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Umar N, Alleyne L, Cheung D, Rees J, Trudgill C, Zanetto U, Muzaffar S, Trudgill N. Variation in proliferative and cell cycle markers in Barrett's esophagus in relation to circumferential and axial location in the esophagus. Eur J Gastroenterol Hepatol 2024; 36:306-312. [PMID: 38251437 DOI: 10.1097/meg.0000000000002700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2024]
Abstract
BACKGROUND Adenocarcinoma in Barrett's esophagus (BE) occurs more frequently between 12 and 3 o'clock at the gastroesophageal junction (GEJ). METHODS BE patients were prospectively recruited from December 2013 to July 2016. Expression of p53, Ki-67, cyclin-D1, COX-2 and p21 was assessed in quadrantic biopsies from the proximal and distal margins of the BE segments. Cell cycle marker association with current or subsequent dysplasia or adenocarcinoma was examined. RESULTS 110 patients: median age 64 (IQR, 56-71) years; median BE segment length C4M6; and a median follow-up of 4.7 (IQR, 3.6-5.7) years. In total 13 (11.8%) had evidence of dysplasia or neoplasia (2.7% indefinite for dysplasia, 5.5% low grade, 1.8% high grade and 1.8% adenocarcinoma) at index endoscopy. Six (7%) developed dysplasia or neoplasia (1 low grade, 2 high grade and 3 adenocarcinoma) during follow-up. Ki-67 expression was highest at 3 o'clock, and overall was 49.6% higher in the 12-6 o'clock position compared to 6-12 o'clock [odds ratio (OR), 1.42 (95% confidence interval (CI), 1.00-2.12)]. A similar pattern was found with p21 [1.82 (1.00-3.47)]. There was increased expression of several markers in distal BE biopsies; cyclin-D1 [1.74 (1.29-2.34)]; Cyclo-oxygenase 2 [2.03 (1.48-2.78]) and p21 [2.06 (1.16-3.68)]. Expression of Ki-67 was lower in distal compared to proximal biopsies [0.58 (0.43-0.78)]. P53 expression had high specificity (93.8%) for subsequent low-grade dysplasia, high-grade dysplasia or adenocarcinoma. CONCLUSION Increased cellular proliferation was seen at 12-6 o'clock at the GEJ. Cell-cycle marker expression was increased at the GEJ compared to the proximal BE segment. These findings mirror reflux esophagitis and suggest ongoing reflux contributes to the progression of dysplasia and malignancy in BE.
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Affiliation(s)
- Nosheen Umar
- Sandwell and West Birmingham NHS Trust, West Bromwich, UK
| | - Lance Alleyne
- Sandwell and West Birmingham NHS Trust, West Bromwich, UK
| | - Danny Cheung
- Worcestershire Acute Hospitals NHS Trust, Worcester, UK
| | - James Rees
- Worcestershire Acute Hospitals NHS Trust, Worcester, UK
| | | | | | | | - Nigel Trudgill
- Sandwell and West Birmingham NHS Trust, West Bromwich, UK
- Institute of Cancer and Genomic Sciences, University of Birmingham, UK
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Pateras IS, Igea A, Nikas IP, Leventakou D, Koufopoulos NI, Ieronimaki AI, Bergonzini A, Ryu HS, Chatzigeorgiou A, Frisan T, Kittas C, Panayiotides IG. Diagnostic Challenges during Inflammation and Cancer: Current Biomarkers and Future Perspectives in Navigating through the Minefield of Reactive versus Dysplastic and Cancerous Lesions in the Digestive System. Int J Mol Sci 2024; 25:1251. [PMID: 38279253 PMCID: PMC10816510 DOI: 10.3390/ijms25021251] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 01/12/2024] [Accepted: 01/16/2024] [Indexed: 01/28/2024] Open
Abstract
In the setting of pronounced inflammation, changes in the epithelium may overlap with neoplasia, often rendering it impossible to establish a diagnosis with certainty in daily clinical practice. Here, we discuss the underlying molecular mechanisms driving tissue response during persistent inflammatory signaling along with the potential association with cancer in the gastrointestinal tract, pancreas, extrahepatic bile ducts, and liver. We highlight the histopathological challenges encountered in the diagnosis of chronic inflammation in routine practice and pinpoint tissue-based biomarkers that could complement morphology to differentiate reactive from dysplastic or cancerous lesions. We refer to the advantages and limitations of existing biomarkers employing immunohistochemistry and point to promising new markers, including the generation of novel antibodies targeting mutant proteins, miRNAs, and array assays. Advancements in experimental models, including mouse and 3D models, have improved our understanding of tissue response. The integration of digital pathology along with artificial intelligence may also complement routine visual inspections. Navigating through tissue responses in various chronic inflammatory contexts will help us develop novel and reliable biomarkers that will improve diagnostic decisions and ultimately patient treatment.
