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Wei J, Zhang Y, Liu Y, Wang A, Fan B, Fu T, Jia Z, He L, Ji K, Ji X, Wu X, Zhang J, Li Z, Zhang L, Bu Z, Ji J. Construction and Validation of a Risk-Scoring Model that Preoperatively Predicts Lymph Node Metastasis in Early Gastric Cancer Patients. Ann Surg Oncol 2021; 28:6665-6672. [PMID: 33783640 DOI: 10.1245/s10434-021-09867-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 03/04/2021] [Indexed: 12/19/2022]
Abstract
OBJECTIVE The aim of this study was to create a risk-scoring model to preoperatively predict the incidence of lymph node metastasis (LNM) in early gastric cancer (EGC) patients to guide treatment. METHODS To construct the risk-scoring model, we retrospectively analyzed a primary cohort of 548 EGC patients. Univariate analysis and logistic regression were performed. A risk-scoring model for predicting LNM in EGC patients was developed based on preoperative factors, and another cohort of 73 patients was then analyzed to validate the model. RESULTS In the primary cohort, LNM was pathologically confirmed in 72 (13.1%) patients. In the multivariate analysis, the presence of ulceration and tumor size on gastroscopy, undifferentiated histological type, and presence of enlarged lymph nodes on computed tomography or endoscopic ultrasonography were independent risk factors for LNM. A 17-point risk-scoring model was developed to predict LNM risk. The cut-off score of the model was 8, and the area under the receiver operating characteristic curve (AUC) of the model was 0.835 [95% confidence interval (CI) 0.784-0.886]. In the validation cohort, the AUC of the model was 0.829 (95% CI 0.699-0.959). CONCLUSIONS We developed and validated an effective 17-point risk-scoring model that could preoperatively predict LNM for EGC patients.
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Affiliation(s)
- Jingtao Wei
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Yinan Zhang
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Yiqiang Liu
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Anqiang Wang
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Biao Fan
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Tao Fu
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Ziyu Jia
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Liu He
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Ke Ji
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Xin Ji
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Xiaojiang Wu
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Ji Zhang
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Ziyu Li
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Lianhai Zhang
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Zhaode Bu
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China.
| | - Jiafu Ji
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China.
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González-Mariscal L, Miranda J, Gallego-Gutiérrez H, Cano-Cortina M, Amaya E. Relationship between apical junction proteins, gene expression and cancer. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2020; 1862:183278. [PMID: 32240623 DOI: 10.1016/j.bbamem.2020.183278] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 01/09/2020] [Accepted: 03/06/2020] [Indexed: 12/11/2022]
Abstract
The apical junctional complex (AJC) is a cell-cell adhesion system present at the upper portion of the lateral membrane of epithelial cells integrated by the tight junction (TJ) and the adherens junction (AJ). This complex is crucial to initiate and stabilize cell-cell adhesion, to regulate the paracellular transit of ions and molecules and to maintain cell polarity. Moreover, we now consider the AJC as a hub of signal transduction that regulates cell-cell adhesion, gene transcription and cell proliferation and differentiation. The molecular components of the AJC are multiple and diverse and depending on the cellular context some of the proteins in this complex act as tumor suppressors or as promoters of cell transformation, migration and metastasis outgrowth. Here, we describe these new roles played by TJ and AJ proteins and their potential use in cancer diagnostics and as targets for therapeutic intervention.
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Affiliation(s)
- Lorenza González-Mariscal
- Department of Physiology, Biophysics and Neuroscience, Center of Research and Advanced Studies (Cinvestav), Mexico City, Mexico.
| | - Jael Miranda
- Department of Physiology, Biophysics and Neuroscience, Center of Research and Advanced Studies (Cinvestav), Mexico City, Mexico
| | - Helios Gallego-Gutiérrez
- Department of Physiology, Biophysics and Neuroscience, Center of Research and Advanced Studies (Cinvestav), Mexico City, Mexico
| | - Misael Cano-Cortina
- Department of Physiology, Biophysics and Neuroscience, Center of Research and Advanced Studies (Cinvestav), Mexico City, Mexico
| | - Elida Amaya
- Department of Physiology, Biophysics and Neuroscience, Center of Research and Advanced Studies (Cinvestav), Mexico City, Mexico
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Eom BW, Won Ryu K, Man Yoon H, Kook MC. Predictive value of E-cadherin and EpCAM for detection of metastatic lymph node in early gastric cancer. Chin J Cancer Res 2020; 32:614-620. [PMID: 33223756 PMCID: PMC7666780 DOI: 10.21147/j.issn.1000-9604.2020.05.06] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Objective There has been a demand for a tumor-specific marker for metastatic lymph nodes in sentinel navigation surgery for gastric cancer. The aim of this study is to analyze protein expression in both primary tumors and metastatic lymph nodes in early gastric cancer patients. Methods We collected primary tumors and metastatic lymph nodes from 71 patients who underwent curative gastrectomy and pathologically diagnosed with T1N1 or T1N2 (8th Union for International Cancer Control 8th edition/American Joint Committee on Cancer staging system) gastric cancer. Immunohistochemistry was used to determine the expression of six cell membrane proteins, including carcinoembryonic antigen (CEA), E-cadherin, epithelial cell adhesion molecule (EpCAM), P-cadherin, CD44v6, and c-erbB2 in the patient samples. Results The expression of CEA, E-cadherin, EpCAM, P-cadherin, CD44v6 and c-erbB2 in the evaluable primary tumor samples was 75.4%, 97.1%, 100%, 89.9%, 11.1% and 7.2%, respectively. Among cases wherein both the primary tumor and metastatic lymph nodes were evaluable, double positivity (expression in both primary tumor and metastatic lymph nodes) was observed for CEA, E-cadherin, EpCAM, P-cadherin, CD44v6 and c-erbB2 in 53.2%, 97.9%, 98.1%, 76.6%, 0 and 6.8% of the cases, respectively. The proportion of metastatic lymph nodes positive for CEA, E-cadherin, EpCAM, P-cadherin, CD44v6 and c-erbB2 was 71.4%, 100%, 98.1%, 83.7%, 0, and 75%, respectively in primary tumors positive for the same markers. Conclusions E-cadherin and EpCAM had an overlap of 100% and 98.1% between the primary tumor and metastatic lymph nodes, respectively. Thus, E-cadherin and EpCAM are potential molecular markers to detect metastatic lymph nodes in patients with early gastric cancer.
