|
1
|
Pallasch FB, Freytag V, Kriegs M, Gatzemeier D, Mair T, Voss H, Riecken K, Dawood M, Fehse B, Efferth T, Schlüter H, Schumacher U. The Histogenetic Origin of Malignant Cells Predicts Their Susceptibility towards Synthetic Lethality Utilizing the TK.007 System. Cancers (Basel) 2024; 16:2278. [PMID: 38927982 PMCID: PMC11202008 DOI: 10.3390/cancers16122278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 06/04/2024] [Accepted: 06/08/2024] [Indexed: 06/28/2024] Open
Abstract
BACKGROUND Remarkable differences exist in the outcome of systemic cancer therapies. Lymphomas and leukemias generally respond well to systemic chemotherapies, while solid cancers often fail. We engineered different human cancer cells lines to uniformly express a modified herpes simplex virus thymidine kinase TK.007 as a suicide gene when ganciclovir (GCV) is applied, thus in theory achieving a similar response in all cell lines. METHODS Fifteen different cell lines were engineered to express the TK.007 gene. XTT-cell proliferation assays were performed and the IC50-values were calculated. Functional kinome profiling, mRNA sequencing, and bottom-up proteomics analysis with Ingenuity pathway analysis were performed. RESULTS GCV potency varied among cell lines, with lymphoma and leukemia cells showing higher susceptibility than solid cancer cells. Functional kinome profiling implies a contribution of the SRC family kinases and decreased overall kinase activity. mRNA sequencing highlighted alterations in the MAPK pathways and bottom-up proteomics showed differences in apoptotic and epithelial junction signaling proteins. CONCLUSIONS The histogenetic origin of cells influenced the susceptibility of human malignant cells towards cytotoxic agents with leukemias and lymphomas being more sensitive than solid cancer cells.
Collapse
Affiliation(s)
- Fabian Bernhard Pallasch
- Institute of Anatomy and Experimental Morphology, Center for Experimental Medicine, University Cancer Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany (U.S.)
- Department of Diagnostic and Interventional Radiology, Faculty of Medicine, Medical Center—University of Freiburg, 79106 Freiburg Im Breisgau, Germany
| | - Vera Freytag
- Institute of Anatomy and Experimental Morphology, Center for Experimental Medicine, University Cancer Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany (U.S.)
| | - Malte Kriegs
- Department of Radiotherapy and Radiation Oncology, Hubertus Wald Tumorzentrum–University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
- UCCH Kinomics Core Facility, Hubertus Wald Tumorzentrum–University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Dennis Gatzemeier
- Section Mass Spectrometric and Proteomics, Center of Diagnostics, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
| | - Thomas Mair
- Section Mass Spectrometric and Proteomics, Center of Diagnostics, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
| | - Hannah Voss
- Section Mass Spectrometric and Proteomics, Center of Diagnostics, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
| | - Kristoffer Riecken
- Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Mona Dawood
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany
| | - Boris Fehse
- Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany
| | - Hartmut Schlüter
- Section Mass Spectrometric and Proteomics, Center of Diagnostics, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
| | - Udo Schumacher
- Institute of Anatomy and Experimental Morphology, Center for Experimental Medicine, University Cancer Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany (U.S.)
- Department of Medicine, Medical School Berlin, Mecklenburgische Strasse 57, 14197 Berlin, Germany
| |
Collapse
|
|
2
|
Skubleny D, Lin A, Garg S, McLean R, McCall M, Ghosh S, Spratlin JL, Schiller D, Rayat G. Increased CD4/CD8 Lymphocyte ratio predicts favourable neoadjuvant treatment response in gastric cancer: A prospective pilot study. World J Gastrointest Oncol 2023; 15:303-317. [PMID: 36908322 PMCID: PMC9994053 DOI: 10.4251/wjgo.v15.i2.303] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 11/25/2022] [Accepted: 01/12/2023] [Indexed: 02/14/2023] Open
Abstract
BACKGROUND Despite optimal neoadjuvant chemotherapy only 40% of gastric cancer tumours achieve complete or partial treatment response. In the absence of treatment response, neoadjuvant chemotherapy in gastric cancer contributes to adverse events without additional survival benefit compared to adjuvant treatment or surgery alone. Additional strategies and methods are required to optimize the allocation of existing treatment regimens such as FLOT chemotherapy (5-Fluorouracil, Leucovorin, Oxaliplatin and Docetaxel). Predictive biomarkers detected using immunohistochemistry (IHC) methods may provide useful data regarding treatment response.
AIM To investigate the utility of CD4, CD8, Galectin-3 and E-cadherin in predicting neoadjuvant FLOT chemotherapy tumour response in gastric adenocarcinoma.
METHODS Forty-three adult patients with gastric adenocarcinoma, of which 18 underwent neoadjuvant chemotherapy, were included in a prospective clinical cohort. Endoscopic biopsies were obtained from gastric cancer and normal adjacent gastric mucosa. Differences in expression of Galectin-3, E-cadherin, CD4+ and CD8+ molecules between tumours with and without treatment response to neoadjuvant chemotherapy were assessed with IHC. Treatment response was graded by clinical pathologists using the Tumour Regression Score according to the College of American Pathologists criteria. Treatment response was defined as complete or near complete tumour response, whereas partial or poor/no response was defined as incomplete. Digital IHC images were annotated and quantitatively assessed using QuPath 0.3.1. Biomarker expression between responsive and incomplete response tumours was assessed using a two-sided Wilcoxon test. Biomarker expression was also compared between normal and cancer tissue and between 15 paired tumour samples before and after chemotherapy. We performed a preliminary multivariate analysis and power analysis to guide future study. Statistical analyses were completed using R 4.1.2.
RESULTS The ratio between CD4+ and CD8+ lymphocytes was significantly greater in treatment responsive tumours (Wilcoxon, P = 0.03). In univariate models, CD4+/CD8+ ratio was the only biomarker that significantly predicted favourable treatment response (Accuracy 86%, P < 0.001). Using a glmnet multivariate model, high CD4+/CD8+ ratio and low Galectin-3 expression were the most influential variables in predicting a favourable treatment response. Analyses of paired samples found that FLOT chemotherapy also results in increased expression of CD4+ and CD8+ tumour infiltrating lymphocytes (Paired Wilcoxon, P = 0.002 and P = 0.008, respectively). Our power analysis suggests future study requires at least 35 patients in each treatment response group for CD8 and Galectin-3 molecules, whereas 80 patients in each treatment response group are required to assess CD4 and E-cadherin biomarkers.
CONCLUSION We demonstrate that an elevated CD4+/CD8+ Ratio is a promising IHC-based biomarker to predict favourable treatment response to FLOT neoadjuvant chemotherapy in locally advanced gastric cancer.
Collapse
Affiliation(s)
- Daniel Skubleny
- Department of Surgery, University of Alberta, Edmonton T6G 2R3, AB, Canada
| | - Andrea Lin
- Department of Surgery, University of Alberta, Edmonton T6G 2R3, Alberta, Canada
| | - Saurabh Garg
- Department of Surgery, University of Alberta, Edmonton T6G 2R3, Alberta, Canada
| | - Ross McLean
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton T6G 2R3, Alberta, Canada
| | - Michael McCall
- Department of Surgery, University of Alberta, Edmonton T6G 2R3, Alberta, Canada
| | - Sunita Ghosh
- Department of Oncology, University of Alberta, Edmonton T6G 2R3, Alberta, Canada
| | - Jennifer L Spratlin
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton T5G 1Z2, AB, Canada
| | - Daniel Schiller
- Department of Surgery, University of Alberta, Edmonton T6G 2R3, Alberta, Canada
| | - Gina Rayat
- Department of Surgery, University of Alberta, Edmonton T6G 2R3, Alberta, Canada
| |
Collapse
|
|
3
|
ALK, NUT, and TRK Do Not Play Relevant Roles in Gastric Cancer—Results of an Immunohistochemical Study in a Large Series. Diagnostics (Basel) 2022; 12:diagnostics12020429. [PMID: 35204520 PMCID: PMC8870766 DOI: 10.3390/diagnostics12020429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 02/01/2022] [Accepted: 02/04/2022] [Indexed: 12/24/2022] Open
Abstract
ALK, NUT, and TRK are rare molecular aberrations that are pathognomonic for specific rare tumors. In low frequencies, however, they are found in a wide range of other tumor entities. This study aimed to investigate the frequency, association with clinicopathological characteristics, and prognosis of the immunohistochemical expressions of ALK, NUT, and TRK in 477 adenocarcinomas of the stomach and gastroesophageal junction. Seven cases (1.5%) showed an expression of TRK. In NGS, no NTRK fusion was confirmed. No case with ALK or NUT expression was detected. ALK, NUT, and NTRK expression does not seem to play an important role in gastric carcinomas.