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Affiliation(s)
- Ioannis S. Pateras
- 2nd Department of Pathology, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, 124 62 Athens, Greece; (D.L.); (N.I.K.); (A.I.I.); (I.G.P.)
| | - Ana Igea
- Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain;
- Mobile Genomes, Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela (USC), 15706 Santiago de Compostela, Spain
| | - Ilias P. Nikas
- Medical School, University of Cyprus, 2029 Nicosia, Cyprus
| | - Danai Leventakou
- 2nd Department of Pathology, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, 124 62 Athens, Greece; (D.L.); (N.I.K.); (A.I.I.); (I.G.P.)
| | - Nektarios I. Koufopoulos
- 2nd Department of Pathology, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, 124 62 Athens, Greece; (D.L.); (N.I.K.); (A.I.I.); (I.G.P.)
| | - Argyro Ioanna Ieronimaki
- 2nd Department of Pathology, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, 124 62 Athens, Greece; (D.L.); (N.I.K.); (A.I.I.); (I.G.P.)
| | - Anna Bergonzini
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Alfred Nobels Allé 8, 141 52 Stockholm, Sweden;
- Department of Molecular Biology and Umeå Centre for Microbial Research (UCMR), Umeå University, 901 87 Umeå, Sweden;
| | - Han Suk Ryu
- Department of Pathology, Seoul National University Hospital, Seoul 03080, Republic of Korea;
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 115 27 Athens, Greece;
| | - Teresa Frisan
- Department of Molecular Biology and Umeå Centre for Microbial Research (UCMR), Umeå University, 901 87 Umeå, Sweden;
| | - Christos Kittas
- Department of Histopathology, Biomedicine Group of Health Company, 156 26 Athens, Greece;
| | - Ioannis G. Panayiotides
- 2nd Department of Pathology, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, 124 62 Athens, Greece; (D.L.); (N.I.K.); (A.I.I.); (I.G.P.)
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Her-2 Expression in Gastroesophageal Intestinal Metaplasia, Dysplasia, and Adenocarcinoma. Appl Immunohistochem Mol Morphol 2017; 24:633-638. [PMID: 26186253 PMCID: PMC7771552 DOI: 10.1097/pai.0000000000000243] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Overexpression of human epidermal growth factor receptor 2 protein (Her-2) in Barrett neoplasia is significant for targeted therapy with trastuzumab. Here, we studied the frequency of Her-2 overexpression in Barrett adenocarcinoma and precursor lesions. Retrospective formalin-fixed paraffin-embedded tissue samples of 25 normal (NM) esophageal mucosa, 50 Barrett esophagus (BE) without dysplasia, 49 BE with low-grade dysplasia (LGD), 50 BE with high-grade dysplasia (HGD), and 50 invasive adenocarcinoma (ICA) were used. A BE tissue microarray was built and analyzed by Her-2 immunohistochemistry (IHC) and Her-2 dual in situ hybridization (DISH). Her-2 IHC expression was negative in NM and low in 26% of BE (IHC score: 1+) and in 24.5% of LGD (IHC score: 1 to 2+). Her-2 overexpression was seen in 28% of HGD and in 24% of ICA (IHC score: 2 to 3+). Her-2 DISH was negative in NM and BE but positive in 6% of LGD, 20% of HGD, and 18% of ICA. Differences in Her-2 DISH positivity between NM and HGD or ICA were statistically significant (P = 0.02), but those between NM and LGD or HGD and ICA were not (P = 0.2). Although Her-2 overexpression results in ICA were similar to previous reports, the finding of 28% in HGD was unexpected and may have clinical implications. Positive Her-2 DISH in 6% of LGD is novel, suggesting a role of Her-2 during BE progression.
