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Costache S, de Havilland R, Diaz McLynn S, Sajin M, Baltan A, Wedden S, D’Arrigo C. Implementing an On-Slide Molecular Classification of Gastric Cancer: A Tissue Microarray Study. Cancers (Basel) 2023; 16:55. [PMID: 38201483 PMCID: PMC10778243 DOI: 10.3390/cancers16010055] [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: 10/21/2023] [Revised: 11/25/2023] [Accepted: 12/19/2023] [Indexed: 01/12/2024] Open
Abstract
Background and Objectives: Gastric cancer (GC) is one of the most commonly diagnosed cancers and the fourth cause of cancer death worldwide. Personalised treatment improves GC outcomes. A molecular classification is needed to choose the appropriate therapy. A classification that uses on-slide biomarkers and formalin-fixed and paraffin-embedded (FFPE) tissue is preferable to comprehensive genomic analysis. In 2016, Setia and colleagues proposed an on-slide classification; however, this is not in widespread use. We propose a modification of this classification that has six subgroups: GC associated with Epstein-Barr virus (GC EBV+), GC with mismatch-repair deficiency (GC dMMR), GC with epithelial-mesenchymal transformation (GC EMT), GC with chromosomal instability (GC CIN), CG that is genomically stable (GC GS) and GC not otherwise specified (GC NOS). This classification also has a provision for biomarkers for current or emerging targeted therapies (Her2, PD-L1 and Claudin18.2). Here, we assess the implementation and feasibility of this inclusive working classification. Materials and Methods: We constructed a tissue microarray library from a cohort of 79 resection cases from FFPE tissue archives. We used a restricted panel of on-slide markers (EBER, MMR, E-cadherin, beta-catenin and p53), defined their interpretation algorithms and assigned each case to a specific molecular subtype. Results: GC EBV(+) cases were 6%, GC dMMR cases were 20%, GC EMT cases were 14%, GC CIN cases were 23%, GC GS cases were 29%, and GC NOS cases were 8%. Conclusions: This working classification uses markers that are widely available in histopathology and are easy to interpret. A diagnostic subgroup is obtained for 92% of the cases. The proportion of cases in each subgroup is in keeping with other published series. Widescale implementation appears feasible. A study using endoscopic biopsies is warranted.
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Affiliation(s)
- Simona Costache
- Pathology Department, University of Medicine and Pharmacy “Carol Davila”, 020021 Bucharest, Romania; (M.S.); (A.B.)
- Poundbury Cancer Institute, Dorchester DT1 3BJ, UK; (R.d.H.); (S.D.M.); (C.D.)
| | | | - Sofia Diaz McLynn
- Poundbury Cancer Institute, Dorchester DT1 3BJ, UK; (R.d.H.); (S.D.M.); (C.D.)
| | - Maria Sajin
- Pathology Department, University of Medicine and Pharmacy “Carol Davila”, 020021 Bucharest, Romania; (M.S.); (A.B.)
- Pathology Department, University Emergency Hospital, 050098 Bucharest, Romania
| | - Adelina Baltan
- Pathology Department, University of Medicine and Pharmacy “Carol Davila”, 020021 Bucharest, Romania; (M.S.); (A.B.)
- Poundbury Cancer Institute, Dorchester DT1 3BJ, UK; (R.d.H.); (S.D.M.); (C.D.)
| | - Sarah Wedden
- Cancer Diagnostic Quality Assurance Services (CADQAS), Dorchester DT1 3BJ, UK;
| | - Corrado D’Arrigo
- Poundbury Cancer Institute, Dorchester DT1 3BJ, UK; (R.d.H.); (S.D.M.); (C.D.)
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Lim HJ, Zhuang L, Fitzgerald RC. Current advances in understanding the molecular profile of hereditary diffuse gastric cancer and its clinical implications. J Exp Clin Cancer Res 2023; 42:57. [PMID: 36869400 PMCID: PMC9985294 DOI: 10.1186/s13046-023-02622-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 02/13/2023] [Indexed: 03/05/2023] Open
Abstract
Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome attributed to germline CDH1 mutations that carries a high risk for early onset DGC. HDGC raises a significant health issue due to its high penetrance and mortality unless diagnosed early. The definitive treatment is to undergo prophylactic total gastrectomy which is associated with significant morbidity., highlighting the urgent need for alternative treatment methods. However, there is limited literature examining potential therapeutic strategies building on emerging insights into the molecular basis of progressive lesions in the context of HDGC. The aim of this review is to summarise the current understanding of HDGC in the context of CDH1 pathogenic variants followed by a review of the proposed mechanisms for progression. In addition, we discuss the development of novel therapeutic approaches and highlight pertinent areas for further research. A literature search was therefore performed for relevant studies examining CDH1 germline variants, second-hit mechanisms of CDH1, pathogenesis of HDGC and potential therapeutic strategies in databases, including PubMed, ScienceDirect and Scopus. Germline mutations are mostly truncating CDH1 variants affecting extracellular domains of E-cadherin, generally due to frameshift, single nucleotide variants or splice site mutations. A second somatic hit of CDH1 most commonly occurs via promoter methylation as shown in 3 studies, but studies are limited with a small sample size. The multi-focal development of indolent lesions in HDGC provide a unique opportunity to understand genetic events that drive the transition to the invasive phenotype. To date, a few signalling pathways have been shown to facilitate the progression of HDGC, including Notch and Wnt. In in-vitro studies, the ability to inhibit Notch signalling was lost in cells transfected with mutant forms of E-cadherin, and increased Notch-1 activity correlated with apoptosis resistance. Furthermore, in patient samples, overexpression of Wnt-2 was associated with cytoplasmic and nuclear β-catenin accumulation and increased metastatic potential. As loss-of-function mutations are challenging to target therapeutically, these findings pave the way towards a synthetic lethal approach in CDH1-deficient cells with some promising results in-vitro. In future, if we could better understand the molecular vulnerabilities in HDGC, there may be opportunities to offer alternative treatment pathways to avoid gastrectomy.
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Affiliation(s)
- Hui Jun Lim
- Department of Oncology, Early Cancer Institute, University of Cambridge, Box 197, Cambridge Biomedical Campus, CB2 0XZ, Cambridge, UK.
- Department of Sarcoma, Peritoneal and Rare Tumors (SPRinT), Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
| | - Lizhe Zhuang
- Department of Oncology, Early Cancer Institute, University of Cambridge, Box 197, Cambridge Biomedical Campus, CB2 0XZ, Cambridge, UK
| | - Rebecca C Fitzgerald
- Department of Oncology, Early Cancer Institute, University of Cambridge, Box 197, Cambridge Biomedical Campus, CB2 0XZ, Cambridge, UK
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Tanase C, Gheorghisan-Galateanu AA, Popescu ID, Mihai S, Codrici E, Albulescu R, Hinescu ME. CD36 and CD97 in Pancreatic Cancer versus Other Malignancies. Int J Mol Sci 2020; 21:5656. [PMID: 32781778 PMCID: PMC7460590 DOI: 10.3390/ijms21165656] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 07/31/2020] [Accepted: 08/04/2020] [Indexed: 02/06/2023] Open
Abstract
Starting from the recent identification of CD36 and CD97 as a novel marker combination of fibroblast quiescence in lung during fibrosis, we aimed to survey the literature in search for facts about the separate (or concomitant) expression of clusters of differentiation CD36 and CD97 in either tumor- or pancreatic-cancer-associated cells. Here, we provide an account of the current knowledge on the diversity of the cellular functions of CD36 and CD97 and explore their potential (common) contributions to key cellular events in oncogenesis or metastasis development. Emphasis is placed on quiescence as an underexplored mechanism and/or potential target in therapy. Furthermore, we discuss intricate signaling mechanisms and networks involving CD36 and CD97 that may regulate different subpopulations of tumor-associated cells, such as cancer-associated fibroblasts, adipocyte-associated fibroblasts, tumor-associated macrophages, or neutrophils, during aggressive pancreatic cancer. The coexistence of quiescence and activated states in cancer-associated cell subtypes during pancreatic cancer should be better documented, in different histological forms. Remodeling of the local microenvironment may also change the balance between growth and dormant state. Taking advantage of the reported data in different other tissue types, we explore the possibility to induce quiescence (similar to that observed in normal cells), as a therapeutic option to delay the currently observed clinical outcome.
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Affiliation(s)
- Cristiana Tanase
- Victor Babeș National Institute of Pathology, 99-101 Splaiul Independentei, 050096 Bucharest, Romania; (I.D.P.); (S.M.); (E.C.); (R.A.); (M.E.H.)
- Faculty of Medicine, Titu Maiorescu University, 001863 Bucharest, Romania
| | - Ancuta-Augustina Gheorghisan-Galateanu
- Department of Cellular and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, 8 Eroilor Sanitari Str., 050474 Bucharest, Romania;
- ‘C.I. Parhon’ National Institute of Endocrinology, 001863 Bucharest, Romania
| | - Ionela Daniela Popescu
- Victor Babeș National Institute of Pathology, 99-101 Splaiul Independentei, 050096 Bucharest, Romania; (I.D.P.); (S.M.); (E.C.); (R.A.); (M.E.H.)
| | - Simona Mihai
- Victor Babeș National Institute of Pathology, 99-101 Splaiul Independentei, 050096 Bucharest, Romania; (I.D.P.); (S.M.); (E.C.); (R.A.); (M.E.H.)
| | - Elena Codrici
- Victor Babeș National Institute of Pathology, 99-101 Splaiul Independentei, 050096 Bucharest, Romania; (I.D.P.); (S.M.); (E.C.); (R.A.); (M.E.H.)
| | - Radu Albulescu
- Victor Babeș National Institute of Pathology, 99-101 Splaiul Independentei, 050096 Bucharest, Romania; (I.D.P.); (S.M.); (E.C.); (R.A.); (M.E.H.)
- National Institute for Chemical Pharmaceutical R&D, 001863 Bucharest, Romania
| | - Mihail Eugen Hinescu
- Victor Babeș National Institute of Pathology, 99-101 Splaiul Independentei, 050096 Bucharest, Romania; (I.D.P.); (S.M.); (E.C.); (R.A.); (M.E.H.)
- Department of Cellular and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, 8 Eroilor Sanitari Str., 050474 Bucharest, Romania;
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Microsatellite Alterations and Protein Expression of 5 Major Tumor Suppressor Genes in Gastric Adenocarcinomas. Transl Oncol 2017; 11:43-55. [PMID: 29172180 PMCID: PMC5702876 DOI: 10.1016/j.tranon.2017.10.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Revised: 10/23/2017] [Accepted: 10/23/2017] [Indexed: 01/01/2023] Open
Abstract
PURPOSE: In gastric adenocarcinoma (GC), the major tumor suppressor genes (TSGs) such as p16, PTEN, Rb, E-cadherin, and p53, may play important roles in various regulatory pathways and in tumor suppression. This study evaluated the loss of heterozygosity (LOH) of microsatellite and protein expression of 5 TSGs and the results were examined for their correlation with clinicopathological factors. METHODS: LOH analysis was carried out using polymerase chain reactions with 15 polymorphic microsatellite markers of 5 chromosomes containing TSGs in 100 surgically resected tumors. Protein expression was evaluated by immunohistochemistry (IHC). RESULTS: LOH was detected in 83% of GCs. LOH of 9p21, 10q23, 13q14, 16q22, and 17p13 were detected in 26%, 31%, 24%, 22%, and 35% of cases, respectively. Protein expression of p16, PTEN, Rb, E-cadherin, and p53 were found to be 31%, 39%, 28%, 32%, and 46% of cases. Advanced GCs showed significantly higher rates of 17p13 LOH and p53 expression. 9p21 LOH and E-cadherin IHC were correlated with higher tumor grade. Lymph node metastasis was correlated with the LOH of 9p21, 16q22, and 17p13 and IHC of the Rb and p53. A higher stage was correlated with 10q23 and 17p13 in LOH and p53 for IHC. CONCLUSION: These results suggest that LOH and protein expression of various TSGs are important in carcinogenesis and tumor invasion. Additionally, LOH and IHC may be useful clinical indicators for determining the prognosis of patients with GCs. In particular, the 17p13 LOH and p53 for IHC can be applied as simple evaluations in the clinic.