Collapse
|
|
4
|
Grosser B, Glückstein MI, Dhillon C, Schiele S, Dintner S, VanSchoiack A, Kroeppler D, Martin B, Probst A, Vlasenko D, Schenkirsch G, Märkl B. Stroma AReactive Invasion Front Areas (SARIFA) - a new prognostic biomarker in gastric cancer related to tumor-promoting adipocytes. J Pathol 2021; 256:71-82. [PMID: 34580877 DOI: 10.1002/path.5810] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Revised: 09/14/2021] [Accepted: 09/24/2021] [Indexed: 12/24/2022]
Abstract
Compared to other malignancies, there is a lack of easy-to-evaluate biomarkers for gastric cancer, which is associated with an adverse clinical outcome in many cases. Here, we present Stroma AReactive Invasion Front Areas (SARIFA) as a new histological prognostic marker. We defined SARIFA as the direct contact between a cluster of tumor glands/cells comprising at least five tumor cells and inconspicuous surrounding adipose tissue at the invasion front. A total of 480 adenocarcinomas of the stomach and the gastroesophageal junction from two different collections were classified according to SARIFA. To understand the potential underlying mechanisms, a transcriptome analysis was conducted using digital spatial profiling (DSP). It was found that 20% of the tumors were SARIFA-positive. Kappa values between the three pathologists were good in both collections: 0.74 and 0.78. Patients who presented SARIFA-positive tumors had a significantly lower overall survival in Collections A (median: 20.0 versus 44.0 months; p = 0.014, n = 160) and B (median: 15.0 versus 41.0 months; p < 0.0001, n = 320). SARIFA positivity emerged as a negative independent prognostic factor for overall survival (HR 1.638, 95% CI 1.153-2.326, p = 0.006). Using DSP, the most upregulated genes in SARIFA-positive cases were those associated with triglyceride catabolism and endogenous sterols. COL15A1, FABP2, and FABP4 were differentially expressed in positive cases. At the protein level, the expression of proteins related to lipid metabolism was confirmed. SARIFA combines low inter-observer variability, minimal effort, and high prognostic relevance, and is therefore an extremely promising biomarker related to tumor-promoting adipocytes in gastric cancer. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
Collapse
Affiliation(s)
- Bianca Grosser
- General Pathology and Molecular Diagnostics, Medical Faculty, University of Augsburg, Augsburg, Germany
| | - Marie-Isabelle Glückstein
- General Pathology and Molecular Diagnostics, Medical Faculty, University of Augsburg, Augsburg, Germany
| | - Christine Dhillon
- General Pathology and Molecular Diagnostics, Medical Faculty, University of Augsburg, Augsburg, Germany
| | - Stefan Schiele
- Institute of Mathematics and Computational Statistics, University of Augsburg, Augsburg, Germany
| | - Sebastian Dintner
- General Pathology and Molecular Diagnostics, Medical Faculty, University of Augsburg, Augsburg, Germany
| | | | | | - Benedikt Martin
- General Pathology and Molecular Diagnostics, Medical Faculty, University of Augsburg, Augsburg, Germany
| | - Andreas Probst
- Department of Gastroenterology, University Hospital Augsburg, Augsburg, Germany
| | - Dmytro Vlasenko
- General, Visceral and Transplantation Surgery, University Hospital of Augsburg, Augsburg, Germany
| | | | - Bruno Märkl
- General Pathology and Molecular Diagnostics, Medical Faculty, University of Augsburg, Augsburg, Germany
| |
Collapse
|
|
5
|
Glückstein MI, Dintner S, Arndt TT, Vlasenko D, Schenkirsch G, Agaimy A, Müller G, Märkl B, Grosser B. Comprehensive Immunohistochemical Study of the SWI/SNF Complex Expression Status in Gastric Cancer Reveals an Adverse Prognosis of SWI/SNF Deficiency in Genomically Stable Gastric Carcinomas. Cancers (Basel) 2021; 13:3894. [PMID: 34359794 PMCID: PMC8345509 DOI: 10.3390/cancers13153894] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 07/30/2021] [Indexed: 12/24/2022] Open
Abstract
The SWI/SNF complex has important functions in the mobilization of nucleosomes and consequently influences gene expression. Numerous studies have demonstrated that mutations or deficiency of one or more subunits can have an oncogenic effect and influence the development, progression, and eventual therapy resistance of tumor diseases. Genes encoding subunits of the SWI/SNF complex are mutated in approximately 20% of all human tumors. This study aimed to investigate the frequency, association with clinicopathological characteristics, and prognosis of immunohistochemical expression of proteins of the SWI/SNF complexes, SMARCA2, SMARCA4 SMARCB1, ARID1A, ARID1B, and PBRM1 in 477 adenocarcinomas of the stomach and gastroesophageal junction. Additionally, the tumors were classified immunohistochemically in analogy to The Cancer Genome Atlas (TCGA) classification. Overall, 32% of cases demonstrated aberrant expression of the SWI/SNF complex. Complete loss of SMARCA4 was detected in three cases (0.6%) and was associated with adverse clinical characteristics. SWI/SNF aberration emerged as an independent negative prognostic factor for overall survival in genomically stable patients in analogy to TCGA. In conclusion, determination of SWI/SNF status could be suggested in routine diagnostics in genomically stable tumors to identify patients who might benefit from new therapeutic options.
Collapse
Affiliation(s)
- Marie-Isabelle Glückstein
- Institute of General Pathology and Molecular Diagnostics, University Hospital Augsburg, 86156 Augsburg, Germany; (M.-I.G.); (S.D.); (T.T.A.); (B.M.)
| | - Sebastian Dintner
- Institute of General Pathology and Molecular Diagnostics, University Hospital Augsburg, 86156 Augsburg, Germany; (M.-I.G.); (S.D.); (T.T.A.); (B.M.)
| | - Tim Tobias Arndt
- Institute of General Pathology and Molecular Diagnostics, University Hospital Augsburg, 86156 Augsburg, Germany; (M.-I.G.); (S.D.); (T.T.A.); (B.M.)
- Institute of Mathematics and Computational Statistics, University of Augsburg, 86159 Augsburg, Germany;
| | - Dmytro Vlasenko
- Department of General, Visceral and Transplantation Surgery, University Hospital Augsburg, 86156 Augsburg, Germany;
| | - Gerhard Schenkirsch
- Tumor Data Management, University Hospital Augsburg, 86156 Augsburg, Germany;
| | - Abbas Agaimy
- Institute of Pathology, Friedrich-Alexander-University Erlangen-Nürnberg, University Hospital Erlangen, 91054 Erlangen, Germany;
| | - Gernot Müller
- Institute of Mathematics and Computational Statistics, University of Augsburg, 86159 Augsburg, Germany;
| | - Bruno Märkl
- Institute of General Pathology and Molecular Diagnostics, University Hospital Augsburg, 86156 Augsburg, Germany; (M.-I.G.); (S.D.); (T.T.A.); (B.M.)
| | - Bianca Grosser
- Institute of General Pathology and Molecular Diagnostics, University Hospital Augsburg, 86156 Augsburg, Germany; (M.-I.G.); (S.D.); (T.T.A.); (B.M.)
| |
Collapse
|
|
6
|
Hasan S. An Overview of Promising Biomarkers in Cancer Screening and Detection. Curr Cancer Drug Targets 2020; 20:831-852. [PMID: 32838718 DOI: 10.2174/1568009620666200824102418] [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: 05/13/2020] [Revised: 07/03/2020] [Accepted: 07/13/2020] [Indexed: 11/22/2022]
Abstract
Applications of biomarkers have been proved in oncology screening, diagnosis, predicting response to treatment as well as monitoring the progress of the disease. Considering the crucial role played by them during different disease stages, it is extremely important to evaluate, validate, and assess them to incorporate them into routine clinical care. In this review, the role of few most promising and successfully used biomarkers in cancer detection, i.e. PD-L1, E-Cadherin, TP53, Exosomes, cfDNA, EGFR, mTOR with regard to their structure, mode of action, and reports signifying their pathological significance, are addressed. Also, an overview of some successfully used biomarkers for cancer medicine has been presented. The study also summarizes biomarker-driven personalized cancer therapy i.e., approved targets and indications, as per the US FDA. The review also highlights the increasingly prominent role of biomarkers in drug development at all stages, with particular reference to clinical trials. The increasing utility of biomarkers in clinical trials is clearly evident from the trend shown, wherein ~55 percent of all oncology clinical trials in 2019 were seen to involve biomarkers, as opposed to ~ 15 percent in 2001, which clearly proves the essence and applicability of biomarkers for synergizing clinical information with tumor progression. Still, there are significant challenges in the implementation of these possibilities with strong evidence in cost-- effective manner.
Collapse
Affiliation(s)
- Saba Hasan
- Amity Institute of Biotechnology, Amity University, Uttar Pradesh, Lucknow, India
| |
Collapse
|
|
7
|
Hu MN, Hu SH, Zhang XW, Xiong SM, Deng H. Overview on new progress of hereditary diffuse gastric cancer with CDH1 variants. TUMORI JOURNAL 2020; 106:346-355. [PMID: 32811340 DOI: 10.1177/0300891620949668] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Hereditary diffuse gastric cancer (HDGC), comprising 1%-3% of gastric malignances, has been associated with CDH1 variants. Accumulating evidence has demonstrated more than 100 germline CDH1 variant types. E-cadherin encoded by the CDH1 gene serves as a tumor suppressor protein. CDH1 promoter hypermethylation and other molecular mechanisms resulting in E-cadherin dysfunction are involved in the tumorigenesis of HDGC. Histopathology exhibits characteristic signet ring cells, and immunohistochemical staining may show negativity for E-cadherin and other signaling proteins. Early HDGC is difficult to detect by endoscopy due to the development of lesions beneath the mucosa. Prophylactic gastrectomy is the most recommended treatment for pathogenic CDH1 variant carriers. Recent studies have promoted the progression of promising molecular-targeted therapies and management strategies. This review summarizes recent advances in CDH1 variant types, tumorigenesis mechanisms, diagnosis, and therapy, as well as clinical implications for future gene therapies.
Collapse
Affiliation(s)
- Mu-Ni Hu
- Medical College, Nanchang University, Nanchang, Jiangxi Province, China
| | - Shu-Hui Hu
- Medical College, Nanchang University, Nanchang, Jiangxi Province, China
| | - Xing-Wei Zhang
- Medical College, Nanchang University, Nanchang, Jiangxi Province, China
| | - Shu-Min Xiong
- Department of Ophthalmology, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Huan Deng
- Molecular Medicine and Genetics Center, the Fourth Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China.,Renmin Institute of Forensic Medicine in Jiangxi, Nanchang, Jiangxi Province, China
| |
Collapse
|
|
8
|
Li Z, Liu Z, Shao Z, Li C, Li Y, Liu Q, Zhang Y, Tan B, Liu Y. Identifying multiple collagen gene family members as potential gastric cancer biomarkers using integrated bioinformatics analysis. PeerJ 2020; 8:e9123. [PMID: 32509452 PMCID: PMC7255341 DOI: 10.7717/peerj.9123] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 04/13/2020] [Indexed: 12/24/2022] Open
Abstract
Background Gastric cancer is one of the most common malignant cancers worldwide. Despite substantial developments in therapeutic strategies, the five-year survival rate remains low. Therefore, novel biomarkers and therapeutic targets involved in the progression of gastric tumors need to be identified. Methods We obtained the mRNA microarray datasets GSE65801, GSE54129 and GSE79973 from the Gene Expression Omnibus database to acquire differentially expressed genes (DEGs). We used the Database for Annotation, Visualization, and Integrated Discovery (DAVID) to analyze DEG pathways and functions, and the Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape to obtain the protein-protein interaction (PPI) network. Next, we validated the hub gene expression levels using the Oncomine database and Gene Expression Profiling Interactive Analysis (GEPIA), and conducted stage expression and survival analysis. Results From the three microarray datasets, we identified nine major hub genes: COL1A1, COL1A2, COL3A1, COL5A2, COL4A1, FN1, COL5A1, COL4A2, and COL6A3. Conclusion Our study identified COL1A1 and COL1A2 as potential gastric cancer prognostic biomarkers.