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Abstract
BACKGROUND Patients with Barrett esophagus (BE) are predisposed to developing dysplasia and cancer. Adenocarcinoma, which is associated with BE, is the most common type of esophageal tumor and, typically, it has an aggressive clinical course and a high rate of mortality. METHODS The English-language literature relating to tumor epidemiology, etiology, and the pathogenesis of BE was reviewed and summarized. RESULTS The role of pathologists in the diagnosis and pitfalls associated with grading Barrett dysplasia is addressed. Current molecular testing for Barrett neoplasia, as well as testing methods currently in development, is discussed, focusing on relevant tests for diagnosing tumor types, determining prognosis, and assessing therapeutic response. CONCLUSIONS Grading is essential for developing appropriate treatment plans, follow-up visits, and therapeutic interventions for each patient. Familiarity with current molecular testing methods will help physicians correctly diagnose the disease and select the most appropriate therapy for each of their patients.
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Affiliation(s)
- Sherma Zibadi
- Department of Anatomic Pathology, Moffitt Cancer Center, Tampa, FL 33612, USA.
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Sharma P, Sharma R. miRNA-mRNA crosstalk in esophageal cancer: From diagnosis to therapy. Crit Rev Oncol Hematol 2015; 96:449-62. [PMID: 26257289 DOI: 10.1016/j.critrevonc.2015.07.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Revised: 04/11/2015] [Accepted: 07/07/2015] [Indexed: 12/11/2022] Open
Abstract
The asymptomatic nature of esophageal cancer (EC) at early stages results in late clinical presentation leading to poor prognosis and limited success of therapeutic modalities. Efforts to identify diagnostic/prognostic markers have proven to be unsuccessful for translation into clinics. Hence, there is a pressing need for establishment of novel non-invasive biomarker for early diagnosis/better prognosis of EC. Recently, alteration in microRNA (miRNA) expression has emerged as an important hallmark of cancer. This review summarizes the differential expression of miRNAs in EC and addresses how their aberrant expression influences crucial biological processes such as apoptosis, cell proliferation, invasion and metastasis. Additionally, this review highlights the current status of circulating miRNA based diagnostic/prognostic markers. An effort has been made to find a connection between different miRNAs involved in EC and a detailed analysis has been done to screen out micoRNAs involved in prognosis and multidrug resistance. Further, investigation of these miRNAs would not only provide a gene therapy based strategy to prevent/treat cancer but also to reverse multidrug resistance leading to decreased requirement of harmful chemotherapeutic drugs.
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Affiliation(s)
- Priyanka Sharma
- Research Scholar, University School of Biotechnology, Guru Gobind Singh Indraprastha University, New Delhi 110078, India.
| | - Rinu Sharma
- Assistant Professor, University School of Biotechnology, Guru Gobind Singh Indraprastha University, Sector 16C Dwarka, New Delhi 110078, India.
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Goda K, Dobashi A, Yoshimura N, Chiba M, Fukuda A, Nakao Y, Ohya TR, Sasaki Y, Kato M, Aihara H, Sumiyama K, Toyoizumi H, Kato T, Tajiri H, Ikegami M. Clinicopathological features of narrow-band imaging endoscopy and immunohistochemistry in ultraminute esophageal squamous neoplasms. Dis Esophagus 2014; 27:267-75. [PMID: 23796261 DOI: 10.1111/dote.12090] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
To reveal clinicopathological features of narrow-band imaging (NBI) endoscopy and immunohistochemistry in ultraminute esophageal squamous neoplasms. If a lesion diameter was smaller or same compared with a width of closed biopsy forceps, a lesion was defined to be an ultraminute lesion. Twenty-five consecutive patients with 33 ultraminute esophageal lesions that were removed by endoscopic mucosal resection were included in the present study. We conducted two questionnaire surveys of six endoscopists by their retrospective review of endoscopic still images. The six endoscopists evaluated the endoscopic findings of the ultraminute lesions on still images taken by conventional white-light imaging endoscopy and non-magnified NBI endoscopy in the first questionnaire, and taken by magnified NBI endoscopy in the second questionnaire. An experienced pathologist who was unaware of any endoscopic findings made histological diagnosis and evaluated immunoexpression of p53 and Ki67. The 33 ultraminute lesions were all determined to be either 11 high-grade intraepithelial