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Krstić M, University of Niš, Faculty of Medicine, Department of Pathology, Serbia, Stojnev S, Milenković N, Clinical Center Niš, Center for Pathology, Serbia. T HE CORRELATION OF K LF4 EXPRESSION AND CELL ADHESION MOLECULES IN GASTRIC CANCER. ACTA MEDICA MEDIANAE 2017. [DOI: 10.5633/amm.2017.0322] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
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Farahmand L, Darvishi B, Majidzadeh‐A K, Madjid Ansari A. Naturally occurring compounds acting as potent anti-metastatic agents and their suppressing effects on Hedgehog and WNT/β-catenin signalling pathways. Cell Prolif 2017; 50:e12299. [PMID: 27669681 PMCID: PMC6529111 DOI: 10.1111/cpr.12299] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Accepted: 08/28/2016] [Indexed: 12/19/2022] Open
Abstract
Despite numerous remarkable achievements in the field of anti-cancer therapy, tumour relapse and metastasis still remain major obstacles in improvement of overall cancer survival, which may be at least partially owing to epithelial-mesenchymal transition (EMT). Multiple signalling pathways have been identified in EMT; however, it appears that the role of the Hedgehog and WNT/β-catenin pathways are more prominent than others. These are well-known preserved intracellular regulatory pathways of different cellular functions including proliferation, survival, adhesion and differentiation. Over the last few decades, several naturally occurring compounds have been identified to significantly obstruct several intermediates in Hedgehog and WNT/β-catenin signalling, eventually resulting in suppression of signal transduction. This article highlights the current state of knowledge associated with Hedgehog and WNT/β-catenin, their involvement in metastasis through EMT processes and introduction of the most potent naturally occurring agents with capability of suppressing them, eventually overcoming tumour relapse, invasion and metastasis.
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Affiliation(s)
- L. Farahmand
- Cancer Genetics DepartmentBreast Cancer Research CenterACECRTehranIran
| | - B. Darvishi
- Recombinant Proteins DepartmentBreast Cancer Research CenterACECRTehranIran
| | - K. Majidzadeh‐A
- Cancer Genetics DepartmentBreast Cancer Research CenterACECRTehranIran
- Tasnim Biotechnology Research Center (TBRC)school of medicineAJA University of Medical SciencesTehranIran
| | - A. Madjid Ansari
- Cancer Alternative and Complementary Medicine DepartmentBreast Cancer Research CenterACECRTehranIran
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Kaya S, Gumus M, Gurbuz Y, Cabuk D, Acikgoz O, Temiz S, Uygun K. The prognostic value of β-catenin and LEF-1 expression in patients with operable gastric carcinoma. Am J Transl Res 2016; 8:1228-1236. [PMID: 27158409 PMCID: PMC4846966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2015] [Accepted: 02/08/2016] [Indexed: 06/05/2023]
Abstract
AIM The aim of this study is to evaluate the prognostic value of β-catenin and LEF-1 expression in patients with operable gastric cancer that receive adjuvant treatment and the relationship between demographic and histopathological variables. MATERIAL AND METHOD In this study, 82 gastric cancer patients treated with adjuvant treatment after surgery and followed in the Medical Oncology Department of Kocaeli University were included. β-catenin and LEF-1 expression were examined by immunuhistochemical analysis in paraffin embedded tumor tissues of the patients. RESULTS Median age was 56 (26-81) and follow up was 19 months (4-61). Performance status (ECOG) were 0-1 in all patients. Male/female ratio was 53/29 (64.6/35.4%). The median disease free survival (DFS) time was 17 months (SE: 3 95% CI: 11-23) and 3 years DFS rate was 39.7%. The median overall survival (OS) time was 28 months (SE: 4 95% CI: 20-36) and 3 years OS rate was 41.2%. There was no statistical correlation between β-catenin and LEF-1 expression and age, gender, performance status, tumor localization, T and N stage, lymphovascular, perinoral invasion, grade and operation type (>0.005). According to univariate analysis, we did not find significant effect of age, gender, T stage, lymphovascular, perinoral invasion, grade and operation type on overall survival (p>0.005). Good performance status (ECOG 0), tumor infiltration without diffuse type like linitis plastica, and lower N stage had positive effect on survival respectively (p=0.04, 0.033 and 0.005). CONCLUSION In this study group, we found that only N stage was an independent prognostic factor (<0.005). Demographic features of the patients, histopathological characteristics other than N stage, β-catenin and LEF-1 prognostic effects have not been shown.
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Affiliation(s)
- Serap Kaya
- Department of Medical Oncology, Medical Faculty, Kocaeli UniversityKocaeli, Turkey
| | - Mahmut Gumus
- Department of Medical Oncology, Medical Faculty, Bezmialem UniversityIstanbul, Turkey
| | - Yesim Gurbuz
- Department of Pathology, Medical Faculty, Kocaeli UniversityKocaeli, Turkey
| | - Devrim Cabuk
- Department of Medical Oncology, Medical Faculty, Kocaeli UniversityKocaeli, Turkey
| | - Ozgur Acikgoz
- Department of Medical Oncology, Medical Faculty, Kocaeli UniversityKocaeli, Turkey
| | - Suleyman Temiz
- Department of Medical Oncology, Medical Faculty, Kocaeli UniversityKocaeli, Turkey
| | - Kazim Uygun
- Department of Medical Oncology, Medical Faculty, Kocaeli UniversityKocaeli, Turkey
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Wang N, He YL, Pang LJ, Zou H, Liu CX, Zhao J, Hu JM, Zhang WJ, Qi Y, Li F. Down-regulated E-cadherin expression is associated with poor five-year overall survival in bone and soft tissue sarcoma: results of a meta-analysis. PLoS One 2015; 10:e0121448. [PMID: 25822802 PMCID: PMC4378985 DOI: 10.1371/journal.pone.0121448] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2014] [Accepted: 09/02/2014] [Indexed: 01/04/2023] Open
Abstract
Purpose To conduct a meta-analysis to evaluate the prognostic role of E-cadherin expression in bone and soft tissue sarcomas. Methods The PubMed, EMBASE, and Web of Science databases were searched using terms related to E-cadherin, sarcoma, and prognosis for all articles published in English before March 2014. Pooled effect was calculated from the available data to evaluate the association between negative E-cadherin expression and 5-year overall survival and tumor clinicopathological features in sarcoma patients. Pooled odds ratios (OR) and risk ratios (RR) with 95% confidence intervals (CI) were calculated using a fixed-effects model. Result Eight studies met the selection criteria and reported on 812 subjects. A total of 496 subjects showed positive E-cadherin expression (59.9%). Negative E-cadherin expression in bone and soft tissue sarcomas was correlated with lower 5-year overall survival (OR = 3.831; 95% CI: 2.246–6.534), and was associated with higher clinical stage (RR = 1.446; 95% CI: 1.030–2.028) and with male sex (RR = 0.678; 95% CI: 0.493–0.933). Conclusion In the E-cadherin negative group, 5-year overall survival was significantly worse than in the E-cadherin positive group. However, further studies are required to confirm these results.
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Affiliation(s)
- Ning Wang
- Department of Pathology, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Shihezi University and Chinese Ministry of Education, Shihezi, Xinjiang, China
| | - Yong-Lai He
- Department of ICU intensive care, the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Li-Juan Pang
- Department of Pathology, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Shihezi University and Chinese Ministry of Education, Shihezi, Xinjiang, China
| | - Hong Zou
- Department of Pathology, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Shihezi University and Chinese Ministry of Education, Shihezi, Xinjiang, China
| | - Chun-Xia Liu
- Department of Pathology, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Shihezi University and Chinese Ministry of Education, Shihezi, Xinjiang, China
| | - Jin Zhao
- Department of Pathology, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Shihezi University and Chinese Ministry of Education, Shihezi, Xinjiang, China
| | - Jian-Ming Hu
- Department of Pathology, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Shihezi University and Chinese Ministry of Education, Shihezi, Xinjiang, China
| | - Wen-Jie Zhang
- Department of Pathology, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Shihezi University and Chinese Ministry of Education, Shihezi, Xinjiang, China
| | - Yan Qi
- Department of Pathology, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Shihezi University and Chinese Ministry of Education, Shihezi, Xinjiang, China
- * E-mail: (FL); (YQ)
| | - Feng Li
- Department of Pathology, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Shihezi University and Chinese Ministry of Education, Shihezi, Xinjiang, China
- * E-mail: (FL); (YQ)
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May R, Qu D, Weygant N, Chandrakesan P, Ali N, Lightfoot SA, Li L, Sureban SM, Houchen CW. Brief report: Dclk1 deletion in tuft cells results in impaired epithelial repair after radiation injury. Stem Cells 2014; 32:822-7. [PMID: 24123696 DOI: 10.1002/stem.1566] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2013] [Accepted: 09/08/2013] [Indexed: 02/06/2023]
Abstract
The role of Dclk1(+) tuft cells in the replacement of intestinal epithelia and reestablishing the epithelial barrier after severe genotoxic insult is completely unknown. Successful restoration requires precise coordination between the cells within each crypt subunit. While the mechanisms that control this response remain largely uncertain, the radiation model remains an exceptional surrogate for stem cell-associated crypt loss. Following the creation of Dclk1-intestinal-epithelial-deficient Villin-Cre;Dclk1(flox/flox) mice, widespread gene expression changes were detected in isolated intestinal epithelia during homeostasis. While the number of surviving crypts was unaffected, Villin-Cre;Dclk1(flox/flox) mice failed to maintain tight junctions and died at approximately 5 days, where Dclk1(flox/flox) mice lived until day 10 following radiation injury. These findings suggest that Dclk1 plays a functional role critical in the epithelial restorative response.