Collapse
Affiliation(s)
- Zhaoxing Li
- Department of General Surgery, The Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
| | - Zhao Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery, Peking University Cancer Hospital and Institute, Beijing, China
| | - Zhiting Shao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing, China
| | - Chuang Li
- The Second Hospital of Shijiazhuang, Shijiazhuang, China
| | - Yong Li
- Department of General Surgery, The Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
| | - Qingwei Liu
- Department of General Surgery, The Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
| | | | - Bibo Tan
- Department of General Surgery, The Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yu Liu
- Department of General Surgery, The Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
| |
Collapse
|
|
9
|
S100P is a molecular determinant of E-cadherin function in gastric cancer. Cell Commun Signal 2019; 17:155. [PMID: 31767037 PMCID: PMC6878717 DOI: 10.1186/s12964-019-0465-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 10/22/2019] [Indexed: 12/11/2022] Open
Abstract
Background E-cadherin has been awarded a key role in the aetiology of both sporadic and hereditary forms of gastric cancer. In this study, we aimed to identify molecular interactors that influence the expression and function of E-cadherin associated to cancer. Methods A data mining approach was used to predict stomach-specific candidate genes, uncovering S100P as a key candidate. The role of S100P was evaluated through in vitro functional assays and its expression was studied in a gastric cancer tissue microarray (TMA). Results S100P was found to contribute to a cancer pathway dependent on the context of E-cadherin function. In particular, we demonstrated that S100P acts as an E-cadherin positive regulator in a wild-type E-cadherin context, and its inhibition results in decreased E-cadherin expression and function. In contrast, S100P is likely to be a pro-survival factor in gastric cancer cells with loss of functional E-cadherin, contributing to an oncogenic molecular program. Moreover, expression analysis in a gastric cancer TMA revealed that S100P expression impacts negatively among patients bearing Ecad− tumours, despite not being significantly associated with overall survival on its own. Conclusions We propose that S100P has a dual role in gastric cancer, acting as an oncogenic factor in the context of E-cadherin loss and as a tumour suppressor in a functional E-cadherin setting. The discovery of antagonist effects of S100P in different E-cadherin contexts will aid in the stratification of gastric cancer patients who may benefit from S100P-targeted therapies. Graphical abstract ![]()
Collapse
|
|
10
|
Lin HW, Fu CF, Chang MC, Lu TP, Lin HP, Chiang YC, Chen CA, Cheng WF. CDH1, DLEC1 and SFRP5 methylation panel as a prognostic marker for advanced epithelial ovarian cancer. Epigenomics 2018; 10:1397-1413. [PMID: 30324802 DOI: 10.2217/epi-2018-0035] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
AIM To investigate the CDH1, DLEC1 and SFRP5 gene methylation panel for advanced epithelial ovarian carcinoma (EOC). MATERIALS & METHODS One hundred and seventy-seven advanced EOC specimens were evaluated by methylation-specific PCR. We also used The Cancer Genome Atlas dataset to evaluate the panel. RESULTS The presence of two or more methylated genes was significant in recurrence (hazard ratio [HR]: 1.91 [1.33-2.76]; p = 0.002) and death (HR: 1.96 [1.26-3.06]; p = 0.006) in our cohort. In The Cancer Genome Atlas dataset, the presence of two or three methylated genes was significant in death (HR: 1.59 [1.15-2.18]; p = 0.0047) and close to the significance level in recurrence (HR: 1.37 [0.99-1.88]; p = 0.058). CONCLUSION The CDH1, DLEC1 and SFRP5 methylation panel is a potential prognostic biomarker for advanced EOC.
Collapse
Affiliation(s)
- Han-Wei Lin
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei 10055, Taiwan
| | - Chi-Feng Fu
- Department of Obstetrics & Gynecology, E-da Cancer Hospital, Kaohsiung 82445, Taiwan
| | - Ming-Cheng Chang
- Department of Obstetrics & Gynecology, College of Medicine, National Taiwan University, Taipei 10041, Taiwan.,Institute of Nuclear Energy Research, Atomic Energy Council, Executive Yuan, Taoyuan 32546, Taiwan
| | - Tzu-Pin Lu
- Institute of Epidemiology & Preventive Medicine, College of Public Health, National Taiwan University, Taipei 10055, Taiwan
| | - Hsiu-Ping Lin
- Department of Obstetrics & Gynecology, College of Medicine, National Taiwan University, Taipei 10041, Taiwan
| | - Ying-Cheng Chiang
- Department of Obstetrics & Gynecology, College of Medicine, National Taiwan University, Taipei 10041, Taiwan
| | - Chi-An Chen
- Department of Obstetrics & Gynecology, College of Medicine, National Taiwan University, Taipei 10041, Taiwan
| | - Wen-Fang Cheng
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei 10055, Taiwan.,Department of Obstetrics & Gynecology, College of Medicine, National Taiwan University, Taipei 10041, Taiwan.,Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 10002, Taiwan
| |
Collapse
|
|
11
|
Abbas M, Faggian A, Sintali DN, Khan GJ, Naeem S, Shi M, Dingding C. Current and future biomarkers in gastric cancer. Biomed Pharmacother 2018; 103:1688-1700. [DOI: 10.1016/j.biopha.2018.04.178] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 04/24/2018] [Accepted: 04/24/2018] [Indexed: 02/06/2023] Open
|
|
12
|
Wong SHM, Fang CM, Chuah LH, Leong CO, Ngai SC. E-cadherin: Its dysregulation in carcinogenesis and clinical implications. Crit Rev Oncol Hematol 2018; 121:11-22. [PMID: 29279096 DOI: 10.1016/j.critrevonc.2017.11.010] [Citation(s) in RCA: 260] [Impact Index Per Article: 37.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Revised: 10/15/2017] [Accepted: 11/16/2017] [Indexed: 02/06/2023] Open
Abstract
E-cadherin is a transmembrane glycoprotein which connects epithelial cells together at adherens junctions. In normal cells, E-cadherin exerts its tumour suppressing role mainly by sequestering β-catenin from its binding to LEF (Lymphoid enhancer factor)/TCF (T cell factor) which serves the function of transcribing genes of the proliferative Wnt signaling pathway. Despite the ongoing debate on whether the loss of E-cadherin is the cause or effect of epithelial-mesenchymal transition (EMT), E-cadherin functional loss has frequently been associated with poor prognosis and survival in patients of various cancers. The dysregulation of E-cadherin expression that leads to carcinogenesis happens mostly at the epigenetic level but there are cases of genetic alterations as well. E-cadherin expression has been linked to the cellular functions of invasiveness reduction, growth inhibition, apoptosis, cell cycle arrest and differentiation. Studies on various cancers have shown that these different cellular functions are also interdependent. Recent studies have reported a rapid expansion of E-cadherin clinical relevance in various cancers. This review article summarises the multifaceted effect E-cadherin expression has on cellular functions in the context of carcinogenesis as well as its clinical implications in diagnosis, prognosis and therapeutics.
Collapse
Affiliation(s)
- Sonia How Ming Wong
- School of Biosciences, Faculty of Science, University of Nottingham Malaysia Campus, 43500, Semenyih, Selangor, Malaysia.
| | - Chee Mun Fang
- School of Pharmacy, Faculty of Science, University of Nottingham Malaysia Campus, 43500, Semenyih, Selangor, Malaysia.
| | - Lay-Hong Chuah
- School of Pharmacy, Monash University Malaysia, Bandar Sunway, 47500, Subang Jaya, Selangor, Malaysia.
| | - Chee Onn Leong
- School of Pharmacy, International Medical University, Bukit Jalil, 57000, Kuala Lumpur, Malaysia; Centre for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, 57000, Kuala Lumpur, Malaysia.
| | - Siew Ching Ngai
- School of Biosciences, Faculty of Science, University of Nottingham Malaysia Campus, 43500, Semenyih, Selangor, Malaysia.
| |
Collapse
|
|
13
|
Predicting the Functional Impact of CDH1 Missense Mutations in Hereditary Diffuse Gastric Cancer. Int J Mol Sci 2017; 18:ijms18122687. [PMID: 29231860 PMCID: PMC5751289 DOI: 10.3390/ijms18122687] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 11/28/2017] [Accepted: 11/30/2017] [Indexed: 12/20/2022] Open
Abstract
The role of E-cadherin in Hereditary Diffuse Gastric Cancer (HDGC) is unequivocal. Germline alterations in its encoding gene (CDH1) are causative of HDGC and occur in about 40% of patients. Importantly, while in most cases CDH1 alterations result in the complete loss of E-cadherin associated with a well-established clinical impact, in about 20% of cases the mutations are of the missense type. The latter are of particular concern in terms of genetic counselling and clinical management, as the effect of the sequence variants in E-cadherin function is not predictable. If a deleterious variant is identified, prophylactic surgery could be recommended. Therefore, over the last few years, intensive research has focused on evaluating the functional consequences of CDH1 missense variants and in assessing E-cadherin pathogenicity. In that context, our group has contributed to better characterize CDH1 germline missense variants and is now considered a worldwide reference centre. In this review, we highlight the state of the art methodologies to categorize CDH1 variants, as neutral or deleterious. This information is subsequently integrated with clinical data for genetic counseling and management of CDH1 variant carriers.
Collapse
|
|
14
|
Diagnostic, Predictive, Prognostic, and Therapeutic Molecular Biomarkers in Third Millennium: A Breakthrough in Gastric Cancer. BIOMED RESEARCH INTERNATIONAL 2017; 2017:7869802. [PMID: 29094049 PMCID: PMC5637861 DOI: 10.1155/2017/7869802] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 07/12/2017] [Indexed: 02/08/2023]
Abstract
Introduction Gastric cancer is the fifth most common cancer and the third cause of cancer death. The clinical outcomes of the patients are still not encouraging with a low rate of 5 years' survival. Often the disease is diagnosed at advanced stages and this obviously negatively affects patients outcomes. A deep understanding of molecular basis of gastric cancer can lead to the identification of diagnostic, predictive, prognostic, and therapeutic biomarkers. Main Body This paper aims to give a global view on the molecular classification and mechanisms involved in the development of the tumour and on the biomarkers for gastric cancer. We discuss the role of E-cadherin, HER2, fibroblast growth factor receptor (FGFR), MET, human epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (HGFR), mammalian target of rapamycin (mTOR), microsatellite instability (MSI), PD-L1, and TP53. We have also considered in this manuscript new emerging biomarkers as matrix metalloproteases (MMPs), microRNAs, and long noncoding RNAs (lncRNAs). Conclusions Identifying and validating diagnostic, prognostic, predictive, and therapeutic biomarkers will have a huge impact on patients outcomes as they will allow early detection of tumours and also guide the choice of a targeted therapy based on specific molecular features of the cancer.
