With the description of ultrasensitive ISH technologies for low copy mRNA demonstration and the relative ease by which microRNA can be visualised, the applications for research and diagnostic purposes is set to increase dramatically. In this review ISH is considered with emphasis on recent technological developments and surveyed for present and future applications in the context of the demonstration of genes, mRNA and microRNA in health and disease.
Collapse
Affiliation(s)
- Anthony Warford
- University of Westminster, 115 New Cavendish Street, London W1W 6UW, United Kingdom.
| |
Collapse
|
|
38
|
Inokuchi M, Otsuki S, Fujimori Y, Sato Y, Nakagawa M, Kojima K. Clinical significance of MET in gastric cancer. World J Gastrointest Oncol 2015; 7:317-327. [PMID: 26600931 PMCID: PMC4644854 DOI: 10.4251/wjgo.v7.i11.317] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2015] [Revised: 04/06/2015] [Accepted: 08/28/2015] [Indexed: 02/05/2023] Open
Abstract
Chemotherapy has become the global standard treatment for patients with metastatic or unresectable gastric cancer (GC), although outcomes remain unfavorable. Many molecular-targeted therapies inhibiting signaling pathways of various tyrosine kinase receptors have been developed, and monoclonal antibodies targeting human epidermal growth factor receptor 2 or vascular endothelial growth factor receptor 2 have become standard therapy for GC. Hepatocyte growth factor and its receptor, c-MET (MET), play key roles in tumor growth through activated signaling pathways from receptor in GC cells. Genomic amplification of MET leads to the aberrant activation found in GC tumors and is related to survival in patients with GC. This review discusses the clinical significance of MET in GC and examines MET as a potential therapeutic target in patients with GC. Preclinical studies in animal models have shown that MET antibodies or small-molecule MET inhibitors suppress tumor-cell proliferation and tumor progression in MET-amplified GC cells. These drugs are now being evaluated in clinical trials as treatments for metastatic or unresectable GC.
Collapse
|
|
39
|
Han N, Kim MA, Lee HS, Kim WH. Evaluation of Fibroblast Growth Factor Receptor 2 Expression, Heterogeneity and Clinical Significance in Gastric Cancer. Pathobiology 2015; 82:269-79. [PMID: 26516773 DOI: 10.1159/000441149] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Accepted: 09/18/2015] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND We aimed to evaluate the protein and mRNA expression of fibroblast growth factor receptor 2 (FGFR2) by immunohistochemistry (IHC) and mRNA in situ hybridization (ISH), respectively, and to assess the heterogeneity of FGFR2 expression in gastric cancer (GC). METHODS A tissue microarray containing 362 surgically resected GC tissues and 135 matched metastatic lymph nodes was evaluated using FGFR2b IHC and FGFR2 ISH. FGFR2 fluorescence ISH was also performed in 188 cases. RESULTS All FGFR2-amplified cases (5 of 188) showed FGFR2b protein and FGFR2 mRNA overexpression (p < 0.001), and FGFR2 amplification was not identified in FGFR2b IHC- and FGFR2 mRNA ISH-negative cases. Kaplan-Meier survival analysis revealed that FGFR2b protein and FGFR2 mRNA overexpression was significantly associated with a poor overall survival (p < 0.001 and p = 0.012, respectively), and multivariate analyses showed that FGFR2 mRNA overexpression was an independent biomarker of a poor overall survival. Intratumoral heterogeneity of FGFR2b protein and FGFR2 mRNA overexpression was observed in 5 of 9 (55.5%) and 18 of 21 (85.7%) cases, respectively. Discordant FGFR2b and FGFR2 expression results between primary and matched metastatic lymph nodes were observed in 5 of 9 (55.5%) and 4 of 14 (28.6%) cases, respectively. CONCLUSIONS Intratumoral heterogeneity and discordant FGFR2b expression in primary tumors and metastatic lymph nodes are common in GC.