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Affiliation(s)
- Randal May
- Department of Medicine, The University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA; Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma, USA
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Kaygusuz EI. Immunohistochemical expression of CD44 standard and E-cadherin in atypical leiomyoma and leiomyosarcoma of the uterus. J OBSTET GYNAECOL 2014; 35:279-82. [DOI: 10.3109/01443615.2014.948821] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Bae SM, Lim W, Jeong W, Lee JY, Kim J, Han JY, Bazer FW, Song G. Hormonal regulation of beta-catenin during development of the avian oviduct and its expression in epithelial cell-derived ovarian carcinogenesis. Mol Cell Endocrinol 2014; 382:46-54. [PMID: 24055276 DOI: 10.1016/j.mce.2013.09.010] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Revised: 09/04/2013] [Accepted: 09/06/2013] [Indexed: 01/19/2023]
Abstract
Beta-catenin (CTNNB1) is a dual function molecule that acts as a key component of the cadherin complex and WNT signaling pathway. It has a crucial role in embryogenesis, tumorigenesis, angiogenesis and progression of metastasis. Recently, it has been suggested that the CTNNB1 complex is a major regulator of development of the mouse oviduct and uterus. However, little is known about the CTNNB1 gene in chickens. Therefore, in this study, we focused on the CTNNB1 gene in the chicken reproductive tract and hormonal control of its expression in the chicken oviduct. CTNNB1 was localized specifically to the luminal and glandular epithelium of the four segments of chicken oviduct and DES (diethylstilbestrol, a synthetic non-steroidal estrogen) increased its expression primarily in LE of the magnum. In addition, CTNNB1 mRNA and protein were expressed abundantly in glandular epithelium of endometrioid-type ovarian carcinoma, but not in normal ovaries. Moreover, CTNNB1 expression was post-transcriptionally regulated via its 3'-UTR by binding with target miRNAs including miR-217, miR-1467, miR-1623 and miR-1697. Collectively, these results indicate that CTNNB1 is a novel gene regulated by estrogen in epithelial cells of the chicken oviduct and that it is also abundantly expressed in epithelial cells of endometrioid-type ovarian carcinoma suggesting that it could be used as a marker for diagnosis of ovarian cancer in laying hens and women.
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Affiliation(s)
- Seung-Min Bae
- WCU Biomodulation Major, Department of Agricultural Biotechnology, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea
| | - Whasun Lim
- WCU Biomodulation Major, Department of Agricultural Biotechnology, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea
| | - Wooyoung Jeong
- WCU Biomodulation Major, Department of Agricultural Biotechnology, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea
| | - Jin-Young Lee
- WCU Biomodulation Major, Department of Agricultural Biotechnology, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea
| | - Jinyoung Kim
- Department of Animal Resources Science, Dankook University, Cheonan 330-714, Republic of Korea
| | - Jae Yong Han
- WCU Biomodulation Major, Department of Agricultural Biotechnology, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea
| | - Fuller W Bazer
- WCU Biomodulation Major, Department of Agricultural Biotechnology, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea; Center for Animal Biotechnology and Genomics and Department of Animal Science, Texas A&M University, College Station, TX 77843-2471, USA
| | - Gwonhwa Song
- WCU Biomodulation Major, Department of Agricultural Biotechnology, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea; Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Republic of Korea.
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LI XIAOFENG, ZHANG XIAOTING, LIU XIZHI, TAN ZHIWEN, YANG CELI, DING XIAOFENG, HU XIANG, ZHOU JIANLIN, XIANG SHUANGLIN, ZHOU CHANG, ZHANG JIAN. Caudatin induces cell apoptosis in gastric cancer cells through modulation of Wnt/β-catenin signaling. Oncol Rep 2013; 30:677-84. [DOI: 10.3892/or.2013.2495] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2013] [Accepted: 04/16/2013] [Indexed: 11/05/2022] Open
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13
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Tian W, Wang G, Yang J, Pan Y, Ma Y. Prognostic role of E-cadherin and Vimentin expression in various subtypes of soft tissue leiomyosarcomas. Med Oncol 2013; 30:401. [PMID: 23292832 DOI: 10.1007/s12032-012-0401-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2012] [Accepted: 10/05/2012] [Indexed: 10/27/2022]
Abstract
The gain of E-cadherin and loss of Vimentin known as "Cadherin switching" resulting in epithelial differentiation play an important role in tumor cell invasion and metastasis. In soft tissue leiomyosarcoma (LMS), aberrant expression of E-cadherin and down-regulation of Vimentin-related Mesenchymal to Epithelial Reverting Transition was defined, but the role of these proteins in various subtypes of LMS have not been well demonstrated yet. The aim of this study was to evaluate the prognostic role of E-cadherin and Vimentin expression in 45 soft tissue leiomyosarcoma samples by Immunohistochemistry analysis. E-cadherin was positive in a small proportion of LMS, accounting for 15.6 % (7/45). All LMS samples expressed Vimentin, concluding 20 patients as strong positive group (44.4 %), 25 patients as week positive group (55.6 %). Although the aberrant expression of E-cadherin had no differences among various subtypes of LMS, it was significantly associated with early clinical stages. The patients with strong positive expression of Vimentin suffered significant high risk of recurrence and metastasis and also had significant worse overall survival. These data suggest that the epithelial differentiation of LMS evaluated by E-cadherin expression does not belong to certain subtypes in LMS. The patients with the gain of E-cadherin and loss of Vimentin expression represent favorable trend of survival. They might serve as good biomarkers of the LMS clinical outcome after further investigations.
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Affiliation(s)
- Wei Tian
- Department of Bone and Soft Tissue Tumor, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
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14
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Mukherjee N, Bhattacharya N, Alam N, Roy A, Roychoudhury S, Panda CK. Subtype-specific alterations of the Wnt signaling pathway in breast cancer: clinical and prognostic significance. Cancer Sci 2012; 103:210-20. [PMID: 22026417 DOI: 10.1111/j.1349-7006.2011.02131.x] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
The aim of the study is to understand the importance of the Wnt/β-catenin pathway in the development of breast cancer (BC) and its association with different clinicopathological parameters. Alterations (deletion/methylation/expression) of some Wnt/β-catenin pathway antagonists like APC, SFRP1/2, CDH1 and activator β-catenin (CTNNB1) were analyzed in primary BC in Indian patients. High frequencies (65-70%) of overall alterations (deletion/methylation) of the antagonists were seen in the BC samples. Also, 99% (156/158) of the samples showed alterations in any one of the genes, indicating the importance of this pathway in the development of this tumor. Co-alterations of these genes were observed in 30% of samples, with significantly high alterations in late-onset (37%) and estrogen receptor (ER)-/progesterone receptor (PR)- (37%) BC compared with early onset (21%) and ER/PR+ (18%) BC samples, respectively. Significantly high (P-value = 0.001-0.02) alterations of APC and CDH1 genes were seen in ER-/PR- BC compared with ER/PR+ BC. Immunohistochemical analysis showed reduced expression of the Wnt antagonists in BC concordant with their molecular alterations. Nuclear localization of β-catenin showed significant association with alterations in the antagonists and was also significantly high in the ER-/PR- BC samples. Alterations of SFRP2 coupled with a late clinical stage and low/nulliparity predicted the worst prognosis in BC patients. Therefore, the present study suggests that cumulative alterations in more than one Wnt antagonist along with increased nuclear accumulation of β-catenin play an important role in the development of BC and have significant clinical as well as prognostic importance.
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Affiliation(s)
- Nupur Mukherjee
- Department of Oncogene Regulation, Chittaranjan National Cancer Institute, Kolkata, India
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Prognostic significance of Wnt-1, β-catenin and E-cadherin expression in advanced colorectal carcinoma. Pathol Oncol Res 2011; 17:955-63. [PMID: 21678109 PMCID: PMC3185231 DOI: 10.1007/s12253-011-9409-4] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2010] [Accepted: 04/27/2011] [Indexed: 12/13/2022]
Abstract
Wnt/β-catenin pathway plays an important role in initiation and progression of colorectal oncogenesis. The aim of this study was to determine expression and localization of E-cadherin, β-catenin and Wnt-1 proteins in colorectal tumors. Expression of β-catenin, E-cadherin and Wnt-1 was determined by immunohistochemistry on advanced colorectal cancers. Abnormal expression of E-cadherin, β-catenin, Wnt-1 was observed. Additionally, we revealed correlations between levels of studied proteins and histoclinical data. In multivariate analysis nuclear β-catenin, higher carcinoembryonic antigen serum level before treatment, female sex and tumor localized in colon or rectum were independent unfavorable prognostic factors. These findings support the hypothesis that Wnt/β-catenin pathway plays an important role in advanced colorectal carcinoma.
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Boyault S, Drouet Y, Navarro C, Bachelot T, Lasset C, Treilleux I, Tabone E, Puisieux A, Wang Q. Mutational characterization of individual breast tumors: TP53 and PI3K pathway genes are frequently and distinctively mutated in different subtypes. Breast Cancer Res Treat 2011; 132:29-39. [PMID: 21512767 DOI: 10.1007/s10549-011-1518-y] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2011] [Accepted: 04/09/2011] [Indexed: 01/21/2023]
Abstract
Understanding how cancer genes are mutated in individual tumors is an important issue with potential clinical and therapeutic impact. This is especially relevant with recently developed targeted therapies since mutated genes can be targets and/or predictors. However, to date, gene mutation profiling in individual tumors is still underexplored. Breast cancer is composed of various subtypes. We presumed that this heterogeneity reflected the involvement of different molecular mechanisms including gene mutations that affect defined signaling pathways. Unlike the majority of published mutational studies, this study was aimed to draw a mutation profile in individual tumors by screening a panel of cancer genes in the same tumor. Thus, five genes frequently mutated in breast cancers: TP53, PIK3CA, PTEN, CDH1, and AKT1 were screened in each of 120 human primary breast tumors. Mutations in at least one of these genes were found in 62.5% of the tumors, of which the majority carried a single-gene mutation. Interestingly, a substantial proportion of tumors carried mutations either in TP53 or in genes of the PI3K pathway (PIK3CA or PTEN or AKT1). These two distinct mutation patterns were significantly associated to hormone receptor expression but independent of HER2 status.
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Affiliation(s)
- Sandrine Boyault
- Laboratoire de Recherche Translationnelle, Centre Léon Bérard, 28 rue Laënnec, 69373 Lyon Cedex 08, France
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17
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Bruyere F, Namdarian B, Corcoran NM, Pedersen J, Ockrim J, Voelzke BB, Mete U, Costello AJ, Hovens CM. Snail expression is an independent predictor of tumor recurrence in superficial bladder cancers. Urol Oncol 2010; 28:591-6. [DOI: 10.1016/j.urolonc.2008.11.005] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2008] [Revised: 11/06/2008] [Accepted: 11/09/2008] [Indexed: 10/21/2022]
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Mangé A, Chaurand P, Perrochia H, Roger P, Caprioli RM, Solassol J. Liquid chromatography-tandem and MALDI imaging mass spectrometry analyses of RCL2/CS100-fixed, paraffin-embedded tissues: proteomics evaluation of an alternate fixative for biomarker discovery. J Proteome Res 2010; 8:5619-28. [PMID: 19856998 DOI: 10.1021/pr9007128] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Human tissues are an important source of biological material for the discovery of novel biomarkers. Fresh-frozen tissue could represent an ideal supply of archival material for molecular investigations. However, immediate flash freezing is usually not possible, especially for rare or valuable tissue samples such as biopsies. Here, we investigated the compatibility of RCL2/CS100, a non-cross-linking, nontoxic, and nonvolatile organic fixative, with shotgun proteomic analyses. Several protein extraction protocols compatible with mass spectrometry were investigated from RCL2/CS100-fixed and fresh-frozen colonic mucosa, breast, and prostate tissues. The peptides and proteins identified from RCL2/CS100 tissue were then comprehensively compared with those identified from matched fresh-frozen tissues using a bottom-up strategy based on nano-reversed phase liquid chromatography coupled with tandem mass spectrometry (nanoRPLC-MS/MS). Results showed that similar peptides could be identified in both archival conditions and the proteome coverage was not obviously compromised by the RCL2/CS100 fixation process. NanoRPLC-MS/MS of laser capture microdissected RCL2/CS100-fixed tissues gave the same amount of biological information as that recovered from whole RCL2/CS100-fixed or frozen tissues. We next performed MALDI tissue profiling and imaging mass spectrometry and observed a high level of agreement in protein expression as well as excellent agreement between the images obtained from RCL2/CS100-fixed and fresh-frozen tissue samples. These results suggest that RCL2/CS100-fixed tissues are suitable for shotgun proteomic analyses and tissue imaging. More importantly, this alternate fixative opens the door to the analysis of small, valuable, and rare target lesions that are usually inaccessible to complementary biomarker-driven genomic and proteomic research.