Collapse
|
|
15
|
Gao H, Lan X, Li S, Xue Y. Relationships of MMP-9, E-cadherin, and VEGF expression with clinicopathological features and response to chemosensitivity in gastric cancer. Tumour Biol 2017; 39:1010428317698368. [PMID: 28459196 DOI: 10.1177/1010428317698368] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
The matrix metalloproteinase-9, E-cadherin, and vascular endothelial growth factor play an important role in behavior of tumor cell growth, invasion, and metastasis. In this study, we investigated the relationships of matrix metalloproteinase-9, E-cadherin, and vascular endothelial growth factor expression with clinicopathological features and results of chemosensitivity tested by collagen gel droplet–embedded culture–drug sensitivity test in gastric cancer. Fresh specimens were used for collagen gel droplet–embedded culture–drug sensitivity test and paired fixed specimens were used for immunohistochemistry. Positive expression of matrix metalloproteinase-9 was associated with poorly differentiated carcinoma (p = 0.032), lymph node metastasis (p = 0.022), and tumor stage (p = 0.023). Negative expression of E-cadherin was associated with poorly differentiated carcinoma (p = 0.007), lymph node metastasis (p = 0.012), and tumor stage (p = 0.007). Positive expression of vascular endothelial growth factor was associated with tumor size (p = 0.040) and stage (p = 0.007). Collagen gel droplet–embedded culture–drug sensitivity test was successfully evaluated in 56 patients. Among them, 29 (51.7%) patients were resistant to TS-1 and 31 (55.3%) patients were resistant to L-OHP. The L-OHP resistance rate in vascular endothelial growth factor positive patients was significantly higher than that in negative patients (p = 0.031). The L-OHP resistance rate in E-cadherin negative patients was significantly higher than that in positive patients (p = 0.014). In conclusion, matrix metalloproteinase-9, E-cadherin, and vascular endothelial growth factor were involved in tumor invasion and metastasis. Positive expression of matrix metalloproteinase-9 and vascular endothelial growth factor and negative expression of E-cadherin were malignant markers for gastric cancer. Positive expression of vascular endothelial growth factor and negative expression of E-cadherin were associated with L-OHP resistance.
Collapse
Affiliation(s)
- Hongyu Gao
- Department of Gastroenterology Surgery, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, China
| | - Xiuwen Lan
- Department of Gastroenterology Surgery, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, China
| | - Sen Li
- Department of Gastroenterology Surgery, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, China
| | - Yingwei Xue
- Department of Gastroenterology Surgery, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, China
| |
Collapse
|
|
16
|
Gulati N, Shetty DC, Rathore AS, Juneja S, Jain A. E-cadherin-mediated impairment increases anti-apoptotic mechanism through upregulation of Bcl-2: An immunohistochemical study in various patterns of invasion of oral squamous cell carcinoma. J Oral Pathol Med 2017; 46:934-939. [PMID: 28294427 DOI: 10.1111/jop.12569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/08/2017] [Indexed: 11/28/2022]
Abstract
BACKGROUND Bcl-2 and E-cadherin proteins are known to be involved in the control of apoptotic cell death and invasive potential, respectively, which is an important hallmark of tumor regulation that influences their biologic behavior. AIM This study investigates the relationship of Bcl-2 and E-cadherin immunoexpression in various Bryne's patterns of invasion. MATERIAL AND METHODS Immunohistochemical analyses for Bcl-2 and E-cadherin were performed on paraffin-embedded tissue sections on 40 cases (32 cases of Oral squamous cell carcinoma and eight cases of controls) and were scored using qualitative and quantitative (percentage positive) analysis. STATISTICAL ANALYSIS The resulting data were analyzed using SPSS software version 19. Correlation between patterns of invasion and qualitative scores of Bcl-2 and E-cadherin was calculated using Spearman rho correlation. Difference of mean percentage of positive cells of Bcl-2 and E-cadherin in different patterns of invasion was tested by ANOVA followed by Tukey HSD test. RESULTS Bcl-2 and E-cadherin immunoreactivity was positively correlated with Bryne's pattern of invasion (P value<.05). An inverse relation was found between Bcl-2 and E-cadherin expression with Bryne's patterns 1-5 of invasion. CONCLUSIONS The results pointed to the antagonistic role of E-cadherin and Bcl-2 and thus provide the opportunity for cell survival along with increased invasive potential.
Collapse
Affiliation(s)
- Nikita Gulati
- Department of Oral and Maxillofacial Pathology and Microbiology, I.T.S. Center for Dental Studies and Research, Ghaziabad (U.P), India
| | - Devi Charan Shetty
- Department of Oral and Maxillofacial Pathology and Microbiology, I.T.S. Center for Dental Studies and Research, Ghaziabad (U.P), India
| | - Ajit Singh Rathore
- Department of Oral and Maxillofacial Pathology and Microbiology, I.T.S. Center for Dental Studies and Research, Ghaziabad (U.P), India
| | - Saurabh Juneja
- Department of Oral and Maxillofacial Pathology and Microbiology, I.T.S. Center for Dental Studies and Research, Ghaziabad (U.P), India
| | - Anshi Jain
- Department of Oral and Maxillofacial Pathology and Microbiology, I.T.S. Center for Dental Studies and Research, Ghaziabad (U.P), India
| |
Collapse
|
|
17
|
|
|
18
|
Thang ND, Minh NV, Huong PT. Translocation of BBAP from the cytoplasm to the nucleus reduces the metastatic ability of vemurafenib-resistant SKMEL28 cells. Mol Med Rep 2016; 15:317-322. [PMID: 27922665 DOI: 10.3892/mmr.2016.5976] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2015] [Accepted: 11/01/2016] [Indexed: 11/06/2022] Open
Abstract
To the best of our knowledge, the present study is the first to demonstrate that treatment of vemurafenib-resistant SKMEL28 (SKMEL28-R) cells with paclitaxel leads to a shift in localization of the E3-ligase BBAP from the cytoplasm to the nucleus, consequently decreasing the metastatic ability of this cell line. The present study revealed that the movement of BBAP from the cytoplasm to nucleus initiated a change in cell morphology. In addition, the translocation of BBAP led to a decrease of metastatic characteristics in SKMEL28‑R cells, including migration and invasion via downregulation of the phosphorylated form of focal adhesion kinase and N‑cadherin, as well as an upregulation of p21 and E-cadherin. The results of the present study suggested that BBAP may not only be a novel biomarker for melanoma, but also a novel therapeutic target for treatment of metastatic melanoma.
Collapse
Affiliation(s)
- Nguyen Dinh Thang
- Department of Biochemistry and Plant Physiology, Faculty of Biology, VNU University of Science, Vietnam National University, Hanoi 120564, Vietnam
| | - Nguyen Van Minh
- Key Laboratory of Enzyme and Protein Technology, VNU University of Science, Vietnam National University, Hanoi 120564, Vietnam
| | - Pham Thu Huong
- Key Laboratory of Enzyme and Protein Technology, VNU University of Science, Vietnam National University, Hanoi 120564, Vietnam
| |
Collapse
|
|
19
|
Baniak N, Senger JL, Ahmed S, Kanthan SC, Kanthan R. Gastric biomarkers: a global review. World J Surg Oncol 2016; 14:212. [PMID: 27514667 PMCID: PMC4982433 DOI: 10.1186/s12957-016-0969-3] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Accepted: 08/02/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Gastric cancer is an aggressive disease with a poor 5-year survival and large global burden of disease. The disease is biologically and genetically heterogeneous with a poorly understood carcinogenesis at the molecular level. Despite the many prognostic, predictive, and therapeutic biomarkers investigated to date, gastric cancer continues to be detected at an advanced stage with resultant poor clinical outcomes. MAIN BODY This is a global review of gastric biomarkers with an emphasis on HER2, E-cadherin, fibroblast growth factor receptor, mammalian target of rapamycin, and hepatocyte growth factor receptor as well as sections on microRNAs, long noncoding RNAs, matrix metalloproteinases, PD-L1, TP53, and microsatellite instability. CONCLUSION A deeper understanding of the pathogenesis and biological features of gastric cancer, including the identification and characterization of diagnostic, prognostic, predictive, and therapeutic biomarkers, hopefully will provide improved clinical outcomes.
Collapse
Affiliation(s)
- Nick Baniak
- Department of Pathology and Laboratory Medicine, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK S7N 0W8 Canada
| | - Jenna-Lynn Senger
- Department of Surgery, University of Alberta, 116 St & 85 Ave, Edmonton, T6G 2R3, T6G 2B7 AB Canada
| | - Shahid Ahmed
- Division of Medical Oncology, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK S7N 0W8 Canada
| | - S. C. Kanthan
- Department of General Surgery, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK S7N 0W8 Canada
| | - Rani Kanthan
- Department of General Surgery, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK S7N 0W8 Canada
| |
Collapse
|
|
20
|
van der Post RS, Gullo I, Oliveira C, Tang LH, Grabsch HI, O'Donovan M, Fitzgerald RC, van Krieken H, Carneiro F. Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 908:371-91. [PMID: 27573781 DOI: 10.1007/978-3-319-41388-4_18] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Familial clustering is seen in 10 % of gastric cancer cases and approximately 1-3 % of gastric cancer arises in the setting of hereditary diffuse gastric cancer (HDGC). In families with HDGC, gastric cancer presents at young age. HDGC is predominantly caused by germline mutations in CDH1 and in a minority by mutations in other genes, including CTNNA1. Early stage HDGC is characterized by a few, up to dozens of intramucosal foci of signet ring cell carcinoma and its precursor lesions. These include in situ signet ring cell carcinoma and pagetoid spread of signet ring cells. Advanced HDGC presents as poorly cohesive/diffuse type carcinoma, normally with very few typical signet ring cells, and has a poor prognosis. Currently, it is unknown which factors drive the progression towards aggressive disease, but it is clear that most intramucosal lesions will not have such progression.Immunohistochemical profile of early and advanced HDGC is often characterized by abnormal E-cadherin immunoexpression, including absent or reduced membranous expression, as well as "dotted" or cytoplasmic expression. However, membranous expression of E-cadherin does not exclude HDGC. Intramucosal HDGC (pT1a) presents with an "indolent" phenotype, characterized by typical signet ring cells without immunoexpression of Ki-67 and p53, while advanced carcinomas (pT > 1) display an "aggressive" phenotype with pleomorphic cells, that are immunoreactive for Ki-67 and p53. These features show that the IHC profile is different between intramucosal and more advanced HDGC, providing evidence of phenotypic heterogeneity, and may help to define predictive biomarkers of progression from indolent to aggressive, widely invasive carcinomas.