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Affiliation(s)
- Bang Wool Eom
- Center for Gastric Cancer, National Cancer Center, Goyang-si 10408, Republic of Korea
| | - Keun Won Ryu
- Center for Gastric Cancer, National Cancer Center, Goyang-si 10408, Republic of Korea
| | - Hong Man Yoon
- Center for Gastric Cancer, National Cancer Center, Goyang-si 10408, Republic of Korea
| | - Myeong-Cherl Kook
- Center for Gastric Cancer, National Cancer Center, Goyang-si 10408, Republic of Korea
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Eom BW, Joo J, Park B, Jo MJ, Choi SH, Cho SJ, Ryu KW, Kim YW, Kook MC. Nomogram Incorporating CD44v6 and Clinicopathological Factors to Predict Lymph Node Metastasis for Early Gastric Cancer. PLoS One 2016; 11:e0159424. [PMID: 27482895 PMCID: PMC4970798 DOI: 10.1371/journal.pone.0159424] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 07/01/2016] [Indexed: 12/25/2022] Open
Abstract
Background Treatment strategy for early gastric cancer depends on the probability of lymph node metastasis. The aim of this study is to develop a nomogram predicting lymph node metastasis in early gastric cancer using clinicopathological factors and biomarkers. Methods A literature review was performed to identify biomarkers related to lymph node metastasis in gastric cancer. Seven markers were selected and immunohistochemistry was performed in 336 early gastric cancer tissues. Based on the multivariable analysis, a prediction model including clinicopatholgical factors and biomarkers was developed, and benefit of adding biomarkers was evaluated using the area under the receiver operating curve and net reclassification improvement. Functional study in gastric cancer cell line was performed to evaluate mechanism of biomarker. Results Of the seven biomarkers studied, α1 catenin and CD44v6 were significantly associated with lymph node metastasis. A conventional prediction model, including tumor size, histological type, lymphatic blood vessel invasion, and depth of invasion, was developed. Then, a new prediction model including both clinicopathological factors and CD44v6 was developed. Net reclassification improvement analysis revealed a significant improvement of predictive performance by the addition of CD44v6, and a similar result was shown in the internal validation using bootstrapping. Prediction nomograms were then constructed based on these models. In the functional study, CD44v6 was revealed to affect cell proliferation, migration and invasion. Conclusions Overexpression of CD44v6 was a significant predictor of lymph node metastasis in early gastric cancer. The prediction nomograms incorporating CD44v6 can be useful to determine treatment plans in patients with early gastric cancer.
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Affiliation(s)
- Bang Wool Eom
- Department of Medicine, Yonsei University Graduate School of Medicine, Seoul, Republic of Korea
- Gastric Cancer Branch, Research Institute & Hospital, National Cancer Center, Goyang, Gyeonggi-do, Republic of Korea
| | - Jungnam Joo
- Cancer Biostatistics Branch, Research Institute for National Cancer Control & evaluation, National Cancer Center, Goyang, Gyeonggi-do, Republic of Korea
| | - Boram Park
- Cancer Biostatistics Branch, Research Institute for National Cancer Control & evaluation, National Cancer Center, Goyang, Gyeonggi-do, Republic of Korea
| | - Min Jung Jo
- Gastric Cancer Branch, Research Institute & Hospital, National Cancer Center, Goyang, Gyeonggi-do, Republic of Korea
| | - Seung Ho Choi
- Department of Medicine, Yonsei University Graduate School of Medicine, Seoul, Republic of Korea
| | - Soo-Jeong Cho
- Gastric Cancer Branch, Research Institute & Hospital, National Cancer Center, Goyang, Gyeonggi-do, Republic of Korea
| | - Keun Won Ryu
- Gastric Cancer Branch, Research Institute & Hospital, National Cancer Center, Goyang, Gyeonggi-do, Republic of Korea
| | - Young-Woo Kim
- Gastric Cancer Branch, Research Institute & Hospital, National Cancer Center, Goyang, Gyeonggi-do, Republic of Korea
| | - Myeong-Cherl Kook
- Gastric Cancer Branch, Research Institute & Hospital, National Cancer Center, Goyang, Gyeonggi-do, Republic of Korea
- * E-mail:
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Zhao J, Shu P, Duan F, Wang X, Min L, Shen Z, Ruan Y, Qin J, Sun Y, Qin X. Loss of OLFM4 promotes tumor migration through inducing interleukin-8 expression and predicts lymph node metastasis in early gastric cancer. Oncogenesis 2016; 5:e234. [PMID: 27294866 PMCID: PMC4945743 DOI: 10.1038/oncsis.2016.42] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Revised: 01/15/2016] [Accepted: 05/11/2016] [Indexed: 12/26/2022] Open
Abstract
Endoscopic surgery is increasingly used for early gastric cancer (EGC) treatment worldwide, and lymph node metastasis remains the most important risk factor for endoscopic surgery in EGC patients. Olfactomedin 4 (OLFM4) is mainly expressed in the digestive system and upregulated in several types of tumors. However, the role of OLFM4 in EGC has not been explored. We evaluated OLFM4 expression by immunohistochemical staining in 105 patients with EGC who underwent gastrectomy. The clinicopathological factors and OLFM4 expression were co-analyzed to predict lymph node metastasis in EGC. The metastatic mechanism of OLFM4 in gastric cancer was also investigated. We found that OLFM4 was upregulated in EGC tumor sections, and relatively low expression of OLFM4 was observed in patients with lymph node metastasis. OLFM4 expression as well as tumor size and differentiation were identified as independent factors, which could be co-analyzed to generate a better model for predicting lymph node metastasis in EGC patients. In vitro studies revealed that knockdown of OLFM4 promoted the migration of gastric cancer cells through activating the NF-κB/interleukin-8 axis. Negative correlation between OLFM4 and interleukin-8 expression was also observed in EGC tumor samples. Our study implies that OLFM4 expression is a potential predictor of lymph node metastasis in EGC, and combing OLFM4 with tumor size and differentiation could better stratify EGC patients with different risks of lymph node metastasis.
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Affiliation(s)
- J Zhao
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - P Shu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - F Duan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.,Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - X Wang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - L Min
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Z Shen
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Y Ruan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - J Qin
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Y Sun
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - X Qin
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
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Wang YW, Zhu ML, Wang RF, Xue WJ, Zhu XR, Wang LF, Zheng LZ. Predictable factors for lymph node metastasis in early gastric cancer analysis of clinicopathologic factors and biological markers. Tumour Biol 2016; 37:8567-78. [PMID: 26733174 DOI: 10.1007/s13277-015-4721-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Accepted: 12/21/2015] [Indexed: 12/29/2022] Open
Abstract
Predicting lymph node metastasis (LNM) accurately is very important to decide treatment strategies preoperatively. The aim of this study was to explore risk factors that predict the presence of LNM in early gastric cancer (EGC). A total of 230 patients with EGC who underwent curative gastrectomy with lymph adenectomy at Xinhua Hospital from January 2006 to July 2014 were retrospectively reviewed. We studied the relationship between clinicopathological factors, biological markers (p53, ki67, nm23, vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), E-cadherin (E-cad), beta-catenin (b-catenin), glutathione S-transferase (GST), and topoisomerase II (Topo II)), and LNM of EGC patients by chi-square test and logistic regression analysis. Meta-analyses were further conducted to review the effects of the proteins (P53, ki67, E-cad, and b-catenin) on LNM in ECG patients. LNM was detected in 42 (18.3 %) of 230 patients. Incidences of LNM was distinct in different tumor size (p = 0.044), depth of submucosal invasion (p < 0.0001), and P53 overexpression (p = 0.004). Multivariate analysis further indentified that large tumor size (≥20 mm, odds ratio (OR) = 2.168, p = 0.041), submucosa (OR = 4.000, p = 0.0005), and P53 overexpression (OR = 3.010, p = 0.022) were independent risk factors of LNM in EGC patients. The meta-analysis revealed a significantly statistical association of P53, ki67, and b-catenin with an increased risk of LNM in EGC patients (P53, OR = 1.81, p = 0.017; ki67, OR = 2.53, p = 0.0003; b-catenin, OR = 0.53, p = 0.01). Tumor size (≥20 mm), the depth of invasion (submucosa), and P53 overexpression may be helpful predictors of LNM in EGC patients. Furthermore, the results of meta-analysis revealed that P53, ki67 overexpression, and abnormal expression of b-catenin may be associated with LNM in EGC. The results need further validation in single large studies.