Collapse
Affiliation(s)
- Nayoung Han
- Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | | | | | | |
Collapse
|
|
40
|
Hierro C, Rodon J, Tabernero J. Fibroblast Growth Factor (FGF) Receptor/FGF Inhibitors: Novel Targets and Strategies for Optimization of Response of Solid Tumors. Semin Oncol 2015; 42:801-19. [PMID: 26615127 DOI: 10.1053/j.seminoncol.2015.09.027] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The fibroblast growth factor receptor (FGFR) pathway plays a major role in several biological processes, from organogenesis to metabolism homeostasis and angiogenesis. Several aberrations, including gene amplifications, point mutations, and chromosomal translocations have been described across solid tumors. Most of these molecular alterations promote multiple steps of carcinogenesis in FGFR oncogene-addicted cells, increasing cell proliferation, angiogenesis, and drug resistance. Data suggest that upregulation of FGFR signaling is a common event in many cancer types. The FGFR pathway thus arises as a potential promising target for cancer treatment. Several FGFR inhibitors are currently under development. Initial preclinical results have translated into limited successful clinical responses when first-generation, nonspecific FGFR inhibitors were evaluated in patients. The future development of selective and unselective FGFR inhibitors will rely on a better understanding of the tissue-specific role of FGFR signaling and identification of biomarkers to select those patients who will benefit the most from these drugs. Further studies are warranted to establish the predictive significance of the different FGFR-aberrations and to incorporate them into clinical algorithms, now that second-generation, selective FGFR inhibitors exist.
Collapse
Affiliation(s)
- Cinta Hierro
- Molecular Therapeutics Research Unit, Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Jordi Rodon
- Molecular Therapeutics Research Unit, Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Josep Tabernero
- Molecular Therapeutics Research Unit, Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
| |
Collapse
|
|
41
|
Metzger ML, Behrens HM, Böger C, Haag J, Krüger S, Röcken C. MET in gastric cancer--discarding a 10% cutoff rule. Histopathology 2015; 68:241-53. [PMID: 26033401 PMCID: PMC4744765 DOI: 10.1111/his.12745] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 05/26/2015] [Indexed: 12/20/2022]
Abstract
Aims We aimed to develop a putative predictive biomarker score for future hepatocyte growth factor receptor (MET)‐targeted therapy of gastric cancer (GC). Methods and results MET expression and MET amplification were analysed by immunohistochemistry (IHC) and chromogenic in‐situ hybridization (CISH) in 470 GC patients. Immunostaining was documented with the HistoScore. The percentage area of MET‐amplified tumour cell clones was assessed by virtual microscopy. The expression of MET was heterogeneous in primary and metastatic GC. Immunostaining intensity (MET‐IHC 2+/3+) correlated with MET amplification and a positive MET status was defined by a combination of MET‐IHC 2+ or 3+ with MET amplification, or MET‐IHC 3+ without MET amplification. The prognostic significance of the MET status was independent from the percentage area of positive tumour cells (e.g. <10 versus ≥10%). MET‐positive GCs were microsatellite stable and of KRAS/PIK3CA wild‐type. MET‐positive GCs had a very poor prognosis, with a median survival of 5.4 months and a hazard ratio of 2.126. Conclusions A combination of immunohistochemistry and CISH is suitable to assess MET status. If MET status is used as a predictive biomarker, prospective studies should pay specific attention to adequate tissue sampling, should ignore cutoff values for tumour areas, may consider the KRAS and PIK3CA genotype as negative predictive markers and should carry out the analysis expeditiously.