Collapse
Affiliation(s)
- Rachel S van der Post
- Department of Pathology, Radboud University Medical Centre, 9101, Nijmegen, 6500 HB, The Netherlands
| | - Irene Gullo
- Department of Pathology, Centro Hospitalar de São João, Al. Prof. Hernâni Monteiro, Porto, 4200-319, Portugal.,Department of Pathology and Oncology, Faculdade de Medicina da Universidade do Porto (FMUP), Al. Prof. Hernâni Monteiro, Porto, 4200-319, Portugal.,Instituto de Patologia e Imunologia Molecular da Universidade do Porto (Ipatimup), Porto, Portugal and Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Dr. Roberto Frias S/N, Porto, 4200-465, Portugal
| | - Carla Oliveira
- Department of Pathology, Centro Hospitalar de São João, Al. Prof. Hernâni Monteiro, Porto, 4200-319, Portugal.,Department of Pathology and Oncology, Faculdade de Medicina da Universidade do Porto (FMUP), Al. Prof. Hernâni Monteiro, Porto, 4200-319, Portugal
| | - Laura H Tang
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY, 10065, USA
| | - Heike I Grabsch
- GROW School of Oncology and Developmental Biology and Department of Pathology, Maastricht University Medical Centre, Peter Debyelaan 25, Maastricht, 6229 HX, The Netherlands
| | - Maria O'Donovan
- Department of Histopathology, Cambridge University Hospitals NHS Trust, Cambridge, CB2 0QQ, UK
| | - Rebecca C Fitzgerald
- MRC Cancer Unit, Hutchison-MRC Research Centre, University of Cambridge, 197, Biomedical Campus, Cambridge, CB2 0XZ, UK
| | - Han van Krieken
- Department of Pathology, Radboud University Medical Centre, 9101, Nijmegen, 6500 HB, The Netherlands
| | - Fátima Carneiro
- Department of Pathology, Centro Hospitalar de São João, Al. Prof. Hernâni Monteiro, Porto, 4200-319, Portugal. .,Department of Pathology and Oncology, Faculdade de Medicina da Universidade do Porto (FMUP), Al. Prof. Hernâni Monteiro, Porto, 4200-319, Portugal. .,Instituto de Patologia e Imunologia Molecular da Universidade do Porto (Ipatimup), Porto, Portugal and Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Dr. Roberto Frias S/N, Porto, 4200-465, Portugal.
| |
Collapse
|
|
21
|
HU YUNHUI, LI KAIYONG, ASADUZZAMAN MUHAMMAD, CUELLA RAQUEL, SHI HUI, RAGUZ SELINA, COOMBES RAOULCHARLES, ZHOU YUAN, YAGÜE ERNESTO. miR-106b~25 cluster regulates multidrug resistance in an ABC transporter-independent manner via downregulation of EP300. Oncol Rep 2015; 35:1170-8. [DOI: 10.3892/or.2015.4412] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Accepted: 09/04/2015] [Indexed: 11/06/2022] Open
|
|
22
|
Corso G, Figueiredo J, Biffi R, Trentin C, Bonanni B, Feroce I, Serrano D, Cassano E, Annibale B, Melo S, Seruca R, De Lorenzi F, Ferrara F, Piagnerelli R, Roviello F, Galimberti V. E-cadherin germline mutation carriers: clinical management and genetic implications. Cancer Metastasis Rev 2014; 33:1081-1094. [PMID: 25332147 DOI: 10.1007/s10555-014-9528-y] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Hereditary diffuse gastric cancer is an autosomic dominant syndrome associated with E-cadherin protein (CDH1) gene germline mutations. Clinical criteria for genetic screening were revised in 2010 by the International Gastric Cancer Linkage Consortium at the Cambridge meeting. About 40 % of families fulfilling clinical criteria for this inherited disease present deleterious CDH1 germline mutations. Lobular breast cancer is a neoplastic condition associated with hereditary diffuse gastric cancer syndrome. E-cadherin constitutional mutations have been described in both settings, in gastric and breast cancers. The management of CDH1 asymptomatic mutation carriers requires a multidisciplinary approach; the only life-saving procedure is the prophylactic total gastrectomy after thorough genetic counselling. Several prophylactic gastrectomies have been performed to date; conversely, no prophylactic mastectomies have been described in CDH1 mutant carriers. However, the recent discovery of novel germline alterations in pedigree clustering only for lobular breast cancer opens up a new debate in the management of these individuals. In this critical review, we describe the clinical management of CDH1 germline mutant carriers providing specific recommendations for genetic counselling, clinical criteria, surveillance and/ or prophylactic surgery.
Collapse
Affiliation(s)
- Giovanni Corso
- Molecular Senology Unit, via G. Ripamonti 435, European Institute of Oncology, 20141, Milan, Italy,
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
23
|
Zheng L, Fu Y, Zhuang L, Gai R, Ma J, Lou J, Zhu H, He Q, Yang B. Simultaneous NF-κB inhibition and E-cadherin upregulation mediate mutually synergistic anticancer activity of celastrol and SAHA in vitro and in vivo. Int J Cancer 2014; 135:1721-32. [PMID: 24615207 DOI: 10.1002/ijc.28810] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Accepted: 02/13/2014] [Indexed: 12/31/2022]
Abstract
Suberoylanilide hydroxamic acid (SAHA) is a promising histone deacetylase (HDAC) inhibitor approved by the US Food and Drug Administration (FDA) and whose clinical application for solid tumours is partially limited by decreased susceptibility in cancer cells due to nuclear factor (NF)-κB activation. As an NF-κB inhibitor, celastrol exhibits potent anticancer effects but has failed to enter clinical trials due to its toxicity. In this report, we demonstrated that the combination of celastrol and SAHA exerted substantial synergistic efficacy against human cancer cells in vitro and in vivo accompanied by enhanced caspase-mediated apoptosis. This drug combination inhibited the activation of NF-κB caused by SAHA monotherapy and consequently led to increased apoptosis in cancer cells. Interestingly, E-cadherin was dramatically downregulated in celastrol-resistant cancer cells, and E-cadherin expression was closely related to decreased sensitivity to celastrol. However, our combination treatment significantly augmented the expression of E-cadherin, suggesting that mutual mechanisms contributed to the synergistic anticancer activity. Furthermore, the enhanced anticancer efficacy of celastrol combined with SAHA was validated in a human lung cancer 95-D xenograft model without increased toxicity. Taken together, our data demonstrated the synergistic anticancer effects of celastrol and SAHA due to their reciprocal sensitisation, which was simultaneously regulated by NF-κB and E-cadherin; thus, the combination of celastrol and SAHA was superior to other combination regimens that rely on a single mechanism. Our findings not only open new opportunities for the clinical development of SAHA but should also motivate the clinical investigation of celastrol, which has been hampered by its toxicity.
Collapse
Affiliation(s)
- Lin Zheng
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | | | | | | | | | | | | | | | | |
Collapse
|
|
24
|
Durães C, Almeida GM, Seruca R, Oliveira C, Carneiro F. Biomarkers for gastric cancer: prognostic, predictive or targets of therapy? Virchows Arch 2014; 464:367-78. [DOI: 10.1007/s00428-013-1533-y] [Citation(s) in RCA: 124] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Revised: 11/12/2013] [Accepted: 12/23/2013] [Indexed: 12/12/2022]
|
|
25
|
Carneiro P, Figueiredo J, Bordeira-Carriço R, Fernandes MS, Carvalho J, Oliveira C, Seruca R. Therapeutic targets associated to E-cadherin dysfunction in gastric cancer. Expert Opin Ther Targets 2013; 17:1187-201. [PMID: 23957294 DOI: 10.1517/14728222.2013.827174] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Epithelial cadherin (E-cadherin) plays a key role in epithelial cell-cell adhesion, contributing to tissue differentiation and homeostasis. Throughout the past decades, research has shed light on the molecular mechanisms underlying E-cadherin's role in tumor progression, namely in invasion and metastization. Emerging evidence established E-cadherin as a tumor suppressor and suggests that targeting E-cadherin or downstream signaling molecules may constitute effective cancer therapeutics. AREAS COVERED This review aims to cover E-cadherin-mediated signaling during cancer development and progression and highlight putative therapeutic targets. EXPERT OPINION Reconstitution of E-cadherin expression or targeting of E-cadherin downstream molecules holds promise in cancer therapies. Considering the high frequency of CDH1 promoter hypermethylation as a second hit in malignant lesions from hereditary diffuse gastric cancer patients, histone deacetylase inhibitors are potential therapeutic agents in combination with conventional chemotherapy, specifically in initial tumor stages. Concerning E-cadherin-mediated signaling, we propose that HER receptors (as epidermal growth factor receptor) and Notch downstream targets are clinically relevant and should be considered in gastric cancer therapeutics and control.
Collapse
Affiliation(s)
- Patrícia Carneiro
- IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto , Rua Dr. Roberto Frias s/n, 4200-465 Porto , Portugal +00351 225570700 ; +00351 225570799 ;
| | | | | | | | | | | | | |
Collapse
|
|
26
|
Murakami M, Fukuzawa M, Yamamoto M, Hamaya K, Tamura Y, Sugiyama A, Takahashi R, Murakami T, Amagase K, Takeuchi K. Effects of Helicobacter pylori infection on gastric parietal cells and E-cadherin in Mongolian gerbils. J Pharmacol Sci 2013; 121:305-11. [PMID: 23545479 DOI: 10.1254/jphs.12191fp] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
Abstract
Atrophic gastritis caused by infection with Helicobacter pylori is characterized by parietal cell loss, which is a main risk factor for gastric cancer. Parietal cells play a crucial role in the regulation of cell lineage maturation and proliferation in the gastric units. Among the classical cadherins, E-cadherin plays an important role not only in epithelial cell-cell connections, but also in the maintenance of epithelial polarity and gastric glandular architecture and regulation of cell proliferation. The aim of this study is to elucidate how parietal cells and E-cadherin are altered in gastritis with Helicobacter pylori infection. We studied the effects of Helicobacter pylori on gastric mucosal E-cadherin 2 weeks after inoculation and investigated the relationship between parietal cell loss and the amount of E-cadherin on parietal cells in Mongolian gerbils. The number of parietal cells and amount of staining of E-cadherin below the isthmus were investigated by immunohistochemistry. It was shown that a reduction in intercellular E-cadherin preceded the disappearance of parietal cells. The gastric glands where parietal cells were lost were replaced by mucus secreting cells without E-cadherin. These results suggest that Helicobacter pylori damaged E-cadherin on parietal cells and caused massive parietal cell loss, leading to the deregulation of gastric morphology.