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Affiliation(s)
- Alain Mangé
- Department of Cellular Biology, CHU Arnaud de Villeneuve, Montpellier, France
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19
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Gnad T, Feoktistova M, Leverkus M, Lendeckel U, Naumann M. Helicobacter pylori-induced activation of beta-catenin involves low density lipoprotein receptor-related protein 6 and Dishevelled. Mol Cancer 2010; 9:31. [PMID: 20137080 PMCID: PMC2825249 DOI: 10.1186/1476-4598-9-31] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2009] [Accepted: 02/05/2010] [Indexed: 01/12/2023] Open
Abstract
Background The human microbial pathogen Helicobacter pylori resides in the stomach of about fifty percent of the world's population and represents a risk factor for chronic gastritis, peptic ulcers and, in rare cases, gastric cancer. Alterations of the Wnt/β-catenin signaling pathway have been described in almost every human cancer disease, due to the regulation of target genes being involved in cell cycle control, differentiation, cell migration or stem cell control. Our study aimed to elucidate the role of proximal Wnt signaling components low density lipoprotein receptor-related protein 6 (LRP6) and Dishevelled (Dvl) in the activation of β-catenin early after infection of gastric epithelial cells with H. pylori. Results Infection of gastric epithelial NCI-N87 cells with H. pylori induces rapid phosphorylation of the Wnt/β-catenin pathway co-receptor LRP6 independent of the cytotoxin-associated gene A (CagA) or vacuolating cytotoxin A (VacA). However, bacteria lacking a functional type 4 secretion system (T4SS) failed to induce LRP6 phosphorylation. Further, we identified proteins of the Dvl family, namely Dvl2 and Dvl3, which are involved in LRP6 phosphorylation. H. pylori-induced nuclear accumulation of β-catenin and its transcriptional activation, and expression of Wnt target genes are strongly reduced in stable knockdown cell lines deficient for LRP6, Dvl2 or Dvl3. Conclusion We analysed the H. pylori-induced activation of Wnt-signaling factors and demonstrate for the first time that the canonical Wnt-signaling proteins LRP6 and Dvl2 and Dvl3 are involved in the regulation of β-catenin.
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Affiliation(s)
- Thorsten Gnad
- Institute of Experimental Internal Medicine, Otto von Guericke University, Magdeburg, Germany
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20
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Chandrashekar C, Angadi PV, Krishnapillai R. β-Catenin expression in benign and malignant salivary gland tumors. Int J Surg Pathol 2009; 19:433-40. [PMID: 20034989 DOI: 10.1177/1066896909346366] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
OBJECTIVE To assess the expression of β-catenin in benign and malignant salivary gland tumors and to investigate the possible role of β-catenin in the behavior of salivary gland tumors. STUDY DESIGN Paraffin embedded tissues from 45 salivary gland tumors were studied immunohistochemically for expression of β-catenin. RESULT Reduced/aberrant β-catenin expression was seen in benign and malignant salivary gland tumors. Cytoplasmic localization and reduced membranous expression were comparatively observed more in malignant salivary gland tumors. Additionally, in pleomorphic adenomas (PAs), β-catenin exhibited intense staining in cells arranged in the form of ducts/tubules, whereas cells in clusters and sheets showed weaker immunoreactivity. CONCLUSION Reduced and cytoplasmic localization of β-catenin could indicate lack of differentiation, invasive potential, and aggressive behavior in malignant salivary gland tumors. Furthermore, change in expression based on the arrangement of tumor cells may suggest that β-catenin may have a role in morphological variations seen in PAs.
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Affiliation(s)
- Chetana Chandrashekar
- Department of Oral Pathology and Microbiology, Manipal College of Dental Sciences, Manipal, Karnataka, India.
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21
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Zali MR, Moaven O, Asadzadeh Aghdaee H, Ghafarzadegan K, Ahmadi KJ, Farzadnia M, Arabi A, Abbaszadegan MR. Clinicopathological significance of E-cadherin, β-catenin and p53 expression in gastric adenocarinoma. JOURNAL OF RESEARCH IN MEDICAL SCIENCES : THE OFFICIAL JOURNAL OF ISFAHAN UNIVERSITY OF MEDICAL SCIENCES 2009; 14:239-247. [PMID: 21772890 PMCID: PMC3129111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/09/2008] [Accepted: 05/05/2009] [Indexed: 11/13/2022]
Abstract
BACKGROUND E-cadherin/catenin complexes exert a role in cell adhesion. β-catenin is a key player in Wnt signaling pathway in gastric cancer. P53 is a tumor suppressor gene which also regulates apoptosis. We assessed the expression of E-cadherin, β-catenin and p53 in gastric adenocarcinoma, and their correlations with clinicopathological features. METHODS Fifty six formalin-fixed, paraffin-embedded archival specimens of gastric adenocarcinoma were randomly included as cases. Adjacent tumor-free gastric mucosa of different premalignant stages was obtained from the cases. Immunohistochemical staining was performed to assess E-cadherin, β-catenin and p53 expression. RESULTS All chronic atrophic gastritis and intestinal metaplasia revealed normal membranous staining. Only one patient with dysplasia had abnormal expression of E-cadherin and β-Catenin. Abnormal E-cadherin, β-catenin and p53 expression was found in 50%, 48.2% and 76.8% of cancer specimens respectively. Abnormal expression of E-cadherin was significantly correlated with aberrant β-catenin expression. Abnormal E-cadherin and β-catenin expression were significantly correlated with depth of tumor invasion and advanced gastric cancer (p < 0.05), lower degree of differentiation and diffused tumor type (p < 0.001). Node metastasis was not influenced by abnormal expression of E-cadherin and β-catenin. P53 was not associated with clinicopathological variables. CONCLUSIONS Abnormal expression of the E-cadherin and β-catenin were associated with each other and influenced by histogenesis of gastric cancer and malignant behavior of tumor but not significant in premalignant lesions. They are more frequent in diffuse type and associated with advanced gastric cancer. P53 alterations are more frequent in the Iranian population compared with others.
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Affiliation(s)
- Mohammad Reza Zali
- Research Center for Gastroenterology and Liver Disease (RCGLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Omeed Moaven
- Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamid Asadzadeh Aghdaee
- Research Center for Gastroenterology and Liver Disease (RCGLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kamran Ghafarzadegan
- Department of Pathology, Omid Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Khadijeh Jami Ahmadi
- Department of New Techniques and Sciences, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehdi Farzadnia
- Department of Pathology, Imam-Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Azadeh Arabi
- Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Reza Abbaszadegan
- Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
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Shim HS, Yoon BS, Cho NH. Prognostic significance of paired epithelial cell adhesion molecule and E-cadherin in ovarian serous carcinoma. Hum Pathol 2009; 40:693-8. [PMID: 19157508 DOI: 10.1016/j.humpath.2008.10.013] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2008] [Revised: 09/29/2008] [Accepted: 10/20/2008] [Indexed: 11/17/2022]
Abstract
This study was designed to investigate the prognostic significance of the expression of paired epithelial cell adhesion molecule and E-cadherin in ovarian serous carcinoma. The expression of epithelial cell adhesion molecule and E-cadherin was examined immunohistochemically on a tissue microarray of formalin-fixed paraffin-embedded tissue specimens from 72 consecutive patients. The overexpression of epithelial cell adhesion molecule was correlated with poor survival (P = .036). In contrast, the reduced expression of E-cadherin was correlated with poor survival (P = .034). When patients were subclassified into 4 groups according to positivity and negativity of epithelial cell adhesion molecule and E-cadherin expression, the epithelial cell adhesion molecule-positive E-cadherin-negative group showed the worst survival rate (P = .002, compared with the epithelial cell adhesion molecule-negative E-cadherin-positive group). These data suggest that the overexpression of epithelial cell adhesion molecule and reduced expression of E-cadherin in combination is more significant than a single marker for predicting poor survival.
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Affiliation(s)
- Hyo Sup Shim
- Department of Pathology, Yonsei University College of Medicine, Seoul 120-752, Korea
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23
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Expressions of Beta-catenin, E-cadherin and MMP-7 in ovarian epithelial tumors. Chin J Cancer Res 2008. [DOI: 10.1007/s11670-008-0190-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
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Heatley MK. Immunohistochemical biomarkers of value in distinguishing primary ovarian carcinoma from gastric carcinoma: a systematic review with statistical meta-analysis. Histopathology 2008; 52:267-76. [PMID: 17825056 DOI: 10.1111/j.1365-2559.2007.02824.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
AIMS To compare the relative risk of antigen expression being detected immunohistochemically in ovarian and gastric carcinoma aggregated from studies performed for diagnostic purposes, with the relative risks of their expression in all patients in the English literature. METHODS AND RESULTS Both types of series indicated that cytokeratin (CK) 7 expression was greater and that of CK20 and carcinoembryonic antigen less in ovarian than in gastric carcinoma (P < 0.05). Synthesis of all data available for MUC-2 suggested it was more commonly expressed in ovarian carcinoma, whereas the relative risk in papers that directly compared its expression suggested that it was more common in the gastric carcinoma (P = 0.2, NS). Aggregating all possible data suggested villin was more likely to be expressed in ovarian cancers, whereas studies in which its expression was compared directly in both tumours suggested the opposite. Although statistically significant, patient numbers were small. CONCLUSION Provided sufficient numbers of cases are studied, analysis of studies comparing antigen expression for diagnostic purposes in tumours from two body sites is likely to be supported in the wider literature. The design of such comparative studies is informed by aggregating data from single tumour studies.
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Affiliation(s)
- M K Heatley
- Department of Histopathology, St James' University Hospital, Leeds, UK.
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Yamamoto S, Tsuda H, Honda K, Kita T, Takano M, Tamai S, Inazawa J, Yamada T, Matsubara O. Actinin-4 expression in ovarian cancer: a novel prognostic indicator independent of clinical stage and histological type. Mod Pathol 2007; 20:1278-85. [PMID: 17873890 DOI: 10.1038/modpathol.3800966] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Actinin-4 is an isoform of non-muscular alpha-actinin and actin-bundling protein. By enhancing cell motility, actinin-4 shows different biological properties from another isoform of non-muscular actinin 'actinin-1' and variable clinicopathological implications of actinin-4 have been demonstrated in some human malignancies such as breast cancers, lung cancers, and colorectal cancers. We herein described the clinicopathological and prognostic significance of actinin-4 expression in ovarian cancers. Actinin-4 expression was analyzed immunohistochemically in 265 primary ovarian carcinomas: 116 serous, 71 clear cell, 43 endometrioid, and 35 mucinous adenocarcinomas. With reference to endothelial immunoreactivity, cytoplasmic expression of actinin-4 was classified as either low (including negative) or high. Then, various parameters such as patients' characteristics, histopathological findings including E-cadherin and beta-catenin immunoreactivity, and clinical outcome, were compared between groups showing differences in the intensity or intracellular distribution of actinin-4 immunoreactivity. High expression of actinin-4 was demonstrated in 137 (57%) cases and was associated with serous histology (P=0.0075), high histological grade (P<0.0001), an advanced disease stage (P=0.036), a high degree of residual disease after initial surgery (P=0.0047), poor patient outcome (5-year survival: 52.4% in the high-expression group vs 71.9% in the low expression group, P=0.0043 by log-rank test), and also with reduced E-cadherin and preserved beta-catenin expressions (P=0.0097 and 0.017, respectively). Nuclear immunoreactivity for actinin-4 was detected in 20 (7.5%) cases and was associated with low histological grade (P=0.0079) but not with other variables. Multivariate analysis showed that high actinin-4 expression was an independent prognostic factor for overall survival, as well as a high degree of residual disease and clear-cell histology. Accumulation of actinin-4 in the cytoplasm may be related to a higher propensity for tumor invasiveness and metastasis, probably by enhancing cell motility, and could be a novel prognostic indicator for patients with ovarian carcinomas.