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Affiliation(s)
- Yi-Wei Wang
- Department of Oncology, Xin Hua Hospital affiliated to Shanghai Jiaotong University School of Medicine, NO.1665, Kong Jiang Road, Shanghai, 200092, People's Republic of China
| | - Mei-Ling Zhu
- Department of Oncology, Xin Hua Hospital affiliated to Shanghai Jiaotong University School of Medicine, NO.1665, Kong Jiang Road, Shanghai, 200092, People's Republic of China
| | - Rui-Fen Wang
- Department of Pathology, Xin Hua Hospital affiliated to Shanghai Jiaotong University School of Medicine, NO.1665, Kong Jiang Road, Shanghai, 200092, People's Republic of China
| | - Wen-Ji Xue
- Department of Oncology, Xin Hua Hospital affiliated to Shanghai Jiaotong University School of Medicine, NO.1665, Kong Jiang Road, Shanghai, 200092, People's Republic of China
| | - Xue-Ru Zhu
- Department of Oncology, Xin Hua Hospital affiliated to Shanghai Jiaotong University School of Medicine, NO.1665, Kong Jiang Road, Shanghai, 200092, People's Republic of China
| | - Li-Feng Wang
- Department of Pathology, Xin Hua Hospital affiliated to Shanghai Jiaotong University School of Medicine, NO.1665, Kong Jiang Road, Shanghai, 200092, People's Republic of China.
| | - Lei-Zhen Zheng
- Department of Oncology, Xin Hua Hospital affiliated to Shanghai Jiaotong University School of Medicine, NO.1665, Kong Jiang Road, Shanghai, 200092, People's Republic of China.
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Kamikihara T, Ishigami S, Arigami T, Matsumoto M, Okumura H, Uchikado Y, Kita Y, Kurahara H, Kijima Y, Ueno S, Natsugoe S. Clinical implications of N-cadherin expression in gastric cancer. Pathol Int 2012; 62:161-6. [PMID: 22360503 DOI: 10.1111/j.1440-1827.2011.02774.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Neo-expression of N-cadherin in cancer cells is regarded as a significant event in tumor progression via epithelial-mesenchymal transition (EMT). No reports have detailed the clinical impact of N-cadherin expression in gastric cancer. We retrospectively examined the co-expression of N-cadherin and E-cadherin in human gastric carcinoma and analyzed the clinicopathological significance of N-cadherin expression. One hundred and forty-six gastric cancer patients who received curative gastrectomy were enrolled. E-cadherin and N-cadherin immunoreactivity in cancer tissue was evaluated by the avidin-biotin-peroxidase complex technique. The correlation between N-cadherin and E-cadherin expression and clinicopathological parameters were analyzed. N-cadherin-positive and -negative expression were found in 31 and 115 patients, respectively. N-cadherin expression positively correlated with hematogenous recurrence (P < 0.01) and negatively correlated with patients' postoperative outcomes (P < 0.05). Moreover, only in the E-cadherin-preserved group was prognostic significance found according to N-cadherin expression (P < 0.01). We could not show a significant relationship between N-cadherin expression and EMT in gastric cancer. However, neo N-cadherin expression significantly affected patient's survival in gastric cancer. Therefore, we concluded that neo N-cadherin expression may be a useful prognostic marker independent of E-cadherin expression.
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Affiliation(s)
- Takahito Kamikihara
- Digestive Surgery, Surgical Oncology, Kagoshima University School of Medicine, Kagoshima, Japan
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Predictable factors for lymph node metastasis in early gastric cancer-analysis of single institutional experience. J Gastrointest Surg 2011; 15:1783-8. [PMID: 21796460 DOI: 10.1007/s11605-011-1624-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2011] [Accepted: 07/12/2011] [Indexed: 01/31/2023]
Abstract
INTRODUCTION Prediction of lymph node metastasis in early gastric cancer (EGC) is very important to decide treatment strategies preoperatively. The aim of this study was to evaluate factors that predict the presence of lymph node metastasis and to identify the differences between mucosal and submucosal gastric cancers. METHODS A total of 376 patients with EGC who underwent gastrectomy from March 1999 through December 2007 were retrospectively identified. The clinopathological factors and biological markers (p53, Ki67) were analyzed. RESULTS The rate of lymph node metastasis was 9.6% (mucosal cancer 2.8%, submucosal cancer 18.4%). Tumor size, depth of invasion, macroscopic type, and lymphovascular invasion were related to lymph node metastasis in EGC. When the carcinomas were confined to the mucosal layer, tumor size and lymphovascular invasion showed significant correlation with lymph node metastasis. On the other side, macroscopic type and lymphovascular invasion were association with lymph node metastasis in submucosal carcinoma. CONCLUSION The risk factors for lymph node metastasis in EGC are quite different depending on depth of tumor invasion. To predict lymph node metastasis in EGC, it is recommended that distinct assessment according to individual situation should be clearly established.
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Gonçalves AR, Carneiro AJV, Martins I, de Faria PAS, Ferreira MA, de Mello ELR, Fogaça HS, Elia CCS, de Souza HSP. Prognostic significance of p53 protein expression in early gastric cancer. Pathol Oncol Res 2011; 17:349-355. [PMID: 21116760 DOI: 10.1007/s12253-010-9333-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2010] [Accepted: 10/28/2010] [Indexed: 01/11/2023]
Abstract
Mutations of the p53 tumor suppressor gene have been associated with abnormalities in cell cycle regulation, DNA repair and synthesis, apoptosis, and it has been implicated in the prognosis of advanced gastric cancer. The aim of this study was to evaluate the occurrence of p53 gene mutation and its possible prognostic implications in early gastric cancer. In a retrospective study, we studied 80 patients with early gastric cancer treated surgically between 1982 and 2001. Mutation of p53 gene was investigated in surgical gastric specimens by immunohistochemistry, and results were analyzed in relation to gender, age, macroscopic appearance, size and location of tumor, presence of lymph nodes, Lauren's histological type, degree of differentiation, and the 5-year survival. The expression of p53 was more frequent among the intestinal type (p = 0.003), the differentiated (p = 0.007), and the macroscopically elevated tumors (p = 0.038). Nevertheless, the isolated expression of p53 was not associated with the 5-year survival, or with the frequency of lymph node involvement. The degree of differentiation was detected as an independent factor related to the outcome of patients (0.044). Significantly shorter survival time was found in p53-negative compared with p53-positive patients, when considering the degree of differentiation of tumors, as assessed by Cox regression analysis (0.049). The association of p53 with the intestinal type, the degree of differentiation and morphological characteristics, may reflect the involvement of chronic inflammatory process underlying early gastric cancer. In this population sample, the expression of p53 alone has no prognostic value for early gastric cancer. However, the significant difference in p53 expression between subgroups of degree of differentiation of tumors can influence post-operative outcome of patients and may be related to possible distinct etiopathogenic subtypes.