neoplasias (HGIENs) or 22 low-grade intraepithelial neoplasias (LGIENs). The tumor diameters were histologically confirmed to be <3 mm. All of the ultraminute tumors were visualized as unstained areas and brownish areas by real-time endoscopy with Lugol dye staining and non-magnified NBI endoscopy, respectively. All of the ultraminute IENs were visualized as brownish areas by real-time non-magnified NBI endoscopy. Three of the 25 patients with the ultraminute IENs (12%) had multiple brownish areas (more than several areas) in the esophagus on real-time non-magnified NBI endoscopy. All of the ultraminute IENs were visualized as unstained areas by real-time Lugol chromoendoscopy. Twenty of the 25 patients (80%) had multiple unstained areas (more than several areas) in the esophagus on real-time Lugol chromoendoscopy. The first questionnaire survey revealed that a significantly higher detection rate of the ultraminute IENs on non-magnified NBI endoscopy images compared with conventional white-light imaging endoscopy ones (100% vs. 72%, respectively: P < 0.0001). The second questionnaire survey revealed that presence rates of any magnified NBI endoscopy findings were not significantly different between HGIENs and LGIENs. Proliferation, dilation, and various shapes of intrapapillary capillary loops indicated remarkably high presence rates of more than 90% in both HGIENs and LGIENs. Six of 22 LGIENs (27%) and 3 of 11 HGIENs (27%) show a positive expression for p53. None of peri-IEN epithelia was positive for p53. A mean of Ki67 labeling index of LGIENs was 33% and that of HGIENs 36%. Ki67 labeling index was significantly greater in the LGIENs and HGIENs compared with that in the peri-IEN epithelia. There were no significant differences in p53 expression and Ki67 labeling index between the HGIENs and LGIENs. Non-magnified/magnified NBI endoscopy could facilitate visualization and characterization of ultraminute esophageal squamous IENs. The ultraminute HGIENs and LGIENs might have comparable features of magnified NBI endoscopy and immunohistochemistry.
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Affiliation(s)
- K Goda
- Department of Endoscopy, The Jikei University School of Medicine, Tokyo, Japan
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γ-Glutamylcyclotransferase as a novel immunohistochemical biomarker for the malignancy of esophageal squamous tumors. Hum Pathol 2014; 45:331-41. [DOI: 10.1016/j.humpath.2013.09.009] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2013] [Revised: 09/18/2013] [Accepted: 09/20/2013] [Indexed: 11/20/2022]
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Kastelein F, Biermann K, Steyerberg EW, Verheij J, Kalisvaart M, Looijenga LHJ, Stoop HA, Walter L, Kuipers EJ, Spaander MCW, Bruno MJ. Aberrant p53 protein expression is associated with an increased risk of neoplastic progression in patients with Barrett's oesophagus. Gut 2013; 62:1676-83. [PMID: 23256952 DOI: 10.1136/gutjnl-2012-303594] [Citation(s) in RCA: 152] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
OBJECTIVE The value of surveillance for patients with Barrett's oesophagus (BO) is under discussion given the overall low incidence of neoplastic progression and lack of discriminative tests for risk stratification. Histological diagnosis of low-grade dysplasia (LGD) is the only accepted predictor for progression to date, but has a low predictive value. The aim of this study was therefore to evaluate the value of p53 immunohistochemistry for predicting neoplastic progression in patients with BO. DESIGN We conducted a case-control study within a prospective cohort of 720 patients with BO. Patients who developed high-grade dysplasia (HGD) or oesophageal adenocarcinoma (OAC) were classified as cases and patients without neoplastic progression were classified as controls. P53 protein expression was determined by immunohistochemistry in more than 12 000 biopsies from 635 patients and was scored independently by two expert pathologists who were blinded to long-term outcome. RESULTS During follow-up, 49 (8%) patients developed HGD or OAC. P53 overexpression was associated with an increased risk of neoplastic progression in patients with BO after adjusting for age, gender, Barrett length and oesophagitis (adjusted relative risks (RR(a)) 5.6; 95% CI 3.1 to 10.3), but the risk was even higher with loss of p53 expression (RR(a) 14.0; 95% CI 5.3 to 37.2). The positive predictive value for neoplastic progression increased from 15% with histological diagnosis of LGD to 33% with LGD and concurrent aberrant p53 expression. CONCLUSIONS Aberrant p53 protein expression is associated with an increased risk of neoplastic progression in patients with BO and appears to be a more powerful predictor of neoplastic progression than histological diagnosis of LGD.