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Affiliation(s)
- Sohei Yamamoto
- Department of Basic Pathology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, Japan
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Shan K, Xiao-Wei M, Na W, Xiu-Feng Z, Deng-Gui W, Wei G, Zheng-Mao Z, Yan L. Association of three single nucleotide polymorphisms of the E-cadherin gene with endometriosis in a Chinese population. Reproduction 2007; 134:373-8. [PMID: 17660246 DOI: 10.1530/rep-07-0104] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Endometriosis, one of the most frequent diseases in gynecology, is a benign but invasive and metastatic disease. The altered expression of E-cadherin may play an important role in developing endometriosis. In this paper, we discuss the association of three single nucleotide polymorphisms (SNPs) on the E-cadherin gene and risk of endometriosis. We examined the genotype frequency of three polymorphisms in 152 endometriosis patients and 189 control women. There was a significant difference in the frequency of the E-cadherin 3'-UTR C --> T genotypes between endometriosis and controls (P = 0.01). The frequency of the C allele in patients (71.1%) was significantly higher than in the controls (63.8%; P = 0.04). When compared with the T/T + T/C genotypes, the C/C genotype had a significantly increased susceptibility to endometriosis, with an adjusted odds ratio of 1.79 (95% confidence interval = 1.17-2.76). No significant difference was found between endometriosis and control women on two polymorphisms (-160 C --> A, -347 G --> GA) at the gene promoter region of E-cadherin. The -160 C --> A and -347 G --> GA polymorphisms displayed linkage disequilibrium (D' = 0.999). The -160 A/-347 GA haplotype was only detected in endometriosis patients (2%). These data show a relation between the E-cadherin 3'-UTR C --> T polymorphism, the -160 A/-347 GA haplotype of two promoter polymorphisms and risk of endometriosis, suggesting a potential role in endometriosis development, at least in North Chinese women.
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Affiliation(s)
- Kang Shan
- Department of Obstetrics and Gynecology, Fourth Hospital, Hebei Medical University, Shijiazhuang 050011, China
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Li Y, Liang J, Kang S, Dong Z, Wang N, Xing H, Zhou R, Li X, Zhao X. E-cadherin gene polymorphisms and haplotype associated with the occurrence of epithelial ovarian cancer in Chinese. Gynecol Oncol 2007; 108:409-14. [PMID: 18035404 DOI: 10.1016/j.ygyno.2007.10.024] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2007] [Revised: 10/10/2007] [Accepted: 10/15/2007] [Indexed: 02/08/2023]
Abstract
BACKGROUNDS AND AIMS E-cadherin plays an important role in the origin of epithelial ovarian cancer. However, the exact molecular mechanism by which this occurs is unknown. The polymorphisms located at the E-cadherin may contribute to an increased risk for certain cancers. In this paper, we studied the association between polymorphisms of E-cadherin and the risk of epithelial ovarian cancer. METHODS We assessed the -160C/A, -347G/GA polymorphism within the promoter region and 3'-UTR +54C/T polymorphism of E-cadherin in epithelial ovarian cancer and control women. We also tested the expression of E-cadherin protein in ovarian cancer tissue among three genotype (3'-UTR +54C/T polymorphism) carriers. RESULTS There was no significant difference in genotype distribution of the -160C/A and -347G/GA SNPs in the E-cadherin gene promoter region between ovarian cancer patients and controls, but haplotype -160A/-347GA relative to haplotype -160C/-347G was 48.6 (95% CI=2.9-806.2) for epithelial ovarian cancer risk. The C/C genotype of the 3'-UTR +54C/T polymorphism relative to the C/T+T/T genotype was 1.85 (95% CI=1.27-2.69) for epithelial ovarian cancer risk. E-cadherin protein expression in was lower in C/C genotype carriers than T allele carriers in ovarian cancer tissue (P=0.02). CONCLUSIONS The C/C genotype of 3'-UTR C/T SNP and -160C/-374GA haplotype in E-cadherin gene may be a potential susceptibility factor for risk of epithelial ovarian cancer in Chinese, which indicated that the lower expression of E-cadherin might play an important role in the pathogenesis of epithelial ovarian cancer.
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Affiliation(s)
- Yan Li
- Department of Molecular Biology, Hebei Cancer Institute, Hebei Medical University, Fourth Hospital, Jiankanglu 12, Shijiazhuang 050011, China.
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The E-cadherin repressor Snail is associated with lower overall survival of ovarian cancer patients. Br J Cancer 2007; 98:489-95. [PMID: 18026186 PMCID: PMC2361433 DOI: 10.1038/sj.bjc.6604115] [Citation(s) in RCA: 106] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Epithelial ovarian cancer is the leading cause of death among female genital malignancies. Reduced expression of the cell adhesion molecule E-cadherin was previously shown to be associated with adverse prognostic features. The role of the E-cadherin repressor Snail in ovarian cancer progression remains to be elucidated. We analysed formalin-fixed and paraffin-embedded specimens of 48 primary ovarian tumours and corresponding metastases for expression of E-cadherin and Snail by immunohistochemistry. We found a significant correlation between E-cadherin expression in primary cancers and their corresponding metastases (P<0.001). This correlation was found for Snail expression as well (P<0.001). There was a significant (P=0.008) association of reduced E-cadherin expression in primary ovarian cancer with shorter overall survival. Similarly, Snail expression in corresponding metastases (P=0.047) was associated with reduced overall survival of the patients. Additionally, the group of patients showing reduced E-cadherin and increased Snail immunoreactivity in primary tumours and corresponding metastases, respectively, had a significantly higher risk of death (P=0.002 and 0.022, respectively) when compared to the patient group with the reference expression profile E-cadherin positive and Snail negative. Taken together, the results of our study show that the E-cadherin repressor Snail is associated with lower overall survival of ovarian cancer patients.
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Jung IM, Chung JK, Kim YA, Kim JE, Heo SC, Ahn YJ, Hwang KT, Kim BG, Lee KL, Kim CW, Kim WH, Chang MS. Epstein-Barr virus, beta-catenin, and E-cadherin in gastric carcinomas. J Korean Med Sci 2007; 22:855-61. [PMID: 17982235 PMCID: PMC2693853 DOI: 10.3346/jkms.2007.22.5.855] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Activated beta-catenin is suggested to inhibit NF-kappaB activation, and we previously demonstrated that NF-kappaB nuclear positivity was more frequent in Epstein-Barr virus (EBV)-infected gastric carcinomas. It is controversial that beta-catenin and E-cadherin are prognostic markers in gastric carcinomas. To define a relationship between beta-catenin and EBV, and the prognostic value of beta-catenin and E-cadherin, we analyzed in situ hybridization for EBV-encoded small RNAs, beta-catenin, and E-cadherin immunohistochemistry, and clinicopathological features in 111 gastric carcinomas. EBV infection was detected in seven carcinomas (6.3%); none of seven showed beta-catenin nuclear accumulation, and five out of seven revealed beta-catenin membranous loss or cytoplasmic expression. Eighty cases (72.1%) showed beta-catenin alteration; i.e., loss of membrane staining in 65 (58.6 %), cytoplasmic expression in 35 (31.5%), and nuclear accumulation in 15 (13.5%). E-cadherin alteration was observed in 34 cases (30.6%) and correlated with beta-catenin alteration. On multivariate analysis, the combined immunoexpression group of beta-catenin nuclear accumulation/ E-cadherin alteration and the advanced TNM cancer stage group showed poor patient's survival (p<0.05). In conclusion, beta-catenin activation through nuclear accumulation hardly occurred in EBV-infected gastric carcinomas. The combined immunoexpression pattern of beta-catenin and E-cadherin can be used as a prognostic marker in gastric carcinomas.
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Affiliation(s)
- In Mok Jung
- Department of Surgery, Seoul National University Boramae Hospital, Seoul, Korea
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Jung Kee Chung
- Department of Surgery, Seoul National University Boramae Hospital, Seoul, Korea
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Young A Kim
- Department of Pathology, Seoul National University Boramae Hospital, Seoul, Korea
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - Je Eun Kim
- Department of Pathology, Seoul National University Boramae Hospital, Seoul, Korea
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - Seung Chul Heo
- Department of Surgery, Seoul National University Boramae Hospital, Seoul, Korea
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Young Joon Ahn
- Department of Surgery, Seoul National University Boramae Hospital, Seoul, Korea
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Ki-Tae Hwang
- Department of Surgery, Seoul National University Boramae Hospital, Seoul, Korea
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Byeong Gwan Kim
- Department of Internal Medicine, Seoul National University Boramae Hospital, Seoul, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Kook Lae Lee
- Department of Internal Medicine, Seoul National University Boramae Hospital, Seoul, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Chul Woo Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - Woo Ho Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - Mee Soo Chang
- Department of Pathology, Seoul National University Boramae Hospital, Seoul, Korea
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
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Katz A, Saad ED, Porter P, Pusztai L. Primary systemic chemotherapy of invasive lobular carcinoma of the breast. Lancet Oncol 2007; 8:55-62. [PMID: 17196511 DOI: 10.1016/s1470-2045(06)71011-7] [Citation(s) in RCA: 77] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Invasive lobular carcinoma is the second most frequent histological type of breast cancer and its incidence is increasing. It has unique clinical, biological, and molecular features. Invasive lobular carcinoma is almost invariably positive for the oestrogen receptor and, when compared with invasive ductal carcinoma, it is typically of a lower grade. Even though invasive lobular carcinoma represents a distinct clinical entity, the same criteria used for invasive ductal carcinoma are currently applied to establish the need for primary or adjuvant systemic chemotherapy. We reviewed randomised trials of neoadjuvant and adjuvant chemotherapy and noted that insufficient evidence is available to support or withhold use of chemotherapy in patients with invasive lobular carcinoma. Thus, the benefit from systemic chemotherapy for individuals with this form of breast disease is unclear. Invasive lobular carcinoma deserves to be investigated separately in prospective clinical trials to define the best treatment and prevention strategies.
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Affiliation(s)
- Artur Katz
- Centro Paulista de Oncologia and Hospital Albert Einstein, Sao Paulo, Brazil.
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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.
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Affiliation(s)
- P Dursun
- Department of Obstetrics and Gynecology, Hacettepe University, Ankara, Turkey.