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Affiliation(s)
- Andrea Rodrigues Gonçalves
- Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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10
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Chiba T, Kawachi H, Kawano T, Kumagai J, Kitagaki K, Sekine M, Uchida K, Kobayashi M, Sugihara K, Eishi Y. Independent histological risk factors for lymph node metastasis of superficial esophageal squamous cell carcinoma; implication of claudin-5 immunohistochemistry for expanding the indications of endoscopic resection. Dis Esophagus 2010; 23:398-407. [PMID: 19903192 DOI: 10.1111/j.1442-2050.2009.01023.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Endoscopic resection is curative for superficial esophageal squamous cell carcinoma (ESCC) limited to the lamina propria. Endoscopic resection is not recommended for superficial ESCC invading muscularis mucosa or submucosa, however, because of the high frequency of lymph node metastasis (LNM) in such patients. Methods to more accurately predict LNM by analysis of endoscopically resected specimens are needed. Patients with superficial ESCC who underwent surgery without prior chemoradiotherapy (n= 110) were retrospectively examined to determine whether LNM correlated with immunohistochemical parameters and conventional histological parameters, including depth of invasion and vascular permeation. Cancer cell expression of claudins-1, 5, and 7, E-cadherin, beta-catenin, and matrix metalloproteinase 7 was evaluated. Univariate analysis revealed that LNM correlated with claudin-5 expression, but not any other immunohistochemical parameter examined. Multivariate analysis revealed three independent risk factors for LNM: aberrant claudin-5 expression in cancer cells (odds ratio; OR [95% confidence interval]= 4.61[1.44-14.77]), depth of submucosal invasion greater than 200 microm (3.55 [1.02-13.17]), and positive lymphatic permeation (3.34 [1.22-9.15]). LNM was found in one of 29 (3.4%) patients with none of these three risk factors, and in 32 of 81 (39.5%) patients with one or more of these risk factors. In superficial ESCC, routine analysis of claudin-5 expression in cancer cells together with depth of invasion and lymphatic permeation may be useful for predicting LNM and thereby reducing the number of patients undergoing additional surgery after successful endoscopic resection.
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Affiliation(s)
- T Chiba
- Department of Human Pathology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
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Beronja S, Livshits G, Williams S, Fuchs E. Rapid functional dissection of genetic networks via tissue-specific transduction and RNAi in mouse embryos. Nat Med 2010; 16:821-7. [PMID: 20526348 DOI: 10.1038/nm.2167] [Citation(s) in RCA: 167] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2009] [Accepted: 01/15/2010] [Indexed: 12/13/2022]
Abstract
Using ultrasound-guided in utero infections of fluorescently traceable lentiviruses carrying RNAi or Cre recombinase into mouse embryos, we have demonstrated noninvasive, highly efficient selective transduction of surface epithelium, in which progenitors stably incorporate and propagate the desired genetic alterations. We achieved epidermal-specific infection using small generic promoters of existing lentiviral short hairpin RNA libraries, thus enabling rapid assessment of gene function as well as complex genetic interactions in skin morphogenesis and disease in vivo. We adapted this technology to devise a new quantitative method for ascertaining whether a gene confers a growth advantage or disadvantage in skin tumorigenesis. Using alpha1-catenin as a model, we uncover new insights into its role as a widely expressed tumor suppressor and reveal physiological interactions between Ctnna1 and the Hras1-Mapk3 and Trp53 gene pathways in regulating skin cell proliferation and apoptosis. Our study illustrates the strategy and its broad applicability for investigations of tissue morphogenesis, lineage specification and cancers.
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Affiliation(s)
- Slobodan Beronja
- Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, New York, USA
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Clinicopathological variables associated with lymph node metastasis in submucosal invasive gastric cancer. Gastric Cancer 2008; 10:241-50. [PMID: 18095080 DOI: 10.1007/s10120-007-0442-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2007] [Accepted: 11/06/2007] [Indexed: 02/07/2023]
Abstract
BACKGROUND We aimed to elucidate clinicopathological variables associated with lymph node metastasis of submucosal invasive gastric cancer. METHODS Specimens were surgically resected from 201 patients who had primary submucosal gastric cancer. We studied 39 consecutive patients with lymph node metastasis and 162 patients without lymph node metastasis. We compared the following clinicopathological characteristics of the patients in relation to lymph node metastasis: age, sex, tumor size, histology, extent of submucosal invasion, lymphatic and venous invasion, and ulceration of the tumor. Submucosal invasion was divided subjectively into sm1, sm2, and sm3 (representing invasion of the upper-, middle-, and lower-third of the submucosa, respectively). We also studied the relationship between lymph node metastasis of submucosal gastric cancer and immunohistochemistry for p53, Ki67, vascular endothelial growth factor (VEGF), alpha-fetoprotein, sLe(a), and dendritic cells (DCs). RESULTS In terms of conventional pathological factors, lymph node metastasis in submucosal gastric cancer was related to tumor size (P = 0.002), depth of submucosal invasion (P = 0.001), lymphatic invasion (P < 0.0001), and venous invasion (P = 0.012). Lymph node metastasis in sm1 gastric cancer was significantly related to VEGF expression (P = 0.047). Also, lymph node metastasis in sm3 gastric cancer was significantly correlated with DC expression (P = 0.016). Multivariate analysis showed that tumor size, tumor invasion depth in the submucosal layer, and lymphatic invasion were independent predictors of nodal metastasis in submucosal gastric cancer. CONCLUSION Conventional pathological factors, such as tumor size, depth of submucosal invasion, and lymphatic invasion, have a significant influence on lymph node metastasis. VEGF expression and DC expression may be helpful predictors of lymph node metastasis in patients with sm1 and sm3 gastric cancer, respectively.
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13
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Benjamin JM, Nelson WJ. Bench to bedside and back again: molecular mechanisms of alpha-catenin function and roles in tumorigenesis. Semin Cancer Biol 2007; 18:53-64. [PMID: 17945508 DOI: 10.1016/j.semcancer.2007.08.003] [Citation(s) in RCA: 90] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2007] [Accepted: 08/28/2007] [Indexed: 12/17/2022]
Abstract
The cadherin/catenin complex, comprised of E-cadherin, beta-catenin and alpha-catenin, is essential for initiating cell-cell adhesion, establishing cellular polarity and maintaining tissue organization. Disruption or loss of the cadherin/catenin complex is common in cancer. As the primary cell-cell adhesion protein in epithelial cells, E-cadherin has long been studied in cancer progression. Similarly, additional roles for beta-catenin in the Wnt signaling pathway has led to many studies of the role of beta-catenin in cancer. Alpha-catenin, in contrast, has received less attention. However, recent data demonstrate novel functions for alpha-catenin in regulating the actin cytoskeleton and cell-cell adhesion, which when perturbed could contribute to cancer progression. In this review, we use cancer data to evaluate molecular models of alpha-catenin function, from the canonical role of alpha-catenin in cell-cell adhesion to non-canonical roles identified following conditional alpha-catenin deletion. This analysis identifies alpha-catenin as a prognostic factor in cancer progression.