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Affiliation(s)
- Florine Kastelein
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, , Rotterdam, The Netherlands
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Xu Q, Ma P, Hu C, Chen L, Xue L, Wang Z, Liu M, Zhu H, Xu N, Lu N. Overexpression of the DEC1 protein induces senescence in vitro and is related to better survival in esophageal squamous cell carcinoma. PLoS One 2012; 7:e41862. [PMID: 22844531 PMCID: PMC3402465 DOI: 10.1371/journal.pone.0041862] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2012] [Accepted: 06/26/2012] [Indexed: 11/23/2022] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is a leading cause of cancer-related death in China and has limited effective therapeutic options except for early surgery, since the underlying molecular mechanism driving its precursor lesions towards invasive ESCC is not fully understood. Cellular senescence is the state of the permanent growth arrest of a cell, and is considered as the initial barrier of tumor development. Human differentiated embryo chondrocyte expressed gene 1 (Dec1) is an important transcription factor that related to senescence. In this study, DEC1 immunohistochemical analysis was performed on tissue microarray blocks constructed from ESCC combined with adjacent precursor tissues of 241 patients. Compared with normal epithelia, DEC1 expression was significantly increased in intraepithelial neoplasia and DEC1 expression was significantly decreased in ESCC in comparison with intraepithelial neoplasia. In vitro, DEC1 overexpression induced cellular senescence, and it inhibited cell growth and colony formation in ESCC cell line EC9706. Fresh esophagectomy tissue sections from five ESCC patients were detected by immunohistochemistry of DEC1 and senescence-associated β-galactosidase (SA-β-Gal) activity, and strongly positive expression of DEC1 was correlated to more senescent cells in these fresh tissue sections. Kaplan – Meier method analysis of the 241 patients revealed that DEC1 expression levels were significantly correlated with the survival of ESCC patients after surgery. The expression levels of DEC1 were also correlated with age, tumor embolus, depth of invasion of ESCC, lymph metastasis status and pTNMs. These results suggest that DEC1 overexpression in precursor lesions of ESCC is a protective mechanism by inducing cellular senescence in ESCC initiation, and DEC1 may be a potential prognostic marker of ESCC.
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Affiliation(s)
- Qing Xu
- Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Peiqing Ma
- Department of Pathology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chenfei Hu
- Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lechuang Chen
- Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Liyan Xue
- Department of Pathology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zaozao Wang
- Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Mei Liu
- Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hongxia Zhu
- Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ningzhi Xu
- Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- * E-mail: (NX); (NL)
| | - Ning Lu
- Department of Pathology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- * E-mail: (NX); (NL)
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Çoban Ş, Örmeci N, Savaş B, Ekiz F, Ensari A, Kuzu I, Palabıyıkoğlu M. Evaluation of Barrett's esophagus with CK7, CK20, p53, Ki67, and COX2 expressions using chromoendoscopical examination. Dis Esophagus 2012; 26:189-96. [PMID: 22591041 DOI: 10.1111/j.1442-2050.2012.01352.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Barrett's esophagus (BE) is a complication of chronic gastroesophageal reflux disease and can be diagnosed when there is an endoscopically irregular Z-line and intestinal metaplasia (IM) in a biopsy obtained lower esophagus. It is still not clear whether IM in the gastric cardia or columnar mucosa without IM in the lower esophagus have any significance as BE, which is considered as preneoplastic. The aim of the study was to determine the immunohistochemical features of BE and columnar mucosa in the distal esophagus and also to evaluate the value of chromoendoscopy in the diagnosis of BE in a prospective manner. A total of 12 chromoendoscopic biopsies (six from normal-looking unstained esophagus and six from esophageal mucosa stained with methyl blue suspicious of BE) were taken from 111 cases who underwent endoscopy because of a variety of upper gastrointestinal symptoms. Immunohistochemical analysis was performed using CK7, CK20, p53, Ki67, and cyclooxygenase 2 (COX2). Of the 111 cases, 19 cases with carcinoma (nine adeno, six squamous, four undifferentiated carcinomas) and 17 cases with normal squamous epithelium were excluded, while 75 cases showing columnar epithelium, including 46 (61.3%) with IM and 29 (38,7%) without IM, were further evaluated immunohistochemically. CK7 was observed in surface, crypt, and glandular epithelium, whereas CK20 was expressed in surface and superficial crypt epithelium. No significant difference was observed between the Barrett and non-Barrett type of CK7/20 staining pattern (P > 0,05). Expression of p53 did not show any difference between BE and columnar mucosa without IM, whereas COX2 expression was significantly increased in BE (P < 0.05) in comparison with columnar mucosa without IM. Ki67 expression was significiantly higher both in upper and lower crypts in BE (P < 0.05). The present study showed that a Barrett pattern does not seem to exist; however, the analysis of COX2 expression and the Ki67 proliferation fraction by immunohistochemistry can be used to separate BE from non-Barrett's metaplasia of the distal esophagus. In our point of view, the immunohistochemical detection of p53 expression in Barrett's metaplasia stage is useless as a marker for early detection of high-risk patients.