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Abstract
Some diffuse type gastric cancers are of hereditary origin. Their histological characteristics are poor cell differentiation and the presence of signet-ring cells. The cause is a mutation of the CDH1 gene which is responsible for abnormal E-cadherin. The transmission mode is autosomal dominant. Because of serious prognosis of symptomatic hereditary diffuse gastric cancer (HDGC), the high penetrance of the gene (67% in men and 83% in women) and the young age of onset of these tumors (before the age of 40), a prophylactic gastrectomy is recommended to the mutation carriers. The search for the genetic mutation should be recommended to families corresponding to clinical criteria such as the number of affected family members, degree of relationship and age of onset of these tumors.
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Newman EA, Mulholland MW. Prophylactic gastrectomy for hereditary diffuse gastric cancer syndrome. J Am Coll Surg 2006; 202:612-7. [PMID: 16571431 DOI: 10.1016/j.jamcollsurg.2005.12.017] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2005] [Accepted: 12/27/2005] [Indexed: 01/24/2023]
Abstract
BACKGROUND Germline mutations in the E-cadherin gene, CDH1, were recently identified in families with hereditary diffuse gastric cancer. The efficacy of endoscopic surveillance by current methods is largely ineffective because most tumors spread diffusely. There has been little evidence that prophylactic gastrectomy should be performed in patients with the genetic mutation, and few data are available on the outcomes of operations in patients with the CDH1 mutation undergoing prophylactic gastrectomy. We report the outcomes of patients with the CDH1 mutation who have undergone prophylactic gastrectomy in the year 2003 to 2004. STUDY DESIGN After genetic counseling and informed consent, two patients underwent total gastrectomy with Roux-en-Y reconstruction. Demographic information, pedigree analysis, preoperative screening results, operative course, and postoperative data, including complications, were collected and reviewed for each patient. RESULTS Pathologic examination of the stomach revealed no evidence of in situ or invasive carcinoma. There were no operative complications. Both patients reported diarrhea and moderate weight loss. There were no other postoperative complications. CONCLUSIONS Prophylactic gastrectomy can be performed safely, without mortality or severe morbidity, in patients with CDH1 mutations, and should be curative in this population of patients.
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Affiliation(s)
- Erika A Newman
- Section of Gastrointestinal Surgery, Department of Surgery, The University of Michigan Medical Center, Ann Arbor, MI 48108, USA
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Cho EY, Choi Y, Chae SW, Sohn JH, Ahn GH. Immunohistochemical study of the expression of adhesion molecules in ovarian serous neoplasms. Pathol Int 2006; 56:62-70. [PMID: 16445817 DOI: 10.1111/j.1440-1827.2006.01925.x] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
To clarify possible roles of adhesion molecules including E-cadherin, beta- and gamma-catenin, CD44s, CD44v6, CD56, and CD99 in ovarian serous neoplasms, an immunohistochemical study was undertaken for 23 benign, 40 borderline, and 95 malignant ovarian serous neoplasms using tissue microarray (TMA). Significantly reduced expression of E-cadherin, and overexpression of CD44s, CD56, and CD99 were more frequently observed in adenocarcinomas than in benign and borderline tumors. Expression of CD44v6 and nuclear beta- and gamma-catenin were detected only in borderline tumors and adenocarcinomas. Reduced expression of E-cadherin was also correlated with high tumor grade (P=0.03), presence of peritoneal seeding (P=0.03), and low overall survival rate (P=0.02). Overexpression of CD44s was significantly associated with high tumor grade (P=0.04), advanced stage (P=0.03), and low overall survival rate (P=0.02). CD56 was increasingly expressed in the case of advanced stage (P=0.005) and peritoneal seeding (P=0.001). Nuclear staining for gamma-catenin was correlated with tumor progression (P=0.004) and advanced International Federation of Gynecology and Obstetrics (FIGO) stage (P=0.02). Only CD44s expression and stage were correlated with overall survival in multivariate study. These results suggest that although E-cadherin, CD44s, CD56, and nuclear gamma-catenin immuno-expression seem to be useful prognostic markers for serous neoplasm of the ovary, CD44s expression and FIGO stage are independent prognostic factors.
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Affiliation(s)
- Eun Yoon Cho
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Scholten AN, Aliredjo R, Creutzberg CL, Smit VTHBM. Combined E-cadherin, alpha-catenin, and beta-catenin expression is a favorable prognostic factor in endometrial carcinoma. Int J Gynecol Cancer 2006; 16:1379-85. [PMID: 16803534 DOI: 10.1111/j.1525-1438.2006.00406.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Cell adhesion molecules, such as epithelial cadherin (E-cadherin), might be involved in the processes of tumor invasion and differentiation. The aim of this study was to investigate the expression of E-cadherin, alpha-catenin, and beta-catenin in endometrial carcinoma and to determine the prognostic value of these factors. We have investigated the expression of E-cadherin, alpha-catenin, and beta-catenin by immunohistochemistry in 225 endometrial carcinomas. The correlation between the E-cadherin and the catenins and their correlation with several histologic and clinical parameters were analyzed. Negative E-cadherin, alpha-catenin, and beta-catenin expression was observed in 44%, 47%, and 33% of endometrial carcinomas, respectively, and was correlated with histologic FIGO grade 3 (P < 0.001). Negative E-cadherin expression was more often observed in nonendometrioid endometrial carcinomas (NEECs) than in endometrioid carcinomas (75% versus 43%; P= 0.04). Combined positive E-cadherin, alpha-catenin, and beta-catenin expression was an independent positive prognostic factor for survival in patients with grade 1-2 carcinomas (P= 0.02). Negative E-cadherin expression was found to be associated with histologic grade 3 and with NEEC. Combined positive E-cadherin, alpha-catenin, and beta-catenin expression was a significant prognostic factor.
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Affiliation(s)
- A N Scholten
- Department of Clinical Oncology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
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36
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Sicinschi LA, Lopez-Carrillo L, Camargo MC, Correa P, Sierra RA, Henry RR, Chen J, Zabaleta J, Piazuelo MB, Schneider BG. Gastric cancer risk in a Mexican population: role of Helicobacter pylori CagA positive infection and polymorphisms in interleukin-1 and -10 genes. Int J Cancer 2006; 118:649-57. [PMID: 16114018 DOI: 10.1002/ijc.21364] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Several polymorphisms of the IL1B and IL10 gene promoters have been reported to be associated with gastric cancer risk in Caucasians. However, studies in other populations have shown differing results. We aimed to test for associations between polymorphisms in IL1B (-31 and +3954), IL10-592 and IL1RN variable number of tandem repeats (VNTR) and risk of gastric cancer in a Mexican population. DNA was extracted from sera of 183 gastric adenocarcinoma patients and 377 controls. The IL1B-31, IL1B+3954 and IL10-592 biallelic polymorphisms were discriminated using 5' Nuclease (TaqMan) assays and Pyrosequencing. The IL1RN penta-allelic VNTR polymorphism was genotyped using PCR followed by GeneScan analysis. A significant interaction was found between IL1B-31 and CagA status for the risk of intestinal-type gastric cancer (p = 0.023). Among CagA positive subjects, those with IL1B-31CC genotype had an increased risk of intestinal-type gastric cancer (OR 3.19, 95%CI = 1.05-9.68), compared to carriers of IL1B-31TT genotype. In contrast, among CagA negative subjects, no significant association of IL1B-31CC genotype with gastric cancer was observed. The IL10-592CC genotype was associated with more than doubling of the risk of the intestinal-type gastric cancer (OR, 2.20, 95%CI = 1.04-4.65). A nonsignificantly increased risk for intestinal-type gastric cancer was found in IL1RN*2 carriers (OR 1.49, 95%CI = 0.89-2.50). None of these polymorphisms was significantly related to the risk of diffuse-type gastric cancer. No significant association was found between risk of gastric cancer and the IL1B+3954 polymorphism. Individuals carrying 2 or more of the risk-associated alleles (IL1B-31C, IL1RN *2 and IL10-592C) were at increased risk for intestinal-type gastric cancer, compared to those with 0 or 1 risk-associated allele. The risk from multiple risk-associated alleles was especially high in subjects infected with CagA positive H. pylori. Our results support the identification of the IL1B-31 promoter polymorphism as a useful marker for risk of intestinal type gastric cancer in persons with CagA positive H. pylori infections.
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Affiliation(s)
- Liviu A Sicinschi
- Department of Pathology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
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Cacev T, Jokić M, Spaventi R, Pavelić K, Kapitanović S. Loss of heterozygosity testing using real-time PCR analysis of single nucleotide polymorphisms. J Cancer Res Clin Oncol 2005; 132:200-4. [PMID: 16283382 DOI: 10.1007/s00432-005-0051-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2005] [Accepted: 10/12/2005] [Indexed: 12/29/2022]
Abstract
PURPOSE Colon cancer is a genetic disease, caused by mutations in different oncogenes and tumor-suppressor genes. The aim of this study is to evaluate the usefulness of real-time PCR SNP analysis as a new technique in the loss of heterozygosity (LOH) analysis at the E-cadherin gene locus in sporadic colon cancer. METHODS One-hundred cases of human sporadic colon cancer and corresponding normal tissue samples were analyzed using two flanking polymorphic markers commonly used in the LOH analysis at the E-cadherin gene locus by conventional VNTR-LOH analysis. Two intragenic E-cadherin SNP markers were analyzed using real-time PCR SNP analysis. RESULTS LOH (17.6%) was detected using flanking markers, however, no LOH was detected when the intragenic E-cadherin SNP markers were introduced into our study. Since these markers are intragenic they more accurately represent the status of the E-cadherin gene than the previously used flanking markers. CONCLUSION In conclusion, real-time PCR SNP analysis was found to be more accurate, faster, simpler, and a more high-throughput method than the conventional VNTR-LOH analysis.
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Affiliation(s)
- Tamara Cacev
- Division of Molecular Medicine, Ruder Bosković Institute, Bijenicka 54, 10000 Zagreb, Croatia.
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Liu P, You SH, Zhang XY, Zhang DF, Ding XJ. Heterozygosity loss of fragile histidine triad gene in gastric cancer and precancerous lesions. Shijie Huaren Xiaohua Zazhi 2005; 13:1190-1193. [DOI: 10.11569/wcjd.v13.i10.1190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To detect the loss of heterozygosity (LOH) of fragile histidine triad (FHIT) gene in gastric cancer and precancerous lesions (dysplasia and intestinal metaplasia), and to analyze its role in the carcinogenesis of gastric cancer.
METHODS: The LOH at microsatellites loci D3S1234 and D3S1300 of FHIT gene were measured in samples of gastric cancer (n = 42), dysplasia (n = 44), intestinal metaplasia (n = 51) and their corresponding normal tissues by (polymerase chain reaction) PCR.
RESULTS: The rates of LOH at D3S1234 locus were 32.4%(11/34), 28.6%(10/35) and 10%(4/40) in gastric cancer, dysplasia and intestinal metaplasia respectively, and the ones at D3S1300 locus were 33.3%(12/36) , 32.4%(11/34) and 7.7% (3/39) respectively. The LOH rates at D3S1234 and D3S1300 loci in gastric cancer and atypical hyperplasia were higher than that of intestinal metaplasia (P<0.05, P<0.01 for D3S1234 and D3S1300 respectively). No significant difference of LOH rate was found between gastric cancer and dysplasia.
CONCLUSION: The loss of heterozygosity of FHIT gene may be an early event in the tumorigenesis of gastric cancer.
