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      Down regulation of E-Cadherin (ECAD) - a predictor for occult metastatic disease in sentinel node biopsy of early squamous cell carcinomas of the oral cavity and oropharynx

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          Abstract

          Background

          Prognostic factors in predicting occult lymph node metastasis in patients with head and neck squamous-cell carcinoma (HNSCC) are necessary to improve the results of the sentinel lymph node procedure in this tumour type. The E-Cadherin glycoprotein is an intercellular adhesion molecule in epithelial cells, which plays an important role in establishing and maintaining intercellular connections.

          Objectives

          To determine the value of the molecular marker E-Cadherin in predicting regional metastatic disease.

          Methods

          E-Cadherin expression in tumour tissue of 120 patients with HNSCC of the oral cavity and oropharynx were evaluated using the tissue microarray technique. 110 tumours were located in the oral cavity (91.7%; mostly tongue), 10 tumours in the oropharynx (8.3%). Intensity of E-Cadherin expression was quantified by the Intensity Reactivity Score (IRS). These results were correlated with the lymph node status of biopsied sentinel lymph nodes. Univariate and multivariate analysis was used to determine statistical significance.

          Results

          pT-stage, gender, tumour side and location did not correlate with lymph node metastasis. Differentiation grade ( p = 0.018) and down regulation of E-Cadherin expression significantly correlate with positive lymph node status ( p = 0.005) in univariate and multivariate analysis.

          Conclusion

          These data suggest that loss of E-cadherin expression is associated with increased lymhogeneous metastasis of HNSCC. E-cadherin immunohistochemistry may be used as a predictor for lymph node metastasis in squamous cell carcinoma of the oral cavity and oropharynx.

          Level of evidence: 2b

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          Most cited references17

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          Tissue microarrays for high-throughput molecular profiling of tumor specimens.

          Many genes and signalling pathways controlling cell proliferation, death and differentiation, as well as genomic integrity, are involved in cancer development. New techniques, such as serial analysis of gene expression and cDNA microarrays, have enabled measurement of the expression of thousands of genes in a single experiment, revealing many new, potentially important cancer genes. These genome screening tools can comprehensively survey one tumor at a time; however, analysis of hundreds of specimens from patients in different stages of disease is needed to establish the diagnostic, prognostic and therapeutic importance of each of the emerging cancer gene candidates. Here we have developed an array-based high-throughput technique that facilitates gene expression and copy number surveys of very large numbers of tumors. As many as 1000 cylindrical tissue biopsies from individual tumors can be distributed in a single tumor tissue microarray. Sections of the microarray provide targets for parallel in situ detection of DNA, RNA and protein targets in each specimen on the array, and consecutive sections allow the rapid analysis of hundreds of molecular markers in the same set of specimens. Our detection of six gene amplifications as well as p53 and estrogen receptor expression in breast cancer demonstrates the power of this technique for defining new subgroups of tumors.
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            Cadherin switching and bladder cancer.

            Progression to or presentation with muscle invasive disease represents the critical clinical step in bladder cancer, necessitating more aggressive therapy and carrying a significantly worse survival rate. Bladder tumors typically show decreased expression of the cell-cell adhesion molecule E-cadherin as grade and stage progress, accompanied by increased expression of N-cadherin or P-cadherin in muscle invasive tumors. This phenomenon has been described as cadherin switching and may represent the key step in invasion. We introduce some of the concepts of cadherin mediated cell adhesion and biology, and describe cadherin switching in detail for bladder cancer. We performed a PubMed search for articles summarizing important concepts in cadherin biology and presenting primary evidence of cadherin expression in bladder cancer. Cadherin switching promotes a more malignant and invasive phenotype of bladder cancer in patients and laboratory based experimental systems. Bladder cancer is novel in that a switch to N-cadherin and P-cadherin expression occurs, although the precise timing and nature of this process remain unknown. Similarly the associated signaling pathways remain to be fully elucidated. Cadherin switching is an important process late in the molecular pathogenesis of bladder cancer, and it may hold some of the answers to the development of muscle invasive and metastatic disease. Thus, the cadherin cell adhesion molecules represent strong candidate biological and molecular targets for preventing disease progression, and further investigation is warranted. Copyright (c) 2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
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              Tumor lymphangiogenesis and metastasis to lymph nodes induced by cancer cell expression of podoplanin.

              The membrane glycoprotein podoplanin is expressed by several types of human cancers and might be associated with their malignant progression. Its exact biological function and molecular targets are unclear, however. Here, we assessed the relevance of tumor cell expression of podoplanin in cancer metastasis to lymph nodes, using a human MCF7 breast carcinoma xenograft model. We found that podoplanin expression promoted tumor cell motility in vitro and, unexpectedly, increased tumor lymphangiogenesis and metastasis to regional lymph nodes in vivo, without promoting primary tumor growth. Importantly, high cancer cell expression levels of podoplanin correlated with lymph node metastasis and reduced survival times in a large cohort of 252 oral squamous cell carcinoma patients. Based on comparative transcriptional profiling of tumor xenografts, we identified endothelin-1, villin-1, and tenascin-C as potential mediators of podoplanin-induced tumor lymphangiogenesis and metastasis. These unexpected findings identify a novel mechanism of tumor lymphangiogenesis and metastasis induced by cancer cell expression of podoplanin, suggesting that reagents designed to interfere with podoplanin function might be developed as therapeutics for patients with advanced cancer.
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                Author and article information

                Journal
                BMC Cancer
                BMC Cancer
                BioMed Central
                1471-2407
                2011
                3 June 2011
                : 11
                : 217
                Affiliations
                [1 ]Otorhinolaryngology, Head and Neck Surgery, University Hospital Zurich, Switzerland
                [2 ]Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland
                [3 ]Clinical Trials Center, Center for Clinical Research, University Hospital Zurich, Switzerland
                [4 ]Department of Radiation Oncology, University Hospital Zurich, Zurich, Switzerland
                [5 ]Department of Pathology, Kantonsspital St.Gallen, Switzerland
                [6 ]Otorhinolaryngology, Head and Neck Surgery, Kantonsspital St.Gallen, Switzerland
                Article
                1471-2407-11-217
                10.1186/1471-2407-11-217
                3128007
                21639893
                048c3178-4e6d-4a64-905f-c4274bf3ba49
                Copyright ©2011 Huber et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 29 August 2010
                : 3 June 2011
                Categories
                Research Article

                Oncology & Radiotherapy
                e-cadherin (ecad),sentinel node biopsy,head and neck squamous cell carcinoma (hnscc),oropharynx,immunohistochemistry,oral cavity

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