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Affiliation(s)
- Jacqueline M Benjamin
- Department of Biological Sciences, Stanford University, 318 Campus Drive, Stanford, CA 94305-5430, USA
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14
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Qualitative and quantitative studies of polygene proteins expression in esophageal precancerous lesions and esophageal carcinoma. Chin J Cancer Res 2007. [DOI: 10.1007/s11670-007-0100-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022] Open
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15
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Park SS, Kang SH, Park JM, Kim JH, Oh SC, Lee JH, Chae YS, Kim SJ, Kim CS, Mok YJ. Expression of liver-intestine cadherin and its correlation with lymph node metastasis in gastric cancer: can it predict N stage preoperatively? Ann Surg Oncol 2006; 14:94-9. [PMID: 17063305 DOI: 10.1245/s10434-006-9114-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2006] [Revised: 05/25/2006] [Accepted: 05/25/2006] [Indexed: 12/31/2022]
Abstract
BACKGROUND Reliable method to predict lymph node metastasis is not yet available. In the present study, therefore, we examined LI-cadherin expression in human gastric cancer and attempted to find its relationship with clinicopathologic data, especially with lymph node metastasis. We also analyzed the expression in preoperative biopsy specimen to uncover its possibility of prognostication for lymph node metastasis. METHODS The paired preoperative endoscopic biopsy and postoperative resected specimens from 208 patients who had surgically been treated for gastric cancer were retrospectively analyzed immunohistochemically for expression of LI-cadherin. RESULTS There were 47 (22.6%) and 161 (77.4%) tumors which had positive and negative LI-cadherin expression, respectively. LI-cadherin expression was significantly correlated with tumor histology and lymph node metastasis: Furthermore, reduced expression of LI-cadherin was closely associated with tumor progression and lymph node metastasis in human gastric carcinoma. LI-cadherin expressions in both resected tumor and preoperative endoscopic tissues were found to be independent factors associated with lymph node metastasis. CONCLUSIONS There is a close association between reduced expression of LI-cadherin and lymph node metastasis in human gastric cancer. Immunohistochemical study of LI-cadherin is relatively simple compared to sentinel node navigation surgery, and it could be a practical prediction method for lymph node metastasis in patients with this malignancy.
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Affiliation(s)
- Sung-Soo Park
- Department of Surgery, Korea University College of Medicine, Seoul, Korea.
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Liu YC, Shen CY, Wu HS, Hsieh TY, Chan DC, Chen CJ, Yu JC, Yu CP, Harn HJ, Chen PJ, Hsieh CB, Chen TW, Hsu HM. Mechanisms inactivating the gene for E-cadherin in sporadic gastric carcinomas. World J Gastroenterol 2006; 12:2168-73. [PMID: 16610016 PMCID: PMC4087641 DOI: 10.3748/wjg.v12.i14.2168] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the role of CDH1/E-cadherin (E-cad) gene alteration profiles including mutation, loss of heterozygosity (LOH), promoter polymorphism and hypermethylation in mechanisms of CDH1 inactivation in gastric carcinoma (GC).
METHODS: Specimens were collected surgically from 70 patients with GC. Allelotyping PCR and detection of LOH, denaturing high pressure liquid chromatography and DNA sequencing, restriction fragment length polymorphism analysis, methylation specific PCR, and immunohistochemical staining were used.
RESULTS: Promoter polymorphism was not a major mechanism of E-cad inactivation. Only one truncating mutation was found in a diffuse type tumor (3%). Both LOH and promoter hypermethylation were major mechanisms of E-cad inactivation, but interestingly, there was a negative association between the fraction of allelic loss (LOH) in tumors and hypermethylation of CDH1. Therefore LOH and hypermethylation were two different tumorigenic pathways involved in GC.
CONCLUSION: Given the findings that somatic mutation was extremely low and the relationship between LOH and hypermethylation was inverse, any two combinations of these three factors cannot fulfill the classical two-hit hypothesis of CDH1 inactivation. Thus, other mechanisms operating at the transcriptional level or at the post-translational level might be required to induce E-cadherin inactivation.
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Affiliation(s)
- Yao-Chi Liu
- Division of General Surgery, Tri-Service General Hospital, No. 325, Sec 2, Cheng-Kung Road, Taipei, Taiwan, China.
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17
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Matsubara S, Ozawa M. Expression of alpha-catenin in alpha-catenin-deficient cells results in a reduced proliferation in three-dimensional multicellular spheroids but not in two-dimensional monolayer cultures. Oncogene 2004; 23:2694-702. [PMID: 14755240 DOI: 10.1038/sj.onc.1207423] [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: 01/12/2023]
Abstract
alpha-Catenin is an intracellular protein that associates with the carboxy-terminal region of cadherin, a cell adhesion molecule, via beta-catenin or gamma-catenin (plakoglobin). Linkage of cadherin to the cytoskeleton by catenins is required for full cadherin activity. Following transfection of an alpha-catenin-deficient colon carcinoma cell line with a series of alpha-catenin constructs, we discovered that the restoration of alpha-catenin expression results in reduced proliferation in three-dimensional multicellular spheroids, but not in two-dimensional monolayer cultures. The cellular function of alpha-catenin has not been compared between cells in three- and two-dimensional culture; this is the first evidence that growth regulation in three-dimensional cultures requires signaling mediated by alpha-catenin. Two classes of constructs, containing deletions in either the central segment or the COOH terminus of the molecule, both induced morphological changes, including cell compaction, and suppressed cell growth in three-dimensional cultures. In alpha-catenin-expressing cells, inhibition of cadherin cell adhesion by treatment with anti-E-cadherin antibodies resulted in a similar phenotype as that observed following the loss of alpha-catenin. Therefore, both the homophilic interaction of the cadherin extracellular domain and the linkage of the cadherin cytoplasmic domain to the actin cytoskeleton by alpha-catenin are necessary for growth control in three-dimensional culture.
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Affiliation(s)
- Shyuichiro Matsubara
- Department of Biochemistry and Molecular Biology, Graduate School of Medical and Dental Science, Kagoshima University, Kagoshima 890-8544, Japan.
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18
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Song SY, Kim S, Kim DS, Son HJ, Rhee JC, Kim YI. Abnormal expression of E-cadherin in early gastric carcinoma: its relationship with macroscopic growth patterns and catenin alpha and beta. J Clin Gastroenterol 2004; 38:252-9. [PMID: 15128072 DOI: 10.1097/00004836-200403000-00011] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
BACKGROUND Abnormal expression of E-cadherin plays an important role in the differentiation and progression of gastric carcinoma. There are a few identifiable clinical, histopathologic, and molecular changes that are related with the macroscopic growth patterns of gastric carcinoma. The aim of this study is to elucidate the relation between the macroscopic growth patterns of gastric carcinoma and the abnormal expression of E-cadherin, alpha- and beta-catenins. STUDY A total of 97 cases of early gastric carcinoma were examined by immunohistochemistry using monoclonal antibodies against E-cadherin, alpha- and beta-catenins. Macroscopically, 52 cases were elevated types and 45 cases were depressed types. RESULTS Early gastric carcinomas with depressed growth showed diffuse histologic type, younger patients' age and smaller size more frequently than tumors with elevated growth. Abnormal expression rates of E-cadherin, alpha- and beta-catenins were 35.1, 36.1, and 46.4%, respectively. Abnormal expression of E-cadherin, alpha- and beta-catenins was significantly associated with depressed tumor growth and diffuse histologic type. By multiple logistic regression analysis. E-cadherin, age, Lauren classification, World Health Organization grade and size were identified as risk factors of macroscopic growth pattern of early gastric carcinomas. Positive associations between E-cadherin and beta-catenin and between alpha- and beta-catenins were found by log linear model analysis. CONCLUSION We suggest that E-cadherin plays an important role in the macroscopic growth as well as microscopic differentiation of early gastric carcinomas.