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Affiliation(s)
- Ş Çoban
- Department of Gastroenterology, Diskapi Yildirim Beyazit Education and Research Hospital, Ankara, Turkey.
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Overexpression of microRNA-223 regulates the ubiquitin ligase FBXW7 in oesophageal squamous cell carcinoma. Br J Cancer 2011; 106:182-8. [PMID: 22108521 PMCID: PMC3251856 DOI: 10.1038/bjc.2011.509] [Citation(s) in RCA: 114] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Background: F-box and WD repeat domain-containing 7 (FBXW7) is a cell cycle regulatory gene whose protein product ubiquitinates positive cell cycle regulators such as c-Myc, cyclin E, and c-Jun, thereby acting as a tumour-suppressor gene. This study focused on microRNA-223 (miR-223), which is a candidate regulator of FBXW7 mRNA. The aim of this study was to clarify the clinical significance of miR-223 and FBXW7 in oesophageal squamous cell carcinoma (ESCC) patients, and to elucidate the mechanism by which FBXW7 is regulated by miR-223. Methods: The expression levels of miR-223 and the expression of FBXW7 protein was examined using 109 resected specimens to determine the clinicopathological significance. We also investigated the role of miR-223 in the regulation of FBXW7 expression in ESCC cell lines in an in vitro analysis. Results: We found that miR-223 expression was significantly higher in cancerous tissues than in the corresponding normal tissues. There was a significant inverse relationship between the expression levels of miR-223 and FBXW7 protein. Moreover, patients with high miR-223 expression demonstrated a significantly poorer prognosis than those with low expression. On the basis of a series of gain-of-function and loss-of-function studies in vitro, we identified FBXW7 as a functional downstream target of miR-223. Conclusion: Our present study indicates that high expression of miR-223 had a significant adverse impact on the survival of ESCC patients through repression of the function of FBXW7.
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Sinicrope FA, Broaddus R, Joshi N, Gerner E, Half E, Kirsch I, Lewin J, Morlan B, Hong WK. Evaluation of difluoromethylornithine for the chemoprevention of Barrett's esophagus and mucosal dysplasia. Cancer Prev Res (Phila) 2011; 4:829-39. [PMID: 21636549 DOI: 10.1158/1940-6207.capr-10-0243] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Patients with Barrett's esophagus (BE) and dysplasia are candidates for chemopreventive strategies to reduce cancer risk. We determined the effects of difluoromethylornithine (DMFO) on mucosal polyamines, gene expression, and histopathology in BE. Ten patients with BE and low-grade dysplasia participated in a single-arm study of DFMO (0.5 g/m(2)/d) given continuously for 6 months. Esophagoscopy with biopsies was conducted at baseline, 3, 6, and 12 months. Dysplasia was graded by a gastrointestinal pathologist. Audiology was assessed (at baseline and at 6 months). Mucosal polyamines were measured by high-performance liquid chromatography. Microarray-based gene expression was analyzed using a cDNA two-color chip. DFMO suppressed levels of the polyamines putrescine (P = 0.02) and spermidine (P = 0.02) and the spermidine/spermine ratio (P < 0.01) in dysplastic BE (6 months vs. baseline) that persisted at 6 months following drug cessation. Among the top 25 modulated genes, we found those regulating p53-mediated cell signaling (RPL11), cell-cycle regulation (cyclin E2), and cell adhesion and invasion (Plexin1). DFMO downregulated Krüppel-like factor 5 (KLF5), a transcription factor promoting cell proliferation, and suppressed RFC5 whose protein interacts with proliferating cell nuclear antigen. Histopathology showed regression of dysplasia (n = 1), stable disease (n = 8), and progression to high-grade dysplasia (n = 1). Polyamines were suppressed in the responder to a greater extent than in stable cases. DFMO was well tolerated, and one patient had subclinical, unilateral ototoxicity. DFMO suppressed mucosal polyamines and modulated genes that may be mechanistically related to its chemopreventive effect. Further study of DFMO for the chemoprevention of esophageal cancer in BE patients is warranted.