Collapse
Affiliation(s)
| | | | - Christine Böger
- Department of Pathology, Christian-Albrechts-University, Kiel, Germany
| | - Jochen Haag
- Department of Pathology, Christian-Albrechts-University, Kiel, Germany
| | - Sandra Krüger
- Department of Pathology, Christian-Albrechts-University, Kiel, Germany
| | - Christoph Röcken
- Department of Pathology, Christian-Albrechts-University, Kiel, Germany
| |
Collapse
|
|
42
|
Elevated Rictor expression is associated with tumor progression and poor prognosis in patients with gastric cancer. Biochem Biophys Res Commun 2015; 464:534-40. [PMID: 26159923 DOI: 10.1016/j.bbrc.2015.07.001] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Accepted: 07/01/2015] [Indexed: 01/22/2023]
Abstract
The rapamycin insensitive companion of mTOR (Rictor) is an essential subunit of mTOR complex 2 (mTORC2), maintains the integrity of the complex and functions as regulator of Akt full activation. Rictor has been implicated to be involved in growth and progression of malignancies, however, little is known about its expression and prognostic role in gastric cancer in particular. Therefore, we investigated the relationship of Rictor expression with clinical outcomes, together with pAktSer473 and pS6, two downstream substrates of mTORC2 and mTORC1, in 396 gastric cancer tissue samples via immunohistochemistry. The results showed that 74.0% and 55.8% of tumors were Rictor and pAktSer473 positive staining, respectively, which correlated well with each other. Patients with positive expressions had poorer overall survival and relapse-free survival compared with those negative staining. Both Rictor and pAktSer473 expression were associated with lymph node metastasis, TNM stage, and WHO grading. Rictor was also correlated with tumor size, depth of invasion, and tumor thrombus, while pAktSer473 was also correlated with distant metastasis. In spite of 67.4% expression rate was presented in gastric cancer tissues, no significant association was observed between pS6Ser235/236, representing mTORC1 activity, and clinicopathological features or prognosis. These results suggest that mTORC2/Rictor/pAkt may play a more important role than mTORC1/pS6 in tumor progression, which could act as a prognostic biomarker or potential therapeutic target in gastric cancer.
Collapse
|
|
43
|
Therapeutic targeting of fibroblast growth factor receptors in gastric cancer. Gastroenterol Res Pract 2015; 2015:796380. [PMID: 26000013 PMCID: PMC4427097 DOI: 10.1155/2015/796380] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Revised: 12/07/2014] [Accepted: 12/08/2014] [Indexed: 12/15/2022] Open
Abstract
Chemotherapy has become the global standard treatment for patients with metastatic or unresectable gastric cancer (GC), although outcomes remain unfavorable. Many molecular-targeted therapies inhibiting signaling pathways of various tyrosine kinase receptors have been developed, and monoclonal antibodies targeting human epidermal growth factor receptor 2 (HER2) have become standard therapy for HER2-positive GC. An inhibitor of vascular endothelial growth factor receptor 2 or MET has also produced promising results in patients with GC. Fibroblast growth factor receptors (FGFR) play key roles in tumor growth via activated signaling pathways in GC. Genomic amplification of FGFR2 leads to the aberrant activation found in GC tumors and is related to survival in patients with GC. This review discusses the clinical relevance of FGFR in GC and examines FGFR as a potential therapeutic target in patients with GC. Preclinical studies in animal models suggest that multitargeted tyrosine kinase inhibitors (TKIs), including FGFR inhibitor, suppress tumor cell proliferation and delay tumor progression. Several TKIs are now being evaluated in clinical trials as treatment for metastatic or unresectable GC harboring FGFR2 amplification.