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Affiliation(s)
- Sang Yong Song
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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19
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Xu CP, Zhou YN, Chen Y. Relationship between abnormal expression of α-catenin and biological behaviors of gastric carcinoma. Shijie Huaren Xiaohua Zazhi 2003; 11:1275-1278. [DOI: 10.11569/wcjd.v11.i9.1275] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [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 assess the expression of α-catenin in gastric carcinoma and to determine its relation with tumor clinicopathological features and patient survival.
METHODS Immunohistochemical staining of α-catenin was performed for 163 cases of gastric carcinomas,44 cases of gastric dysplasia and 25 cases of intestinal metaplasia,and 28 cases of atrophic gastritis.
RESULTS Normal membranous staining was observed in intestinal metaplasia and control biopsy specimens for α-catenin. 76% of tumors and 43% of gastric dysplasia were stained abnormally for α-catenin. Only one of atrophic gastritis showed abnormal staining. Abnormal α-catenin expression occurred more significantly in Borrmann III/IV type than in Borrmann I/II type (P <0.01) A significantly higher proportion of signet-ring (91%), mucinous(79%) and tubular adenocarcinomas (78%) showed abnormal α-catenin expression compared with papillary adenocarcinomas (47%) (P <0.01) Morever, abnormal α-catenin staining occurred more frequently in diffuse type(95%, 38/40) than in intestinal type tumors (68%, 73/108) (P <0.01). No association was found between abnormal α-catenin and tumour invasive depth, lymph node metastasis and distance metastasis (P >0.05, respectively). A survival advantage was not noted in the tumors retaining normal staining of α-catenin.
CONCLUSION Abnormal expression of α-catenin occurs frequently in gastric carcinoma, and is closely related to its poor differentiation. Abnormal expression of α-catenin in gastric dysplasia may be an early event in tumorigenesis.
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Affiliation(s)
- Cai-Pu Xu
- Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Yong-Ning Zhou
- Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Yu Chen
- Institute of Burn Research, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
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Fenoglio-Preiser CM, Wang J, Stemmermann GN, Noffsinger A. TP53 and gastric carcinoma: a review. Hum Mutat 2003; 21:258-70. [PMID: 12619111 DOI: 10.1002/humu.10180] [Citation(s) in RCA: 163] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
In this article, we survey the major p53 (TP53) alterations identified in gastric carcinomas and their precursors. These include p53 expression, mutations, and loss of heterozygosity (LOH). Not only are the various abnormalities summarized, but in addition there is a survey of the literature with respect to the impact of these changes on patient prognosis and treatment response. The majority of published studies involve the immunohistochemical detection of the protein. These use different antibodies, different detection techniques, and different methods of interpretation. Therefore not surprisingly, the results of many of the studies are contradictory with one another. Overall, however, it appears that p53 alterations occur early in the development of gastric carcinoma, being present even in the nonneoplastic mucosa and they increase in frequency as one progresses along the pathway of gastric carcinoma development. p53 immunoreactivity is seen in 17%-90.7% of invasive gastric carcinomas. p53 alterations occur much more commonly in proximal lesions than in distal ones, suggesting that the molecular events leading to the development of gastric carcinoma may be very different in proximal vs. distal tumors. p53 mutations occur in 0%-77% of gastric carcinomas. The mutations are distributed widely across the gene from exons 4-11 with hot spots of mutation at codons 175, 248, 273, 282, 245, and 213. G:C>A:T transitions at CpG sites are the commonest type of mutation. At least 60% of carcinomas with mutations also exhibit p53 LOH.
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Affiliation(s)
- C M Fenoglio-Preiser
- Department of Pathology, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267-0529, USA.
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21
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Tanaka M, Kitajima Y, Sato S, Miyazaki K. Combined evaluation of mucin antigen and E-cadherin expression may help select patients with gastric cancer suitable for minimally invasive therapy. Br J Surg 2003; 90:95-101. [PMID: 12520583 DOI: 10.1002/bjs.4014] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
BACKGROUND MUC1 mucin is known to be highly expressed in carcinomas that show invasive growth and poor prognosis. Impairment of adhesion molecule E-cadherin expression has been widely accepted as a critical event for cancer invasion and metastasis. The present study evaluated the combination of mucin and E-cadherin status as a possible predictor of patients suitable for minimally invasive therapy for gastric cancer. METHODS Two hundred and nine paraffin-embedded specimens of gastric carcinoma (141 early, 68 advanced) were examined by immunohistochemical staining using monoclonal antibodies against MUC1 mucin (MUC-1-CORE, DF3), MUC2 mucin (Ccp58) and E-cadherin (anti-E-cad). RESULTS Gastric carcinoma with MUC1-positive expression demonstrated malignant characteristics. Normal E-cadherin expression showed an inverse correlation with MUC1 expression. Patients with early gastric carcinoma who had a combination of normal E-cadherin and MUC1-negative expression had no recurrence and a favourable prognosis. Moreover, cancers with normal E-cadherin/MUC1-negative expression were not found at an advanced stage in differentiated-type carcinoma. CONCLUSION A normal E-cadherin/MUC1-negative expression pattern in gastric cancer is a favourable marker. Preoperative estimation of the E-cadherin and MUC1 status of an endoscopic biopsy specimen may help select appropriate patients for minimally invasive treatment of gastric cancer.
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Affiliation(s)
- M Tanaka
- Department of Surgery, Saga Medical School, 5-1-1 Nabeshima, Saga, 849-8501, Japan.
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22
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Zhou YN, Xu CP, Han B, Li M, Qiao L, Fang DC, Yang JM. Expression of E-cadherin and β-catenin in gastric carcinoma and its correlation with the clinicopathological features and patient survival. World J Gastroenterol 2002; 8:987-93. [PMID: 12439911 PMCID: PMC4656404 DOI: 10.3748/wjg.v8.i6.987] [Citation(s) in RCA: 79] [Impact Index Per Article: 3.4] [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: The E-cadherin-catenin complex is important for cell-cell adhesion of epithelial cells. Impairment of one or more components of this complex is associated with poor differentiation and increased invasiveness of carcinomas. We evaluated the expression pattern of E-cadherin and β-catenin in gastric carcinoma and dysplasia and analyzed their relationship with tumor clinicopathological features and patient survival.
METHODS: Immunohistochemical staining of E-cadherin and β-catenin was performed from paraffin specimens of 163 gastric carcinomas, 44 gastric mucosal dysplasia, and 25 intestinal metaplasia, 28 atrophic gastritis and 12 healthy controls.