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Rodríguez-Sastre MA, González-Maya L, Delgado R, Lizano M, Tsubaki G, Mohar A, García-Carrancá A. Abnormal distribution of E-cadherin and β-catenin in different histologic types of cancer of the uterine cervix. Gynecol Oncol 2005; 97:330-6. [PMID: 15863126 DOI: 10.1016/j.ygyno.2004.12.062] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2004] [Revised: 12/11/2004] [Accepted: 12/15/2004] [Indexed: 11/20/2022]
Abstract
OBJECTIVE The goal of this study was to analyze the cellular distribution and possible alterations of beta-catenin and E-cadherin proteins in different histologic types of uterine cervical cancer and precursor lesions, compared to normal controls. METHODS We performed an immunochemical staining analysis of the cellular distribution of beta-catenin and E-cadherin proteins in biopsy samples from 20 normal exocervical squamous epithelium, 43 premalignant lesions, and a large series of 126 invasive tumors of different histologic types that included 68 squamous carcinomas, 31 adenosquamous carcinomas, and 27 adenocarcinomas. Statistical significance was evaluated by the chi-square or Fisher's Exact test. RESULTS We observed beta-catenin abnormally distributed in the cytoplasm of 62% of premalignant lesions and more than 70% of invasive cancers, statistically significant when compared with normal tissue (P < 0.05). Similarly, we found that E-cadherin exhibit a significant abnormal distribution in the cytoplasm of 58% of premalignant lesions (P < 0.05) and in more than 71% of squamous carcinoma and adenosquamous carcinoma when compared with normal tissue (P < 0.05). We found no differences in the distribution of E-cadherin between adenocarcinomas compared with control samples. Interestingly, we found that both, beta-catenin and E-cadherin, were absent in the membrane of nearly 40% premalignant lesions. Nuclear staining of beta-catenin was rarely seen in any cases, contrary to what has been reported for this and other neoplasias. CONCLUSION Our findings indicate that cellular alterations of both beta-catenin and E-cadherin are frequent in tumors of the uterine cervix of different histologic types, and support a role for these proteins in cervical cancer development.
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Gamboa-Dominguez A, Dominguez-Fonseca C, Chavarri-Guerra Y, Vargas R, Reyes-Gutierrez E, Green D, Quintanilla-Martinez L, Luber B, Busch R, Becker KF, Becker I, Höfler H, Fend F. E-cadherin expression in sporadic gastric cancer from Mexico: exon 8 and 9 deletions are infrequent events associated with poor survival. Hum Pathol 2005; 36:29-35. [PMID: 15712179 DOI: 10.1016/j.humpath.2004.09.020] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Aberrant expression and mutation of E-cadherin is frequent in gastric carcinoma (GC) especially of the diffuse type. The frequency of CDH1 (gene encoding E-cadherin) mutation in populations with high incidence of diffuse GC and its prognostic significance is unknown. One hundred seventy-seven gastrectomies from Mexican mestizo patients with intestinal (53), mixed (55), or diffuse (69) GC were included. In addition, 101 endoscopic biopsies from patients with GC not subjected to surgery were analyzed. Immunohistochemistry against wild-type E-cadherin (clone 36) and against 2 mutation-specific antibodies (MSA) recognizing mutant CDH1 lacking exon-8 (del 8) or exon-9 (del 9) were performed. Staining was correlated with histotype, tumor node metastasis stage, and follow-up. Abnormal or absent E-cadherin expression (clone 36) was identified in 84% GC, predominantly in diffuse or mixed tumors (P = 0.004) in advanced stages (P = 0.003). No survival differences at 1 and 2 years were observed among patients showing normal, abnormal, or absent wild type E-cadherin expression. Overall reactivity with the MSA was observed in 10 (5.6%) patients who were treated with surgery. In 140 patients, dead from the disease or alive with the disease, the survival at 1 and 2 years was 37% versus 17% and 14% versus 0 for patients without and with del 8/9 positivity, respectively (log rank P = 0.01). Biopsies from patients with inoperable-GC (101) rendered 5 (4.95%) with del 8 or 9 immunoreactivity. Abnormal E-cadherin expression is frequent in GC. However, exon 8 or 9 deletions were observed in only 5.3% tumors in this series from Mexico, at a lower rate than previously published, but associated with a worse prognosis.
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Affiliation(s)
- Armando Gamboa-Dominguez
- Department of Pathology, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico.
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Faleiro-Rodrigues C, Macedo-Pinto IM, Maia SS, Vieira RH, Lopes CS. Biological relevance of E-cadherin-catenin complex proteins in primary epithelial ovarian tumours. Gynecol Obstet Invest 2005; 60:75-83. [PMID: 15785075 DOI: 10.1159/000084614] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2003] [Accepted: 10/18/2004] [Indexed: 01/10/2023]
Abstract
This study analysed the biological relevance of E-cadherin, alpha-catenin, beta-catenin and gamma-catenin immunoexpression pattern (reduced vs. preserved phenotype) in epithelial ovarian tumours. Immunohistochemistry was used to evaluate the expression of these proteins in 154 epithelial ovarian tumours, consisting of 17 benign, 33 borderline and 104 malignant tumours. In borderline tumours, the immunoexpression pattern of E-cadherin (p = 0.014) and alpha-catenin (p = 0.030) associated with histological type. In malignant tumours, the immunoexpression pattern of E-cadherin was related with histological type (p = 0.001). The immunoexpression pattern of beta-catenin associated with histological type and tumour differentiation (p = 0.005, p = 0.025, respectively). The preserved phenotype of E-cadherin was most frequently observed in mucinous tumours, whereas reduced E-cadherin was most frequently observed in serous tumours. The preserved phenotype of beta-catenin associated with endometrioid carcinomas, while reduced beta-catenin associated with poorly differentiated serous and clear cell carcinomas. Although the reduced phenotype was the most frequent immunoexpression observed for all proteins of the E-cadherin-catenin complex in epithelial ovarian tumours, only beta-catenin showed a significant difference between benign, borderline and malignant tumours (p = 0.045), since borderline and malignant tumours most frequently showed the reduced phenotype. The immunohistochemical profile of beta-catenin was shown to be of biological relevance: reduced beta-catenin was correlated with loss of tumour differentiation and serous carcinomas that are known to depict aggressive biological behaviour in epithelial ovarian tumours.
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Affiliation(s)
- C Faleiro-Rodrigues
- Department of Pathology, Portuguese Institute of Oncology of Francisco Gentil, Porto, Portugal.
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Suzuki S, Egami K, Sasajima K, Ghazizadeh M, Shimizu H, Watanabe H, Hasegawa H, Iida S, Matsuda T, Okihama Y, Hosone M, Shimizu K, Kawanami O, Tajiri T. Comparative study between DNA copy number aberrations determined by quantitative microsatellite analysis and clinical outcome in patients with stomach cancer. Clin Cancer Res 2004; 10:3013-9. [PMID: 15131037 DOI: 10.1158/1078-0432.ccr-03-0250] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
PURPOSE We detected the relative DNA copy numbers (RCNs) at target loci in patients with stomach cancer with quantitative microsatellite analysis. We additionally clarified the relationship between DNA copy number aberrations and the clinical outcome of the patients. EXPERIMENTAL DESIGN Fresh frozen samples were obtained from 30 patients who had undergone surgery for stomach cancer. Seven microsatellite loci in chromosomes 8q, 16q, and 20q and one gene-specific locus (ZNF217) were selected as the target loci. The DNA copy number was obtained relatively to a pooled reference consisting of six microsatellite primer sets selected from the regions where few aberrations have been reported in comparative genomic hybridization analysis. On the basis of the TaqMan PCR system, the internal probes used were carrying donor (6-carboxyfluorescein) and acceptor (6-carboxytetramethylrhodamine) fluorescent molecules complementary to CA repeats in the microsatellite markers and to one gene-specific oligomer in the gene-specific marker. RESULTS Chromosome 8q gain, 20q gain, and 16q loss were detected in 18 (60.0%), 8 (26.7%), and 13 (43.3%) cases, respectively. Gains in the RCNs of D8S1801 and D8S1724 were most frequently found (36.7%). There was a significant correlation between the loss of D16S3026 and reduced survival duration (P = 0.0158), and the simultaneous aberrations of D8S1801 gain and D16S3026 loss (double marker positive) was significantly associated with reduced survival duration (P = 0.0008). According to Cox proportional hazards model, the double marker positive was a significant and independent factor indicating an unfavorable prognostic factor (relative risk, 17.176; 95% confidence interval, 2.782-106.026; P = 0.0022). CONCLUSION RCN aberrations in tumor tissues determined by quantitative microsatellite analysis enable identification of the prognostic factors that correlate with clinical outcome of the patients with stomach cancer.
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Affiliation(s)
- Seiji Suzuki
- Department of Surgery, Tama-Nagayama Hospital, Nippon Medical School, Tama-Shi, Tokyo, Japan.
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Blanco D, Vicent S, Elizegi E, Pino I, Fraga MF, Esteller M, Saffiotti U, Lecanda F, Montuenga LM. Altered expression of adhesion molecules and epithelial-mesenchymal transition in silica-induced rat lung carcinogenesis. J Transl Med 2004; 84:999-1012. [PMID: 15195114 DOI: 10.1038/labinvest.3700129] [Citation(s) in RCA: 61] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Loss of the epithelial phenotype and disruption of adhesion molecules is a hallmark in the epithelial-mesenchymal transition (EMT) reported in several types of cancer. Most of the studies about the relevance of adhesion and junction molecules in lung cancer have been performed using established tumors or in vitro models. The sequential molecular events leading to EMT during lung cancer progression are still not well understood. We have used a rat model for multistep lung carcinogenesis to study the status of adherens and tight junction proteins and mesenchymal markers during EMT. After silica-induced chronic inflammation, rats sequentially develop epithelial hyperplasia, preneoplastic lesions, and tumors such as adenocarcinomas and squamous cell carcinomas. In comparison with normal and hyperplastic bronchiolar epithelium and with hyperplastic alveolar type II cells, the expression levels of E-cadherin, alpha-catenin and beta-catenin were significantly reduced in adenomatoid preneoplastic lesions and in late tumors. The loss of E-cadherin in tumors was associated with its promoter hypermethylation. alpha- and beta-catenin dysregulation lead to cytoplasmic accumulation in some carcinomas. No nuclear beta-catenin localization was found at any stage of any preneoplastic or neoplastic lesion. Zonula occludens protein-1 was markedly decreased in 66% of adenocarcinomas and in 100% squamous cell carcinomas. The mesenchymal-associated proteins N-cadherin and vimentin were analyzed as markers for EMT. N-cadherin was de novo expressed in 32% of adenocarcinomas and 33% of squamous cell carcinomas. Vimentin-positive tumor cells were found in 35% of adenocarcinomas and 88% of squamous cell carcinomas. Mesenchymal markers were absent in precursor lesions, both hyperplastic and adenomatoid. The present results show that silica-induced rat lung carcinogenesis is a good model to study EMT in vivo, and also provide in vivo evidence suggesting that the changes in cell-cell adhesion molecules are an early event in lung carcinogenesis, while EMT occurs at a later stage.