Collapse
Affiliation(s)
- Motonobu Murakami
- Department of Pharmacotherapy, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Japan.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
27
|
Chen Y, Sun Y, Chen L, Xu X, Zhang X, Wang B, Min L, Liu W. miRNA-200c increases the sensitivity of breast cancer cells to doxorubicin through the suppression of E-cadherin-mediated PTEN/Akt signaling. Mol Med Rep 2013; 7:1579-84. [PMID: 23546450 DOI: 10.3892/mmr.2013.1403] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2012] [Accepted: 02/20/2013] [Indexed: 02/06/2023] Open
Abstract
Doxorubicin (ADR) is successfully used to treat breast cancer, however, it is often associated with the acquired resistance of breast cancer cells which eliminates the therapeutic efficiency of ADR, leading to relapse and a poorer prognosis. It has been reported that microRNA-200c (miRNA-200c), a non-coding RNA, is important in the epithelial to mesenchymal transition (EMT) and metastasis in breast cancer cells. Recent evidence demonstrated that miRNA-200c is also regulated in chemotherapeutic drug resistance, however, the precise mechanism by which this occurs remains unclear. In this study, we demonstrated that the loss of miRNA-200c correlates with the acquired resistance of breast cancer cells to ADR. In addition, the loss of miRNA-200c correlated with decreased levels of E-cadherin and PTEN, and increased levels of ZEB1 and phospho-Akt (p-Akt) in ADR-resistant breast cancer cells (MCF-7/ADR cells). More importantly, we demonstrated that the gain of miRNA-200c results in an increased sensitivity of cells to ADR, downregulation of ZEB1, upregulation of E-cadherin and PTEN, and inactivation of Akt signaling. Following the co-transfection of E-cadherin siRNA, the miRNA-200c-mediated regulation of Akt signaling and PTEN was inhibited. Results of the present study also demonstrated that Akt signaling is involved in the ADR resistance of breast cancer cells since LY294002, an inhibitor of Akt signaling, partially restored the sensitivity of MCF-7/ADR cells to ADR. In conclusion, miRNA-200c inhibited Akt signaling through its effects on E-cadherin and PTEN, resulting in the inhibition of ADR resistance in breast cancer cells.
Collapse
Affiliation(s)
- Yong Chen
- Department of Medical Oncology, Subei People's Hospital, Yangzhou, Jiangsu 225000, PR China
| | | | | | | | | | | | | | | |
Collapse
|
|
28
|
Carneiro P, Fernandes MS, Figueiredo J, Caldeira J, Carvalho J, Pinheiro H, Leite M, Melo S, Oliveira P, Simões-Correia J, Oliveira MJ, Carneiro F, Figueiredo C, Paredes J, Oliveira C, Seruca R. E-cadherin dysfunction in gastric cancer--cellular consequences, clinical applications and open questions. FEBS Lett 2012; 586:2981-9. [PMID: 22841718 DOI: 10.1016/j.febslet.2012.07.045] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2012] [Revised: 07/16/2012] [Accepted: 07/17/2012] [Indexed: 02/06/2023]
Abstract
E-cadherin plays a major role in cell-cell adhesion and inactivating germline mutations in its encoding gene predispose to hereditary diffuse gastric cancer. Evidence indicates that aside from its recognized role in early tumourigenesis, E-cadherin is also pivotal for tumour progression, including invasion and metastization. Herein, we discuss E-cadherin alterations found in a cancer context, associated cellular effects and signalling pathways, and we raise new key questions that will impact in the management of GC patients and families.
Collapse
Affiliation(s)
- Patrícia Carneiro
- IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto, Rua Dr. Roberto Frias s/n, Porto, Portugal
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
29
|
Paredes J, Figueiredo J, Albergaria A, Oliveira P, Carvalho J, Ribeiro AS, Caldeira J, Costa AM, Simões-Correia J, Oliveira MJ, Pinheiro H, Pinho SS, Mateus R, Reis CA, Leite M, Fernandes MS, Schmitt F, Carneiro F, Figueiredo C, Oliveira C, Seruca R. Epithelial E- and P-cadherins: role and clinical significance in cancer. Biochim Biophys Acta Rev Cancer 2012; 1826:297-311. [PMID: 22613680 DOI: 10.1016/j.bbcan.2012.05.002] [Citation(s) in RCA: 101] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2012] [Revised: 05/09/2012] [Accepted: 05/11/2012] [Indexed: 01/26/2023]
Abstract
E-cadherin and P-cadherin are major contributors to cell-cell adhesion in epithelial tissues, playing pivotal roles in important morphogenetic and differentiation processes during development, and in maintaining integrity and homeostasis in adult tissues. It is now generally accepted that alterations in these two molecules are observed during tumour progression of most carcinomas. Genetic or epigenetic alterations in E- and P-cadherin-encoding genes (CDH1 and CDH3, respectively), or alterations in their proteins expression, often result in tissue disorder, cellular de-differentiation, increased invasiveness of tumour cells and ultimately in metastasis. In this review, we will discuss the major properties of E- and P-cadherin molecules, its regulation in normal tissue, and their alterations and role in cancer, with a specific focus on gastric and breast cancer models.
Collapse
|
|
30
|
Ferreira AC, Suriano G, Mendes N, Gomes B, Wen X, Carneiro F, Seruca R, Machado JC. E-cadherin impairment increases cell survival through Notch-dependent upregulation of Bcl-2. Hum Mol Genet 2011; 21:334-43. [DOI: 10.1093/hmg/ddr469] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
|
|
31
|
Mimata A, Fukamachi H, Eishi Y, Yuasa Y. Loss of E-cadherin in mouse gastric epithelial cells induces signet ring-like cells, a possible precursor lesion of diffuse gastric cancer. Cancer Sci 2011; 102:942-50. [PMID: 21276134 DOI: 10.1111/j.1349-7006.2011.01890.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Alterations in the E-cadherin gene are associated with sporadic and hereditary diffuse-type gastric cancer. To determine how the loss of function of E-cadherin affects gastric epithelial cell phenotypes, we generated transgenic mice using the Cre-loxP system in which the E-cadherin gene is specifically knocked out in the parietal cell lineage. In the transgenic mice, expression of E-cadherin was lost or reduced in proton pump-expressing parietal cells, which became round in shape and were pushed out of the glands to accumulate in the stromal area. Additionally, gastric mucosa exhibited hyperplasia from 3 months in the mice, some cells of which later became positive for trefoil factor 2, a marker of spasmolytic polypeptide-expressing metaplasia. From 6 months, E-cadherin-negative/proton pump-negative cells appeared from the parietal cell lineage, which increased in number to form cell clusters. Moreover, signet ring-like cells, which are morphologically similar to signet ring carcinoma cells, were found in the cell clusters from 12 months. However, no invasive gastric adenocarcinomas were found in the E-cadherin-deficient mice, even at 24 months or later. These data indicate that the loss of E-cadherin induces possible pre-cancerous lesions in the gastric mucosa but may not be sufficient for its malignant conversion.
Collapse
Affiliation(s)
- Ayako Mimata
- Department of Molecular Oncology Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | | | | | | |
Collapse
|
|
32
|
Garcia-Rodríguez L, Abate-Daga D, Rojas A, González JR, Fillat C. E-cadherin contributes to the bystander effect of TK/GCV suicide therapy and enhances its antitumoral activity in pancreatic cancer models. Gene Ther 2011; 18:73-81. [PMID: 20720574 DOI: 10.1038/gt.2010.114] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2010] [Revised: 06/03/2010] [Accepted: 06/22/2010] [Indexed: 11/09/2022]
Abstract
The thymidine kinase/ganciclovir (TK/GCV) cancer gene therapy approach is based on inducing GCV metabolite cytotoxicity in tumor cells expressing the herpes simplex virus TK gene and exposed to GCV. A bystander effect, mediated by gap junctions, accounts for the transfer of toxic metabolites from TK-expressing cells to neighboring cells. It has been proposed that E-cadherin participates in the formation and function of such gap junctions. In this study we investigate the influence of E-cadherin on TK/GCV suicide therapy with a panel of cellular and in vivo models of pancreatic ductal adenocarcinoma. We observed a strong correlation of E-cadherin expression and the TK/GCV bystander effect, associated with the modulation of gap junction communication and connexin expression or localization. Importantly, the co-expression of TK and E-cadherin genes in the adenoviral vector AdTat8TKIE improved TK/GCV cytotoxicity and triggered a potent antitumoral effect, superior to standard AdTat8TK/GCV in MIAPaCa-2 xenografts. The increased expression of E-cadherin resulted in the reduction of the bcl-2 content. Interestingly, the knockdown of bcl-2 sensitized cells to TK/GCV. Thus, we propose that by restoring E-cadherin in pancreatic tumor cells we will improve TK/GCV therapy, both by enhancing the bystander effect and by facilitating the induction of apoptosis.
Collapse
Affiliation(s)
- L Garcia-Rodríguez
- Programa Gens i Malaltia, Centre de Regulació Genòmica, Parc de Recerca Biomèdica de Barcelona, UPF, Barcelona, Spain
| | | | | | | | | |
Collapse
|
|
33
|
Yi JY, Jung YJ, Choi SS, Chung E. TNF-alpha downregulates E-cadherin and sensitizes response to γ-irradiation in Caco-2 cells. Cancer Res Treat 2009; 41:164-70. [PMID: 19809566 DOI: 10.4143/crt.2009.41.3.164] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2009] [Accepted: 06/01/2009] [Indexed: 12/17/2022] Open
Abstract
PURPOSE The purpose of the present study was to assess the biological effects of TNF-alpha in Caco-2 well-differentiated colon adenocarcinoma cells and to determine radiation sensitivity in order to develop TNF-alpha into a cancer therapeutic agent. MATERIALS AND METHODS A cell viability test was conducted via a colorimetric and colony forming assay after 1 day and 3 days of incubation with TNF-alpha. Western blotting analysis and immunofluorescence staining were conducted to explore TNF-alpha-induced morphological and molecular changes in the adhesion molecules, E-cadherin and claudin-4. The effects of γ-irradiation at a dose of 2 Gy on cell survival were evaluated by a clonogenic assay. The molecular changes in apoptosis-regulatory proteins were assessed by Western blotting. RESULTS Caco-2 cells were highly resistant to TNF alpha-induced cell death and 2 Gy of γ-irradiation. However, we observed the downregulation of the adherens junctional protein, E-cadherin and translocation of tight junctional protein, claudin-4 from the membrane to the cytosol induced by TNF-alpha treatment which would indicate cell-cell junction disruptions. These alterations of junctional proteins influenced the regulation of cell death in response to 2 Gy of γ-irradiation. The combined treatment of TNF-alpha with 2 Gy of γ-irradiation reduced the survival of Caco-2 cells by down-regulating bcl-xl and activating JNK pathways. CONCLUSION These results suggest that TNF-alpha might be potentially applied as a therapeutic agent in order to enhance sensitivity to 2 Gy of γ-irradiation administered in radiotherapy for the treatment of human colon cancer.
Collapse
Affiliation(s)
- Jae Youn Yi
- Lab of Modulation of Radiobiological Response, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | | | | | | |
Collapse
|
|
34
|
Wang L, Li Z, Wang C, Yang Y, Sun L, Yao W, Cai X, Wu G, Zhou F, Zha X. E-cadherin decreased human breast cancer cells sensitivity to staurosporine by up-regulating Bcl-2 expression. Arch Biochem Biophys 2009; 481:116-22. [DOI: 10.1016/j.abb.2008.10.021] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2008] [Revised: 10/08/2008] [Accepted: 10/09/2008] [Indexed: 01/30/2023]
|
|
35
|
Carneiro F, Oliveira C, Leite M, Seruca R. Molecular targets and biological modifiers in gastric cancer. Semin Diagn Pathol 2008; 25:274-87. [PMID: 19013893 DOI: 10.1053/j.semdp.2008.07.004] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The overall survival of gastric cancer patients remains poor despite efforts and advances in its prevention, diagnosis, and treatment. The development of new therapies is crucial for the effective control of this disease. An increasing number of genetic and epigenetic alterations have been associated with distinct histological types of gastric cancer. In this review, we will discuss the involvement of E-cadherin, EGFR, ERBB2, MMR genes, KRAS, and PIK3CA in the development and progression of gastric cancer and their role as biomarkers or as novel putative targets for therapy.