RESULTS: Normal membrane staining was observed in intestinal metaplasia, atrophic gastritis and control biopsy specimens for E-cadherin and β-catenin. 36% and 16% of gastric dysplasia were stained abnormally for E-cadherin and β-catenin respectively. Abnormal expression of E-cadherin and β-catenin was demonstrated in 46% and 44% of gastric carcinoma respectively. Abnormal expression of E-cadherin and β- catenin occurred more significantly in Borrmann III/IV than in Borrmann I/II type (P < 0.005, respectively). A significantly higher proportion of signet-ring, mucinous and tubular adenocarcinomas were abnormally expressed for E-cadherin and β-catenin as compared with papillary adenocarcinomas (χ2 = 8.47, P < 0.005, and χ2 = 7.05, P < 0.01, respectively). Morever, abnormal E-cadherin and β-catenin staining occurred more frequently in diffuse than in intestinal type of tumor (χ2 = 18.18 and 17.79, P < 0.005, respectively). There was a significant correlation between abnormal β-catenin expression and positive lymph node metastasis. A survival advantage was noted in tumors retaining normal membranous expression of β-catenin, independent of type, grade, or stage of the disease (P < 0.0005).
CONCLUSION: Abnormal expression of the E-cadherin-catenin complex occurs frequently in gatric carcinoma, closely related to its histogenesis. Abnormal expression of the E-cadherin- catenin complex in gastric dysplasia may be an early event in the tumorigenesis. The close correlation with poor survival suggests that abnormal β-catenin may be a useful prognostic marker.
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Affiliation(s)
- Yong-Ning Zhou
- Department of Gastroenterology, Southwest Hospital, the Third Millitary Medical University, Chongqing, 400038, China.
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Abstract
E-cadherin and its associated cytoplasmic proteins including alpha-, beta-, and gamma-catenin play a pivotal role in the maintenance of normal tissue architecture and the suppression of cancer invasion. The purpose of this study was to evaluate the expression of E-cadherin and alpha-, beta-, and gamma-catenin in a larger sample of early gastric cancer, and to examine the relation between these expressions and various clinicopathologic variables. The expression of E-cadherin and alpha-, beta-, and gamma-catenin was investigated using immunohistochemical technique with formalin-fixed, paraffin-embedded tissue specimens obtained from 108 patients who underwent surgery for early gastric cancer. In the gastric mucosa of noncancerous areas, epithelial cells showed equally strong membranous expression of E-cadherin and alpha-, beta-, and gamma-catenin proteins at the cell-cell boundaries. Reduced expression of E-cadherin and alpha-, beta-, and gamma-catenin was demonstrated in 43.5%, 39.8%, 42.6%, and 50% of cancer tissues, respectively. Whereas 34 tumors (31.5%) displayed preserved expression of all four E-cadherin-catenin complex components, 21 tumors (19.4%) displayed reduced expression of all components of this complex. Reduced expression of E-cadherin and alpha- and gamma-catenin occurred more frequently in diffuse than in intestinal types of cancer, and decreased expression of E-cadherin and alpha-, beta-, and gamma-catenin correlated with poor differentiation. The expression of E-cadherin and beta- and gamma-catenin did not correlate with the patient's age, gender, tumor size, location, macroscopic type, depth of invasion, or lymph node metastasis. Only reduced expression of alpha-catenin correlated with lymph node metastasis. Reduced expression of all four E-cadherin-catenin complex components correlated with poorly differentiated and diffuse-type cancers, but not with the patient's age, gender, tumor size, location, macroscopic type, depth of invasion, or lymph node metastasis. These results suggest that dysfunction of the E-cadherin-catenin complex occurs in an early stage of carcinogenesis, playing a crucial role in disruption of tissue architecture and loss of differentiation in early gastric cancer.
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Affiliation(s)
- Young-Eun Joo
- Department of Internal Medicine, Chonnam National University Medical School, Kwangju, Korea.
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24
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Xu H, el-Gewely MR. P53-responsive genes and the potential for cancer diagnostics and therapeutics development. BIOTECHNOLOGY ANNUAL REVIEW 2002; 7:131-64. [PMID: 11686042 DOI: 10.1016/s1387-2656(01)07035-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
P53 protein regulates cell responses to DNA damage to keep genomic stability by transactivation and trans-repression of its downstream target genes. P53 protein also has activators, inactivators, or co-factors via interaction with other proteins. Both the p53-regulated genes and interacted proteins form a huge network. As tumors usually escape from proliferating controls by means of accumulation of genetic alterations, p53 is one of the most important tumor suppressor genes that can be targeted for diagnosis, prognosis, and therapeutic intervention. Reviewing the p53-network is of great importance. In this review, we are focusing on cancer-related p53 downstream-regulated genes. Various methods dealing with the discovery of p53-regulated genes by the detection of gene expression have been applied. Recently high throughput functional genomics methods, such as DNA microarray, serial analysis of gene expression (SAGE), differential display, and protein two-dimensional gel electrophoresis, have provided a wealth of information on the dynamics of cell context responses. Hundreds of genes have been discovered whose transcriptions are regulated by p53 protein. They were grouped, based on their functions, into sub-classes including cell-cycle regulation, DNA repair, angiogenesis, metastasis, and multidrug resistance. P53 plays a pivotal role in keeping genomic stability and tumor suppression. The deeper we investigate the cell responses as mediated by p53, the more complex p53-network becomes. However, understanding p53-network, offers great opportunities to develop more sensitive and accurate diagnostic/prognostic tools, as well as more efficient therapies for cancer.
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Affiliation(s)
- H Xu
- Department of Biotechnology, Institute of Medical Biology, University of Tromsø, 9037 Tromsø, Norway
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Tanaka M, Kitajima Y, Edakuni G, Sato S, Miyazaki K. Abnormal expression of E-cadherin and beta-catenin may be a molecular marker of submucosal invasion and lymph node metastasis in early gastric cancer. Br J Surg 2002. [PMID: 11856141 DOI: 10.1046/j.1365-2168.2002.01985.x] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
BACKGROUND Impaired expression of E-cadherin and alpha- and beta-catenin is frequently observed in several human cancers. The aim of this study was to examine immunohistochemical expression of these adhesion molecules, focusing on early gastric carcinomas, and to investigate differences between differentiated and undifferentiated gastric cancer at the early phase of carcinogenesis. METHODS Immunohistochemical staining of E-cadherin and alpha- and beta-catenin was performed using specimens from 143 patients with early gastric cancer. RESULTS Abnormal E-cadherin and beta-catenin staining correlated with depth of tumour invasion in differentiated-type tumours. In contrast, abnormal staining was frequently found even in intramucosal carcinoma of undifferentiated-type tumours, suggesting an apparent difference in the onset of E-cadherin-catenin complex abnormality between the two cancer types. Absent staining of beta-catenin was associated with lymph node metastasis. Multivariate analysis revealed abnormal E-cadherin expression as an independent factor that correlated with submucosal invasion in early gastric cancer. CONCLUSION Abnormal E-cadherin expression is a possible marker of submucosal invasion in differentiated-type early gastric cancer and absent beta-catenin staining could be used as a predictor of lymph node metastasis in both types.