Collapse
|
|
44
|
Nagatsuma AK, Aizawa M, Kuwata T, Doi T, Ohtsu A, Fujii H, Ochiai A. Expression profiles of HER2, EGFR, MET and FGFR2 in a large cohort of patients with gastric adenocarcinoma. Gastric Cancer 2015; 18:227-38. [PMID: 24626858 DOI: 10.1007/s10120-014-0360-4] [Citation(s) in RCA: 135] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Accepted: 02/08/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND Some tyrosine kinase receptors (RTKs) play critical roles in gastric cancer progression. Not only trastuzumab, but also several other agents targeting RTKs are being investigated for gastric cancer therapy. However, the simultaneous expression of multiple RTKs, which may interfere with the effectiveness of therapeutic agents, has not been evaluated in a large cohort with gastric adenocarcinoma (GAC). METHODS We performed a tissue microarray analysis in 950 patients with GAC who underwent a gastrectomy without preoperative chemotherapy. The protein expressions of HER2, EGFR, MET and FGFR2 were evaluated using immunohistochemistry, and the gene amplifications of HER2, EGFR and MET were examined using dual-color in situ hybridization. RESULTS The frequency of overexpression was 11.8% for HER2, 23.5% for EGFR, 24.9 % for MET and 31.1% for FGFR2. Whereas strong staining for each of the RTKs was heterogeneous, tumors with homogeneously strong staining areas often exhibited gene amplification. Strong EGFR expression was significantly associated with a poor outcome, but no prognostic correlations were observed in other RTKs. The overexpression of single and multiple RTKs was observed in 40.4 and 22.7% of the cases, respectively. HER2, EGFR, MET and FGFR2 predominance was observed in 10.1, 13.9, 16.1 and 22.9% of the GACs, respectively. CONCLUSIONS Approximately two-thirds of patients with GAC exhibited the expression of at least one RTK and would be candidates for targeted therapies. Moreover, one-third of at least one RTK overexspressing cases showed multiple RTKs expression. Our results may be useful for selecting the most suitable patients for each targeted therapy.
Collapse
Affiliation(s)
- Akiko Kawano Nagatsuma
- Division of Pathology, Research Center for Innovative Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa-city, Chiba, 277-8577, Japan
| | | | | | | | | | | | | |
Collapse
|
|
45
|
Zhang Y, Jain RK, Zhu M. Recent Progress and Advances in HGF/MET-Targeted Therapeutic Agents for Cancer Treatment. Biomedicines 2015; 3:149-181. [PMID: 28536405 PMCID: PMC5344234 DOI: 10.3390/biomedicines3010149] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2015] [Revised: 02/25/2015] [Accepted: 03/03/2015] [Indexed: 12/31/2022] Open
Abstract
The hepatocyte growth factor (HGF): MET axis is a ligand-mediated receptor tyrosine kinase pathway that is involved in multiple cellular functions, including proliferation, survival, motility, and morphogenesis. Aberrancy in the HGF/MET pathway has been reported in multiple tumor types and is associated with tumor stage and prognosis. Thus, targeting the HGF/MET pathway has become a potential therapeutic strategy in oncology development in the last two decades. A number of novel therapeutic agents-either as therapeutic proteins or small molecules that target the HGF/MET pathway-have been tested in patients with different tumor types in clinical studies. In this review, recent progress in HGF/MET pathway-targeted therapy for cancer treatment, the therapeutic potential of HGF/MET-targeted agents, and challenges in the development of such agents will be discussed.
Collapse
Affiliation(s)
- Yilong Zhang
- Department of Clinical Pharmacology, Modeling and Simulation, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
| | - Rajul K Jain
- Kite Pharma, Inc., 2225 Colorado Avenue, Santa Monica, CA 90404, USA.