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Affiliation(s)
- David Blanco
- Department of Histology and Pathology and Division of Oncology (Center for Applied Biomedical Research, CIMA), University of Navarra, Pamplona, Spain
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Faleiro-Rodrigues C, Macedo-Pinto I, Pereira D, Ferreira VM, Lopes CS. Association of E-cadherin and β-catenin immunoexpression with clinicopathologic features in primary ovarian carcinomas. Hum Pathol 2004; 35:663-9. [PMID: 15188131 DOI: 10.1016/j.humpath.2004.01.024] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Epithelial cadherin forms a complex with alpha-, beta-, and gamma-catenin proteins. Reduced expression of E-cadherin-catenins has been shown in human carcinomas and is associated with low histologic differentiation, increased risk of invasion, and metastatic disease. The immunoexpression pattern of E-cadherin and beta-catenin (reduced versus preserved phenotype) was evaluated in 104 primary ovarian carcinomas and related to clinicopathologic features of the tumors. The immunoexpression pattern of E-cadherin was associated with International Federation of Gynaecology and Obstetrics (FIGO) staging (P = 0.043), histologic subtype (P = 0.001), peritoneal metastasis (P = 0.006), and residual tumor (P = 0.036). The reduced phenotype of E-cadherin that was observed in 64% of the carcinomas (67/104) was associated with advanced stage tumors, serous carcinomas, presence of peritoneal metastasis, and residual tumor larger than 2 cm. The immunoexpression pattern of beta-catenin was associated with histologic subtype (P = 0.005), tumor differentiation (P = 0.025), and peritoneal metastasis (P = 0.041). The reduced phenotype of beta-catenin that was observed in 74% of the carcinomas (77/104) was associated with advanced stage tumors, poorly differentiated serous and clear cell carcinomas, presence of peritoneal metastasis, and residual tumor. The immunoexpression pattern of E-cadherin was correlated with beta-catenin (P = 0.001). The reduced phenotype for both E-cadherin and beta-catenin was associated with histologic subtype (P < 0.001) and peritoneal metastasis (P = 0.001). In conclusion, the immunohistochemical profile of E-cadherin and beta-catenin may be useful in identifying a particular subpopulation of ovarian cancer patients who are characterized by an adverse clinical outcome, because the reduced phenotype of these molecules was associated with poor tumor differentiation, peritoneal metastasis, and advanced FIGO stage tumors.
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Affiliation(s)
- Cristina Faleiro-Rodrigues
- Department of Pathology, Portuguese Institute of Oncology of Francisco Gentil, Centro Regional do Norte, Porto, Portugal
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Rezk S, Brynes RK, Nelson V, Thein M, Patwardhan N, Fischer A, Khan A. beta-Catenin expression in thyroid follicular lesions: potential role in nuclear envelope changes in papillary carcinomas. Endocr Pathol 2004; 15:329-37. [PMID: 15681857 DOI: 10.1385/ep:15:4:329] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
The morphologic distinction of benign and malignant thyroid follicular lesions can sometimes be challenging, therefore an immunohistochemical marker to aid in this distinction would be useful. beta-Catenin is one such potential marker. It is part of a membrane-bound cell growth-signaling complex that plays a role in cell adhesion, as well as in promotion of growth through activation of the Wnt signaling pathway. Oncogenic signaling occurs when beta-catenin is released, accumulates in the cytoplasm, translocates into the nucleus, and promotes transcription of genes including bcl-1 (cyclin D1) and c-myc that induce cell proliferation. Paraffin blocks from 133 thyroidectomy specimens were stained with monoclonal antibodies reactive with beta-catenin and cyclin D1. These included 53 cases of papillary thyroid carcinoma (PTC), 46 cases of follicular variant of papillary carcinoma (FVPC), 10 cases of follicular carcinoma (FC), and 24 cases of follicular adenoma (FA). Tissue from six normal thyroid specimens served as a control. The malignant lesions (PTC, FC, and FVPC) expressed strong cytoplasmic/nuclear staining and minimal residual membranous staining in 87%, 80%, and 71% of cases, respectively. In contrast, all normal thyroid tissue and 79% of FAs showed strong membranous reactivity with very minimal cytoplasmic staining. Interestingly, in 83% of PTC cases and 20% FVPCs, the intranuclear inclusions were distinctly beta-catenin positive. Cyclin D1 over expression correlated with cytoplasmic relocalization of beta-catenin in almost all cases, and no evidence of cyclin D1 gene amplification was observed. beta-Catenin can be of a diagnostic utility for thyroid lesions, because it highlights intranuclear inclusions in PTC, and shifts from a membranous localization to a cytoplasmic localization in malignant lesions. We speculate that the localization of beta-catenin in intranuclear inclusions may reflect a cytoskeletal remodeling activity of beta-catenin that is functionally significant for the PTC pathway.
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Affiliation(s)
- S Rezk
- Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA
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Zhao XJ, Li H, Chen H, Liu YX, Zhang LH, Liu SX, Feng QL. Expression of e-cadherin and β-catenin in human esophageal squamous cell carcinoma: relationships with prognosis. World J Gastroenterol 2003; 9:225-32. [PMID: 12532436 PMCID: PMC4611316 DOI: 10.3748/wjg.v9.i2.225] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To elucidate the expression of E-cadherin and β-catenin correlating with its clinical outcome in patients with esophageal squamous cell carcinoma (ESCC), by analyzing their interrelationship with clinicopathological variables and their effects on progress and prognosis.
METHODS: Expression of E-cadherin and β-catenin was determined by SP immunohistochemical technique in patients with ESCC consecutively, their correlation with clinical characteristics was evaluated and analyzed by multivariate analysis.
RESULTS: The rate of expression of E-cadherin decreased to 66.03% (70/106) in ESCC and the protein level was negative correlated with histologic grade, tumor size, clinical staging, lymph node metastasis and venous invasion. Whereas the expression rate of β-catenin was reduced to 69.8% (74/106) and the level of protein expression correlated only with histologic grade. There obviously existed inverse correlation between level of E-cadherin protein and survival, especially in stage I, IIa, IIb (P = 0.0033), Patients with low-expressing tumors for β-catenin and non-expressing tumors for E-cadherin/β-catenin had lower survival period than those with normal-expressing ones (P = 0.0501 and P = 0.0080, respectively). Patients with diminished expression of E-cadherin as grade II or III had shorter survival period than those with normally expressing and grade I, no significance existed between grade I and grade II or III with respect to different status of E-cadherin expression. Furthermore, Correlation analysis showed level of E-cadherin correlated with that of β-catenin (P = 0.005). Cox proportional hazards model analysis suggested downregulation of E-cadherin was an important factor indicating poor prognosis.
CONCLUSION: As a probable independent prognostic factor, it correlates with overall and disease free survival period, expression of E-cadherin but not β-catenin may predict prognosis in patients with ESCC.
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Affiliation(s)
- Xi-Jiang Zhao
- Department of Thoracic Surgery, Cancer Hospital of Tianjin Medical University, Tiyuanbei Street, Block Hexi, Tianjin 300060, China.
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Nabais S, Machado JC, Lopes C, Seruca R, Carneiro F, Sobrinho-Simões M. Patterns of beta-catenin expression in gastric carcinoma: clinicopathological relevance and mutation analysis. Int J Surg Pathol 2003; 11:1-9. [PMID: 12598910 DOI: 10.1177/106689690301100102] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Studies on the expression of beta-catenin (beta-ct) in gastric carcinoma have provided conflicting results, and the role played by beta-ct mutations in gastric carcinogenesis remains unclear. In an attempt to clarify the aforementioned issues we undertook the retrospective study of 157 gastric carcinomas by using immunohistochemistry and molecular genetics. Reduced/absent membranous beta-ct expression was significantly associated with isolated-cell/diffuse histotype both in "pure" diffuse gastric carcinomas and in the isolated-cell/diffuse component of mixed carcinomas. Cytoplasmic and/or nuclear beta-ct expression was particularly prevalent in mixed carcinomas and was significantly associated with lymphatic vessel invasion and lymph node metastases. beta-ct mutations were not detected in any case. We conclude that the pattern of beta-ct expression is closely related to gastric carcinoma histotype. The activation of Wnt/beta-ct pathway is associated with mixed gastric carcinoma and with features of clinical aggressiveness; the mechanism(s) underlying this pathway in gastric carcinoma are not due to beta-ct mutations and remain to be elucidated.
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Affiliation(s)
- Sérgio Nabais
- IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Portugal
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Aust G, Steinert M, Schütz A, Boltze C, Wahlbuhl M, Hamann J, Wobus M. CD97, but not its closely related EGF-TM7 family member EMR2, is expressed on gastric, pancreatic, and esophageal carcinomas. Am J Clin Pathol 2002; 118:699-707. [PMID: 12428789 DOI: 10.1309/a6ab-vf3f-7m88-c0ej] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
CD97 expression is related closely to the dedifferentiation and tumor stage in thyroid carcinomas. We systematically examined the role of CD97 and its closest relative, EMR2, in normal and malignant gastric, esophageal, and pancreatic tissue. The normal tissues were EMR2-, whereas CD97 was expressed slightly in the parietal cells of gastric mucosa and in exocrine pancreatic cells. Interestingly, intralobular and interlobular pancreatic ducts were CD97+. All tumors were EMR2-. CD97 was expressed by 44 of 50 gastric, 14 of 18 pancreatic, and 10 of 13 esophageal carcinomas. Of the 44 gastric cancers, 27 showed disseminated or scattered tumor cells at the invasion front with stronger CD97 expression than tumor cells located in solid tumor formations. There was no correlation between CD97 levels in the tumors or soluble CD97 in the serum samples and the clinicopathologic features of the patients. Taken together, significant numbers of gastric, esophageal, and pancreatic carcinomas are CD97+, whereas its homolog, EMR2, does not have any role in such tumors.
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Affiliation(s)
- Gabriela Aust
- Institute of Anatomy, University of Leipzig, Germany
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Yabuta T, Shinmura K, Tani M, Yamaguchi S, Yoshimura K, Katai H, Nakajima T, Mochiki E, Tsujinaka T, Takami M, Hirose K, Yamaguchi A, Takenoshita S, Yokota J. E-cadherin gene variants in gastric cancer families whose probands are diagnosed with diffuse gastric cancer. Int J Cancer 2002; 101:434-41. [PMID: 12216071 DOI: 10.1002/ijc.10633] [Citation(s) in RCA: 75] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
To identify germline E-cadherin mutations responsible for the predisposition to diffuse gastric cancer (DGC) among the Japanese, we screened 17 patients with familial aggregation of gastric cancer by sequencing analysis. All the patients were diagnosed with DGC and had at least 1 sibling with gastric cancer. Two novel E-cadherin gene variants were detected. One was detected in 1 patient only and associated with an amino acid substitution (Val/Met) at codon 832 in the region essential for binding to beta-catenin. The M832 variant was detected not only in the proband but also in 2 other gastric cancer patients in the family. Immunohistochemical analysis of gastric cancer tissue from the proband revealed that E-cadherin expression was markedly reduced and beta-catenin expression was also reduced in cancer cells. However, no significant difference in the activity of beta-catenin binding was detected between the M832 variant and V832 wild-type E-cadherin in immunofluorescence and immunoprecipitation/Western blot analyses. The other was detected in 5 patients and was located in the splice donor site (IVS1+6T/C); however, RT-PCR analysis indicated that the IVS+6C variant did not cause an aberrant splicing. Thus, the M832 variant could be a germline mutation causative of familial aggregation of DGC, although further functional studies are needed to understand the pathogenic significance of this variant.
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Affiliation(s)
- Tomonori Yabuta
- Biology Division, National Cancer Center Research Institute, Tokyo, Japan
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