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Affiliation(s)
- M Tanaka
- Department of Surgery, Saga Medical School, 5-1-1 Nabeshima, Saga, 849-8501, Japan.
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26
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Ascaño JJ, Frierson H, Moskaluk CA, Harper JC, Roviello F, Jackson CE, El-Rifai W, Vindigni C, Tosi P, Powell SM. Inactivation of the E-cadherin gene in sporadic diffuse-type gastric cancer. Mod Pathol 2001; 14:942-9. [PMID: 11598162 DOI: 10.1038/modpathol.3880416] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Loss of the cell adhesion molecule E-cadherin has been observed in a variety of human carcinomas, and germline E-cadherin mutations have been found in several familial cases of diffuse gastric cancer. We sought to determine the prevalence and nature of E-cadherin alterations in "sporadic" gastric carcinomas. We performed comprehensive sequencing of the coding region, loss of heterozygosity (LOH) analysis, and immunohistochemical protein expression determination on 40 sporadic gastric adenocarcinomas. In total, 7 of 25 diffuse-type cancers harbored genetic alterations in the E-cadherin gene. Novel mutations predicted to significantly compromise protein function were found within 4 of these cancers, 2 of which harbored alterations resulting in biallelic inactivation of the gene product. Three diffuse cancers failed to amplify Exon 8 of E-cadherin, suggesting the presence of a homozygous abnormality. Notably, one germline E-cadherin mutation was also identified within these "sporadic" diffuse cancers. Significant gene mutations were not found in the 14 intestinal-type or histologically mixed cancer. Immunohistochemistry revealed aberrant or negative protein expression in seven diffuse-type tumors, four of which correlated with the genetic alterations. Both diffuse and intestinal-type tumors exhibited low rates of LOH, suggesting that allelic loss at the locus is not a common mechanism for E-cadherin inactivation during gastric tumorigenesis. Our observations suggest that inactivation of the E-cadherin gene occurs only in a subset of diffuse-type gastric cancers, as the majority of cases did not contain genetic alterations or identifiable protein abnormalities. Germline E-cadherin alterations, although rare, may underlie some diffuse gastric cancer cases that have important biologic and practical implications
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Affiliation(s)
- J J Ascaño
- Department of Medicine, University of Virginia Health System, Charlottesville, Virginia 22908, USA
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Zhao YL, Piao CQ, Hall EJ, Hei TK. Mechanisms of radiation-induced neoplastic transformation of human bronchial epithelial cells. Radiat Res 2001; 155:230-234. [PMID: 11121239 DOI: 10.1667/0033-7587(2001)155[0230:morint]2.0.co;2] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Carcinogenesis is a multistage process with sequences of genetic events that govern the phenotypic expression of a series of transformation steps that lead to the development of metastatic cancer. To better understand the mechanisms involved in human bronchial carcinogenesis induced by alpha particles from radon, we have developed a model of neoplastic transformation based on human papillomavirus-immortalized human bronchial epithelial (BEP2D) cells. Cells exposed to alpha particles become tumorigenic after progressing through a series of sequential stages including altered growth pattern, resistance to serum-induced terminal differentiation, agar-positive growth, tumorigenicity, and metastasis, with each step representing a necessary yet insufficient step toward the later, more malignant phase. Cell fusion studies indicated that the radiation-induced tumorigenic phenotype in BEP2D cells can be completely suppressed by fusion with nontumorigenic BEP2D cells. Several cellular differentiation and growth regulation genes such as DCC (deleted in colorectal cancer), CDKN1A (also known as p21(C1P1)) and the gene that encodes DNA-PK were frequently found to be modulated in tumorigenic BEP2D cells and may be related to the process of carcinogenesis.
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Affiliation(s)
- Y L Zhao
- Center for Radiological Research, College of Physicians & Surgeons of Columbia University, New York, New York 10032, USA
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Gao HJ, Yu LZ, Bai JF, Peng YS, Sun G, Zhao HL, Miu K, L XZ, Zhang XY, Zhao ZQ. Multiple genetic alterations and behavior of cellular biology in gastric cancer and other gastric mucosal lesions: H. pylori infection, histological types and staging. World J Gastroenterol 2000; 6:848-854. [PMID: 11819707 PMCID: PMC4728273 DOI: 10.3748/wjg.v6.i6.848] [Citation(s) in RCA: 46] [Impact Index Per Article: 1.8] [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 investigate the expression of multiple genes and the behavior of cellular biology in gastric cancer (GC) and other gastric mucosal lesions and their relations to Helicobacter pylori (H. pylori) infection, tumor staging and histological subtypes.
METHODS: Three hundred and twenty-seven specimens of gastric mucosa obtained via endoscopy or surgical resection, and ABC immunohistochemical staining were used to detect the expression of p53, p16, Bcl-2 and COX-2 proteins. H. pylori was determined by rapid urea test combined with pathological staining or 14C urea breath test. Cellular image analysis was performed in 66 patients with intestinal metaplasia (IM) and/or dysplasia (Dys). In 30 of them, both cancer and the paracancerous tissues were obtained at the time of surgery. Histological pattern, tumor staging, lymph node metastasis, grading of differentiation and other clinical data were studied in the medical records.
RESULTS: p16 expression of IM or Dys was significantly lower in positive H. pylori chronic atrophic gastritis (CAG) than those with negative H. pylori (CAG: 54.8% vs 88.0%, IM:34.4% vs 69.6%, Dys: 23.8% vs 53.6%, all P < 0.05), Bcl-2 or COX-2 expression of IM or Dys in positive H. pylori cases was significantly higher than that without H. pylori (Bcl-2: 68.8% vs 23.9%, 90.5% vs 60.7%; COX-2: 50.0% vs 10.8%, 61.8% vs 17.8%; all P < 0.05). The mean number of most parameters of cellular image analysis in positive H. pylori group was significantly higher than that in negative H. pylori group (Ellipser: 53 ± 14, 40 ± 12 μm, Area 1: 748 ± 572, 302 ± 202 μm2, Area-2: 3050 ± 1661, 1681 ± 1990 μm2, all P < 0.05; Ellipseb: 79 ± 23, 58 ± 15 μm, Ratio 1: 22% ± 5%, 13% ± 4%, Ratio-2: 79% ± 17%, 53% ± 20%, all P < 0.01). There was significant correlation between Bcl-2 and histologic pattern of gas tric carcinoma, and between COX-2 and tumor staging or lymph node metastasis (Bcl-2: 75.0% vs 16.7%; COX-2: 76.0% vs 20.0%, 79.2% vs 16.7%; all P < 0.05).
CONCLUSION: p16, Bcl-2, and COX-2 but not p53 gene may play a role in the early genesis/progression of gastric carcinoma and are associated with H. pylori infection. p53 gene is relatively late event in gastric tumorigenesis and mainly relates to its progression. There is more cellular-biological behavior of malignant tumor in gastric mucosal lesions with H. pylori infection. Aberrant Bcl-2 protein expression appears to be preferentially associated with the intestinal type cancer. COX-2 seems to be related to tumor staging and lymph node metastasis.
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