| | - Min Zhu
- Department of Clinical Pharmacology, Modeling and Simulation, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
| |
Collapse
|
|
46
|
Hale MD, Gotoda T, Hayden JD, Grabsch HI. Endoscopic biopsies from gastrointestinal carcinomas and their suitability for molecular analysis: a review of the literature and recommendations for clinical practice and research. Histopathology 2015; 67:147-57. [PMID: 25431371 DOI: 10.1111/his.12626] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
| | - Takuji Gotoda
- Department of Gastroenterology and Hepatology; Tokyo Medical University; Tokyo Japan
| | - Jeremy David Hayden
- Department of Upper Gastrointestinal Surgery; St James's Institute of Oncology; Leeds Teaching Hospitals NHS Trust; Leeds UK
| | - Heike Irmgard Grabsch
- Leeds Institute of Cancer and Pathology; University of Leeds; Leeds UK
- Department of Pathology; Maastricht University Medical Center; Maastricht The Netherlands
| |
Collapse
|
|
47
|
Chafin D. Two-temperature formalin fixation preserves activation states efficiently. Recent Results Cancer Res 2015; 199:107-17. [PMID: 25636434 DOI: 10.1007/978-3-319-13957-9_11] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Modern pathology is built around the principle of preserving tissues such that the in vivo molecular status is maintained at levels representative of the disease state. Tissues are immersed in a solution of fixative which slowly inactivates biological activities, thus preserving the sample. Further processing ultimately allows the tissue to be embedded into wax for thin sectioning and staining for interpretation microscopically. Every year, around 7 billion tissue samples are submitted for processing in the United States alone. With this huge workload, histology laboratories are looking for faster methods of performing fixation, which currently require from several hours to days to complete. Ideally, this procedure could be standardized and would be quicker with better preservation over a wide range of biologically relevant molecules.
Collapse
Affiliation(s)
- David Chafin
- , 1910 East Innovation PARK Drive, Oro Valley, AZ, 85755, USA,
| |
Collapse
|
|
48
|
Hack SP, Bruey JM, Koeppen H. HGF/MET-directed therapeutics in gastroesophageal cancer: a review of clinical and biomarker development. Oncotarget 2015; 5:2866-80. [PMID: 24930887 PMCID: PMC4102777 DOI: 10.18632/oncotarget.2003] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Aberrant activation of the HGF/MET signaling axis has been strongly implicated in the malignant transformation and progression of gastroesophageal cancer (GEC). MET receptor overexpression in tumor samples from GEC patients has been consistently correlated with an aggressive metastatic phenotype and poor prognosis. In preclinical GEC models, abrogation of HGF/MET signaling has been shown to induce tumor regression as well as inhibition of metastatic dissemination. Promising clinical results in patient subsets in which MET is overexpressed have spurned several randomized studies of HGF/MET-directed agents, including two pivotal global Phase III trials. Available data highlight the need for predictive biomarkers in order to select patients most likely to benefit from HGF/MET inhibition. In this review, we discuss the current knowledge of mechanisms of MET activation in GEC, the current status of the clinical evaluation of MET-targeted therapies in GEC, characteristics of ongoing randomized GEC trials and the associated efforts to identify and validate biomarkers. We also discuss the considerations and challenges for HGF/MET inhibitor drug development in the GEC setting.
Collapse
Affiliation(s)
- Stephen P Hack
- Product Development, Genentech Inc., South San Francisco, CA, USA
| | | | | |
Collapse
|
|
49
|
Abdel-Rahman O. Targeting the hepatocyte growth factor/mesenchymal epithelial transition pathway in gastric cancer: biological rationale and clinical applications. Expert Rev Anticancer Ther 2014; 15:235-45. [PMID: 25353620 DOI: 10.1586/14737140.2014.974564] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Advanced gastric cancer (GC) is a dreadful disease with a poor prognosis and the majority of patients die within 1 year of diagnosis. In the past decade, important signaling pathways promoting tumor proliferation and aggressiveness have been evaluated; the hepatocyte growth factor/mesenchymal epithelial transition (MET) pathway is one of the most promising pathways in that regard. This pathway has been evaluated in preclinical and early clinical settings of GC. From the very early studies, MET expression has been recognized as an important poor prognostic marker in GC. However, only after the development of MET-targeting agents, it became important in terms of antitumor therapy with the clinical evaluation of several MET-targeting agents in GC. The results of the ongoing multicenter studies evaluating MET-targeting agents are eagerly awaited as they may improve our understanding of the precise role of these agents in the treatment armamentarium of advanced GC.
Collapse
Affiliation(s)
- Omar Abdel-Rahman
- Department of Clinical Oncology, Faculty of Medicine, Ain Shams University, Cairo, 113331, Egypt
| |
Collapse
|