Collapse
Affiliation(s)
- Fátima Carneiro
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal.
| | | | | | | |
Collapse
|
|
36
|
Serebriiskii I, Castelló-Cros R, Lamb A, Golemis EA, Cukierman E. Fibroblast-derived 3D matrix differentially regulates the growth and drug-responsiveness of human cancer cells. Matrix Biol 2008; 27:573-585. [PMID: 18411046 PMCID: PMC2603546 DOI: 10.1016/j.matbio.2008.02.008] [Citation(s) in RCA: 134] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2007] [Revised: 02/22/2008] [Accepted: 02/25/2008] [Indexed: 12/26/2022]
Abstract
Recent studies have emphasized the importance of cellular microenvironment in modulating cell growth and signaling. In vitro, collagen matrices, Matrigel, and other synthetic support systems have been used to simulate in vivo microenvironments, and epithelial cells grown in these matrices manifest significant differences in proliferation, differentiation, response to drugs, and other parameters. However, these substrates do not closely resemble the mesenchymal microenvironment that is typically associated with advanced carcinomas in vivo, which is produced to a large extent by fibroblasts. In this study, we have evaluated the ability of a fibroblast-derived three-dimensional matrix to regulate the growth of a panel of 11 human tumor epithelial cell lines. Although proliferative and morphological responses to three-dimensional cues segregated independently, general responsiveness to the matrix correlated with the ability of matrix to influence drug responses. Fibroblast-derived three-dimensional matrix increased beta1-integrin-dependent survival of a subset of human cancer cell lines during taxol treatment, while it sensitized or minimally influenced survival of other cells. beta1-integrin-dependent changes in cell resistance to taxol did not correlate with the degree of modulation of FAK and Akt, implying that additional signaling factors are involved. Based on these results, we propose that these matrices potentially have value as in vitro drug screening platforms.
Collapse
Affiliation(s)
- Ilya Serebriiskii
- Division of Basic Science/Tumor Cell Biology, Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111
| | - Remedios Castelló-Cros
- Division of Basic Science/Tumor Cell Biology, Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111
| | - Acacia Lamb
- Division of Basic Science/Tumor Cell Biology, Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111
| | - Erica A. Golemis
- Division of Basic Science/Tumor Cell Biology, Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111
| | - Edna Cukierman
- Division of Basic Science/Tumor Cell Biology, Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111
| |
Collapse
|
|
37
|
Howard EW, Lee DT, Chiu YT, Chua CW, Wang X, Wong YC. Evidence of a novel docetaxel sensitizer, garlic-derived S-allylmercaptocysteine, as a treatment option for hormone refractory prostate cancer. Int J Cancer 2008; 122:1941-8. [PMID: 18183597 DOI: 10.1002/ijc.23355] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
The recent introduction of docetaxel in the treatment of hormone refractory prostate cancer (HRPC) has made a small but significant impact on patient survival. However, its effect is limited by intolerance and resistance. The aim of our study was to investigate if the garlic-derived compound, S-allylmercaptocysteine (SAMC), was able to act as a docetaxel sensitizing agent. First, the effect of SAMC on docetaxel sensitivity was examined on 3 HRPC cell lines by colony forming assay. We found that SAMC increased the efficacy of docetaxel on colony forming inhibition by 9-50% compared to single agent treatment. Second, using the HRPC CWR22R nude mice model, we found that the combination of SAMC and docetaxel was 53% more potent than docetaxel alone (p = 0.037). In addition, there was no additive toxicity in the mice treated with the combination therapy evidenced by histological and functional analysis of liver, kidney and bone marrow. These results suggest that SAMC is able to increase the anticancer effect of docetaxel without causing additional toxic effect in vivo. Third, flow cytometry and Western blotting analysis on HRPC cell lines demonstrated that SAMC promoted docetaxel-induced G2/M phase cell cycle arrest and apoptotic induction. In addition, immunohistochemistry on CWR22R xenograft revealed a suppression of Bcl-2 expression and upregulation of E-cadherin in the SAMC and docetaxel treated animals. These results suggest that SAMC may promote docetaxel-induced cell death through promoting G2/M cell cycle arrest and apoptosis. Our study implies a potential role for SAMC in improving docetaxel based chemotherapy for the treatment of HRPC.
Collapse
Affiliation(s)
- Edward W Howard
- Cancer Biology Group, Department of Anatomy, Faculty of Medicine, University of Hong Kong, Hong Kong
| | | | | | | | | | | |
Collapse
|
|
38
|
Deletion of exon 8 increases cisplatin-induced E-cadherin cleavage. Exp Cell Res 2008; 314:153-63. [PMID: 17959171 DOI: 10.1016/j.yexcr.2007.09.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2007] [Revised: 08/27/2007] [Accepted: 09/06/2007] [Indexed: 11/21/2022]
Abstract
E-Cadherin-mediated cell-cell adhesion plays a key role in epithelial cell survival and loss of E-cadherin or beta-catenin expression is associated with invasive tumor growth. Somatic E-cadherin mutations have been identified in sporadic diffuse-type gastric carcinoma. Here, we analysed the fate of E-cadherin with an in frame deletion of exon 8 compared to wild-type E-cadherin and the involved signalling events during cisplatin-induced apoptosis. We report that mutant E-cadherin was more readily cleaved during apoptosis than the wild-type form. Also beta-catenin, an important binding partner of E-cadherin, was processed. E-cadherin cleavage resulted in disconnection of the actin cytoskeleton and accumulation of E-cadherin and beta-catenin in the cytoplasm. Inhibitor studies demonstrated that E-cadherin cleavage was caused by a caspase-3-mediated mechanism. We identified the Akt/PKB and the ERK1/2 signalling pathways as important regulators since inhibition resulted in increased E-cadherin cleavage and apoptosis. In summary, we clearly demonstrate that somatic E-cadherin mutations affect apoptosis regulation in that way that they can facilitate the disruption of adherens junctions thereby possibly influencing the response to cisplatin-based chemotherapy. Elucidating the mechanisms that regulate the apoptotic program of tumor cells can contribute to a better understanding of tumor development and potentially be relevant for therapeutic drug design.
Collapse
|
|
39
|
Dursun P, Yuce K, Usubutun A, Ayhan A. Loss of epithelium cadherin expression is associated with reduced overall survival and disease-free survival in early-stage squamous cell cervical carcinoma. Int J Gynecol Cancer 2007; 17:843-50. [PMID: 17343572 DOI: 10.1111/j.1525-1438.2007.00876.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Epithelium cadherin (E-cad) is important for cell-to-cell adhesion of epithelial cells. Impairment of E-cad may have a role in the development and spreading of different malignancies and associated with poor differentiation, increased invasiveness, and poor prognostic factors in nongynecological carcinomas. However, prognostic significance of E-cad expression has not been investigated properly in cervical squamous cell carcinoma (SCC). The objective of this study was to investigate the association between reduced E-cad expression and clinicopathologic variables of cervical carcinoma. Specimens from 53 consecutive patients with stage IB-IIA SCC were evaluated immunohistochemically for E-cad expression, and the results were compared to grade, lymphvascular space invasion (LVSI), deep stromal involvement (DSI), parametrial involvement, lymph node metastasis, recurrences, and survival. Patients were divided into two groups arbitrarily: E-cad expression less than 10% (group 1) and E-cad expression more than 10% (group 2). There was no significant relationship between E-cad expression and DSI, LVSI, lymphatic metastasis. However, there was significant relationship between reduced E-cad expression and parametrial involvement (P= 0.024). Kaplan-Meier survival analysis revealed that reduced E-cad expression is significantly associated with reduced overall survival (OS) and disease-free survival (DFS). Furthermore, Cox regression analysis revealed that reduced E-cad expression is significantly associated with OS (P= 0.004, RR = 6.08, 95% CI: 1.75-21.1) and recurrences (P= 0.027, RR = 1.75, 95% CI: 1.06-2.88). We conclude that loss of E-cad expression is significantly associated with reduced OS and DFS in patients with SCC. Therefore, it might be used as an indicator of aggressive clinical behavior and tailoring aggressive adjuvant therapy in early-stage SCC. Further studies with larger number of patients are needed to evaluate the clinical significance of reduced E-cad expression in SCC.
Collapse
Affiliation(s)
- P Dursun
- Department of Obstetrics and Gynecology, Hacettepe University, Ankara, Turkey.
| | | | | | | |
Collapse
|
|
40
|
Regalo G, Canedo P, Suriano G, Resende C, Campos ML, Oliveira MJ, Figueiredo C, Rodrigues-Pereira P, Blin N, Seruca R, Carneiro F, Machado JC. C/EBPbeta is over-expressed in gastric carcinogenesis and is associated with COX-2 expression. J Pathol 2007; 210:398-404. [PMID: 16981245 DOI: 10.1002/path.2063] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The CCAAT/enhancer-binding protein beta (C/EBPbeta) transcription factor has been associated with several cancer models. In this study, the expression of C/EBPbeta was analysed in a series of 90 gastric carcinomas (GCs). We also assessed the effect of C/EBPbeta on COX-2 expression. In normal gastric mucosa, C/EBPbeta expression was restricted to cells in the proliferative zone. In intestinal metaplasia, dysplasia, and GC of the intestinal and atypical subtypes, C/EBPbeta was over-expressed (p < 0.0001, for the association with histological type). C/EBPbeta and Ki67, a marker of cell proliferation, were also co-expressed in primary GC. We also observed an overlap between C/EBPbeta and COX-2 expression in GC. Using GC cell lines we show that C/EBPbeta can regulate the expression of endogenous COX-2 and transactivate the promoter of the COX-2 gene, depending on its methylation status. These results suggest that C/EBPbeta may be a marker of neoplastic transformation and also play an active role in gastric tumourigenesis by regulating COX-2 expression.
