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      The Characteristics and Prognostic Effect of E-Cadherin Expression in Colorectal Signet Ring Cell Carcinoma

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          Abstract

          Purpose

          Signet ring cell carcinoma (SRCC) is rare. The aim of this study is to understand the clinicopathological features and identify the possible prognostic factors in colorectal SRCC.

          Methods

          Patients with SRCC who underwent primary lesion resection at Fudan University Shanghai Cancer Center from September 2008 to July 2014 were retrospectively analyzed. Patient’s gender, age, tumor location, depth of invasion, lymph node metastasis, synchronous distant metastasis, perineural invasion, lymphovascular invasion, and E-cadherin expression were studied with prognosis, and the correlation between E-cadherin expression and clinicopathological features were analyzed. All clinicopathological and molecular factors were put into multivariate analysis using Cox proportional hazards model for detecting independent prognostic factors.

          Results

          59 patients accounting for 0.89% of total colorectal cancer patients met the criteria and were enrolled in the study. The median survival time is 28.9 months, and the 3-year survival rate is 62.7%. SRCC were seen more common in young male patients. Advanced stage was more common in SRCC, 58 (98.3%) patients had T3/T4 lesions, 52 (88.1%) patients had lymph node metastasis, and 14 (23.7%) patients had distant metastasis. Distant metastases were seen more common in peritoneal cavity. Distant metastasis (HR = 4.194, 95% CI: 1.297–13.567), lymphovascular invasion (HR = 2.888, 95% CI: 1.115–7.483), and E-cadherin expression (HR = 0.272, 95% CI: 0.096–0.768) were independent predictors for survival.

          Conclusions

          SRCC is a rare subtype of colorectal cancer with poor prognosis. Distant metastasis, lymphovascular invasion, and E-cadherin expression can predict prognosis of colorectal SRCCs independently. More precise therapy and more close surveillance are needed for these patients.

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          Most cited references29

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          The cytoplasmic domain of the cell adhesion molecule uvomorulin associates with three independent proteins structurally related in different species.

          Uvomorulin belongs to the group of Ca2+-dependent cell adhesion molecules, which are integral membrane proteins with several structural features in common. In particular, the cytoplasmic part of these proteins is highly conserved in different species, suggesting a common biological function. To test this assumption we transfected a uvomorulin full-length cDNA into uvomorulin-negative mouse NIH 3T3 and L cells. Immunoprecipitations with anti-uvomorulin antibodies detected, in addition to uvomorulin, three independent proteins of 102, 88 and 80 kd which are of host origin and which form complexes with uvomorulin. Using cDNA constructs coding for uvomorulin with cytoplasmic or extracellular deletions it is shown that the 102, 88 and 80 kd proteins complex with the cytoplasmic domain of uvomorulin. Peptide pattern analysis revealed that these three proteins are identical in different mouse cells. When uvomorulin cDNA was introduced into cell lines from other species, such as human HeLa and avian fibroblasts, the expressed uvomorulin was also associated with endogenous 102, 88 and 80 kd proteins and, moreover, each of these proteins showed structural similarities to the respective mouse molecule. A panel of antibodies specific for known cytoplasmic proteins of mol. wts similar to those of the three proteins did not react with any of the described components. This suggests that the 102, 88 and 80 kd proteins constitute a new group of proteins for which we propose the nomenclature of catenin alpha, beta and gamma respectively. The characterization of these proteins provides a first molecular basis for a possible cytoplasmic anchorage of uvomorulin to the cytoskeleton.
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            Dissecting tumor cell invasion: epithelial cells acquire invasive properties after the loss of uvomorulin-mediated cell-cell adhesion

            The generation of invasiveness in transformed cells represents an essential step of tumor progression. We show here, first, that nontransformed Madin-Darby canine kidney (MDCK) epithelial cells acquire invasive properties when intercellular adhesion is specifically inhibited by the addition of antibodies against the cell adhesion molecule uvomorulin; the separated cells then invade collagen gels and embryonal heart tissue. Second, MDCK cells transformed with Harvey and Moloney sarcoma viruses are constitutively invasive, and they were found not to express uvomorulin at their cell surface. These data suggest that the loss of adhesive function of uvomorulin (which is identical to E-cadherin and homologous to L-CAM) is a critical step in the promotion of epithelial cells to a more malignant, i.e., invasive, phenotype. Similar modulation of intercellular adhesion might also occur during invasion of carcinoma cells in vivo.
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              Advanced Gastric Carcinoma with Signet Ring Cell Histology

              Background: Gastric signet ring cell carcinoma (SRC) is a histological type based on microscopic characteristics and not on biological behavior. This study compared the clinicopathological features and prognosis of advanced SRC with non-signet ring cell adenocarcinoma (NSRC) of the stomach. Methods: We reviewed the records of 4,759 consecutive patients diagnosed with advanced gastric adenocarcinoma who were resected surgically from 1987 to 2003. Of these, 662 patients (13.9%) had SRC and were compared with 4,097 patients with NSRC. Results: Significant differences were noted in tumor size, Borrmann type, depth of invasion, lymph node metastasis, peritoneal dissemination and TNM stage. The cumulative 5-year survival rate for advanced SRC was 42.4%, compared with 50.1% in NSRC (p = 0.009). Multivariate analysis showed that tumor size ≧5 cm, Borrmann III and IV, T3–4 invasion and SRC histology were independent risk factors for lymph node metastasis. Depth of invasion, lymph node metastasis, hepatic and peritoneal metastasis and surgical curability were significant factors affecting survival. SRC histology alone was not an independent prognostic factor. Conclusions: Advanced gastric SRC tends toward deeper tumor invasion and more lymph node and peritoneal metastasis than NSRC. Advanced gastric SRC had a worse prognosis than NSRC. Therefore, curative surgical operation with extended lymph node dissection is recommended.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                10 August 2016
                2016
                : 11
                : 8
                : e0160527
                Affiliations
                [1 ]Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
                [2 ]Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
                [3 ]Department of Endoscopy, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
                [4 ]Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China
                University of Navarra, SPAIN
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceived and designed the experiments: JP.

                • Performed the experiments: RW XM.

                • Analyzed the data: RW XM.

                • Contributed reagents/materials/analysis tools: RW XM.

                • Wrote the paper: RW XM YL YH DH SC JP.

                ‡ These authors joint co-authors on this work.

                Article
                PONE-D-16-17712
                10.1371/journal.pone.0160527
                4980044
                27509205
                d62c773a-6312-42b2-8e64-9cf0dc201d38
                © 2016 Wang et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 2 May 2016
                : 19 July 2016
                Page count
                Figures: 2, Tables: 3, Pages: 10
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81101806
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100003399, Science and Technology Commission of Shanghai Municipality;
                Award ID: 134119a8602
                Award Recipient :
                This study was supported by grants from the National Natural Science Foundation of China(No.81101806) and Science and Technology Commission of Shanghai Municipality(No.134119a8602).
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