Collapse
Affiliation(s)
- G Regalo
- IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
41
|
Kippenberger S, Loitsch S, Thaçi D, Müller J, Guschel M, Kaufmann R, Bernd A. Restoration of E-cadherin sensitizes human melanoma cells for apoptosis. Melanoma Res 2006; 16:393-403. [PMID: 17013088 DOI: 10.1097/01.cmr.0000222595.42685.24] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Cell-cell adhesion is considered to be important in the development and maintenance of organ tissue. The spatial association between melanocytes and keratinocytes within human epidermis is achieved by homophilic interaction of E-cadherin molecules located on adjacent cells. In contrast, downregulation of E-cadherin expression in melanoma cells is considered as a key event in metastasis. Besides the adhesive properties, E-cadherin serves as a signal receptor linking to the cadherin-catenin signaling complex. As cadherins act as negative regulators of beta-catenin, a contribution to tumor formation seems likely. In the present study, it was tested whether ectopic expression of E-cadherin triggers apoptosis in human melanoma cell lines (G-361, JPC-298, SK-Mel-13). It was found that restoration of E-cadherin caused sensitization against drug-induced apoptosis. Particularly, the release of mitochondrial cytochrome c was increased in response to staurosporine. Moreover, activation of caspase-3 and caspase-8 was elevated. Similarly, DNA fragmentation, serving as a marker for advanced apoptosis, was amplified in cells transduced with E-cadherin. Interestingly, transduction with an E-cadherin construct lacking the extracellular domain showed no modified apoptosis. In conclusion, our findings suggest therapeutic strategies that enable expression of E-cadherin in order to sensitize human melanoma cells towards apoptosis.
Collapse
Affiliation(s)
- Stefan Kippenberger
- Department of Dermatology, Division of Pneumology, University of Frankfurt Medical School, Frankfurt/Main, Germany.
| | | | | | | | | | | | | |
Collapse
|
|
42
|
Suriano G, Seixas S, Rocha J, Seruca R. A model to infer the pathogenic significance of CDH1 germline missense variants. J Mol Med (Berl) 2006; 84:1023-31. [PMID: 16924464 DOI: 10.1007/s00109-006-0091-z] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2006] [Accepted: 06/23/2006] [Indexed: 12/23/2022]
Abstract
Germline mutations of the E-cadherin gene (CDH1) are involved in the tumorigenesis of hereditary diffuse gastric cancer (HDGC). Recent studies have highlighted the lifesaving potential of total prophylactic gastrectomy for CDH1 germline mutation carriers. In this regard, CDH1 germline mutations of the missense type represent a clinical burden in genetic counseling, as their pathogenic relevance is not straightforward. In this work, we have outlined a possible multivariate approach to infer the significance of such variants. We reviewed all HDGC-associated E-cadherin germline missense mutations reported to date. The information collected included: co-segregation of the mutation within pedigrees, frequency in healthy population control, recurrence in independent families, and functional in vitro and in silico data. We used the neighbor-joining method to group mutations according to the collected information and assessed the robustness of mutation clusters with a bootstrap test. CDH1 germline missense variants were classified according to the parameters defined in the multivariate analysis. This analysis allowed the distribution of the variants into two distinct groups: neutral variants vs mutations. The model described in this study provides an important tool that can ultimately improve the genetic counseling offered to the carriers of the germline CDH1 missense variants.
Collapse
Affiliation(s)
- Gianpaolo Suriano
- Institute of Molecular Pathology and Immunology, University of Porto (IPATIMUP), Rua Dr Roberto Frias S/N 4200-465, Porto, Portugal.
| | | | | | | |
Collapse
|
|
43
|
Katso RM, Pardo OE, Palamidessi A, Franz CM, Marinov M, De Laurentiis A, Downward J, Scita G, Ridley AJ, Waterfield MD, Arcaro A. Phosphoinositide 3-Kinase C2beta regulates cytoskeletal organization and cell migration via Rac-dependent mechanisms. Mol Biol Cell 2006; 17:3729-44. [PMID: 16775008 PMCID: PMC1593155 DOI: 10.1091/mbc.e05-11-1083] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
Receptor-linked class I phosphoinositide 3-kinases (PI3Ks) induce assembly of signal transduction complexes through protein-protein and protein-lipid interactions that mediate cell proliferation, survival, and migration. Although class II PI3Ks have the potential to make the same phosphoinositides as class I PI3Ks, their precise cellular role is currently unclear. In this report, we demonstrate that class II phosphoinositide 3-kinase C2beta (PI3KC2beta) associates with the Eps8/Abi1/Sos1 complex and is recruited to the EGF receptor as part of a multiprotein signaling complex also involving Shc and Grb2. Increased expression of PI3KC2beta stimulated Rac activity in A-431 epidermoid carcinoma cells, resulting in enhanced membrane ruffling and migration speed of the cells. Conversely, expression of dominant negative PI3KC2beta reduced Rac activity, membrane ruffling, and cell migration. Moreover, PI3KC2beta-overexpressing cells were protected from anoikis and displayed enhanced proliferation, independently of Rac function. Taken together, these findings suggest that PI3KC2beta regulates the migration and survival of human tumor cells by distinct molecular mechanisms.
Collapse
Affiliation(s)
- Roy M. Katso
- *Ludwig Institute for Cancer Research, Royal Free and University College Hospital Medical School, London W1W 7BS, United Kingdom
| | | | - Andrea Palamidessi
- European Institute of Oncology, The FIRC Institute for Molecular Oncology, 20139 Milano, Italy
| | - Clemens M. Franz
- *Ludwig Institute for Cancer Research, Royal Free and University College Hospital Medical School, London W1W 7BS, United Kingdom
| | - Marin Marinov
- Division of Clinical Chemistry and Biochemistry, University Children’s Hospital Zurich, CH-8032 Zurich, Switzerland; and
| | - Angela De Laurentiis
- Division of Clinical Chemistry and Biochemistry, University Children’s Hospital Zurich, CH-8032 Zurich, Switzerland; and
| | - Julian Downward
- CRUK London Research Institute, London WC2A 3PX, United Kingdom
| | - Giorgio Scita
- European Institute of Oncology, The FIRC Institute for Molecular Oncology, 20139 Milano, Italy
| | - Anne J. Ridley
- *Ludwig Institute for Cancer Research, Royal Free and University College Hospital Medical School, London W1W 7BS, United Kingdom
- Department of Biochemistry and Molecular Biology, University College London, London WC1E 6BT, United Kingdom
| | - Michael D. Waterfield
- *Ludwig Institute for Cancer Research, Royal Free and University College Hospital Medical School, London W1W 7BS, United Kingdom
- Department of Biochemistry and Molecular Biology, University College London, London WC1E 6BT, United Kingdom
| | - Alexandre Arcaro
- Division of Clinical Chemistry and Biochemistry, University Children’s Hospital Zurich, CH-8032 Zurich, Switzerland; and
| |
Collapse
|
|
44
|
Suriano G, Ferreira P, Mateus AR, Correia J, Henriques L, Seruca R. Genetics of hereditary diffuse gastric cancer: progress and future challenges. Future Oncol 2006; 2:363-70. [PMID: 16787116 DOI: 10.2217/14796694.2.3.363] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Hereditary diffuse gastric cancer (HDGC) is a rare cancer susceptibility syndrome. One third of HDGC syndrome families carry germline mutations of the E-cadherin gene. Owing to the limitation of the current endoscopic screening techniques and since no chemoprevention is yet available, total prophylactic gastrectomy is the only option offered to carriers of inactivating mutations in genetic counseling. In this regard, 30% of the E-cadherin germline mutations reported to date are of the missense type, and since their pathogenic significance is not straightforward, the management of carriers of such mutations is suboptimal. In the absence of definitive clinical evidence, functional in vitro studies together with in silico analysis have been used to infer the pathogenic significance of germline missense mutations. Since most of the HDGC families reported to date are negative for E-cadherin germline mutations, the identification of alternative genes underlying the tumorigenesis of diffuse gastric has become an important target for research.
Collapse
Affiliation(s)
- Gianpaolo Suriano
- Institute of Molecular Pathology & Immunology of the University of Porto, Rua Dr Roberto Frias S/N 4200-465, Porto, Portugal.
| | | | | | | | | | | |
Collapse
|
|
45
|
Pereira PS, Teixeira A, Pinho S, Ferreira P, Fernandes J, Oliveira C, Seruca R, Suriano G, Casares F. E-cadherin missense mutations, associated with hereditary diffuse gastric cancer (HDGC) syndrome, display distinct invasive behaviors and genetic interactions with the Wnt and Notch pathways in Drosophila epithelia. Hum Mol Genet 2006; 15:1704-12. [PMID: 16600987 DOI: 10.1093/hmg/ddl093] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Germline mutations in the human E-cadherin (hEcad) gene, CDH1, are initiating events in cases of human hereditary diffuse gastric cancer (HDGC) indicating that hEcad is a tumor suppressor. Among the hEcad mutations identified so far, some are missense, but the pathological relevance of these missense mutants is still unclear. In vitro assays show that missense mutations result in full-length hEcad molecules that retain some distinct biological activity, but in vivo functional studies in animal models are still lacking. Here we verify the potential of a Drosophila model to in vivo characterize the functional consequences of HDGC-associated germline missense mutations and to identify signaling pathways affected by these mutations. To this end, we have generated transgenic fly strains expressing the wild-type hEcad gene or its missense mutations. Similar to the fly Ecad, expression of wild-type hEcad and missense forms in fly epithelia resulted in their localization to the subapical region. In addition, we verify a genotype-phenotype correlation associated to the specific domain affected by the mutations, because cells expressing normal or missense mutant hEcad display different migratory and invasive behaviors in fly epithelia. We show that some of these effects might be mediated through hEcad interacting with the endogenous fly ss-catenin, Armadillo, thus interfering with the Wnt signaling pathway. Therefore, the use of this simple in vivo system will contribute to characterize the effects that missense hEcad have on cell behavior in a tissue environment, and might help to understand their significance in gastric cancer onset.
Collapse
Affiliation(s)
- Paulo S Pereira
- Instituto de Biologia Molecular e Celular, IBMC, Universidade do Porto, Porto 4150-180, Portugal
| | | | | | | | | | | | | | | | | |
Collapse
|
|
46
|
Abstract
The clinical management of familial gastric cancer is the same as that for sporadic gastric cancer at the current time. As the causative mutations for these cases are identified this should lead to the development of specific treatments which target the molecular abnormality. The only germline mutations identified so far occur within the E-cadherin gene (CDHI) and they account for approximately 30% of familial gastric cancer cases. When index patients fulfilling the clinical criteria for hereditary diffuse gastric cancer syndrome have a CDHI mutation identified then genetic testing of asymptomatic relatives should be considered. The clinical sequelae of testing positive for such a mutation are profound and therefore it is essential that counselling is given prior to genetic testing. The management options are surveillance endoscopy and prophylactic gastrectomy. In this chapter the practicalities of genetic testing are discussed as well as the pros and cons of the two management options. It is essential that experience of these rare families is pooled so that surveillance and treatment can be optimised in the future.
Collapse
|