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Immunohistochemical overexpression of the p53 protein and Ki-67 (MIB-1) antigen in patients with GERD and chronic esophagitis. Appl Immunohistochem Mol Morphol 2010; 18:236-43. [PMID: 20414055 DOI: 10.1097/pai.0b013e3181c49134] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND STUDY AIMS Patients with gastroesophageal reflux disease and Barrett esophagus have an increased risk of developing adenocarcinoma of the esophagus. It is uncertain whether molecular or proliferative alterations are present in the early stages of disease. METHODS One hundred thirty-eight patients with gastroesophageal reflux disease symptoms were subjected to upper gastrointestinal endoscopy with biopsies of the esophageal mucosa. p53 protein expression and the Ki-67 proliferation index were determined by immunohistochemical studies. Patients were divided into 4 groups according to histopathologic diagnosis: G1, normal epithelium (n=58); G2, mild esophagitis (n=42); G3, moderate esophagitis (n=23), and G4, severe esophagitis (n=15). RESULTS p53 overexpression was detected in 7% of G1, 21.4% of G2, 52.2% of G3, and 60% of G4 patients. There were significant differences between G1 and G3 or G4 (P<0.001) and between G2 and G4 (P<0.05). The Ki-67 index was 21.3+/-19.5% in G1, 30.8+/-23.4% in G2, 47.1+/-23.2% in G3, and 48.3+/-25.7% in G4. Significant differences in the Ki-67 index were found between groups: G1 x G3 (P<0.001), G1 x G4 (P<0.001), G2 x G3 (P=0.026), and G2 x G4 (P=0.046). p53 and Ki-67 overexpression were correlated with the severity of esophagitis (P<0.001). CONCLUSIONS p53 overexpression and the Ki-67 (MIB-1) index were correlated with histologic findings of inflammation in the esophageal mucosa, particularly in the moderate and severe forms of chronic esophagitis.
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Aneuploidy and overexpression of Ki67 and p53 as markers for neoplastic progression in Barrett's esophagus: a case-control study. Am J Gastroenterol 2009; 104:2673-80. [PMID: 19638963 DOI: 10.1038/ajg.2009.437] [Citation(s) in RCA: 120] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
OBJECTIVES Surveillance of patients with Barrett's esophagus (BE) aims at early detection and treatment of neoplastic changes, particularly esophageal adenocarcinoma (EAC). The histological evaluation of biopsy samples has its limitations, and biomarkers may improve early identification of BE patients at risk for progression to EAC. The aim of this study was to determine the predictive value of p53, Ki67, and aneuploidy as markers of neoplastic progression in BE. METHODS A total of 27 BE patients with histologically proven progression to high-grade dysplasia (HGD) or EAC (cases) and 27 BE patients without progression (controls) were selected and matched for age, gender, and duration of follow-up. Dysplasia grade was determined in 212 biopsy samples obtained during surveillance endoscopies from cases and in 231 biopsy samples collected from controls. DNA ploidy status was determined by flow cytometry, whereas Ki67 and p53 expression was determined by immunohistochemistry. Hazard ratios (HRs) were calculated by Cox regression adjusted for potentially confounding variables. RESULTS A univariate analysis showed that low-grade dysplasia (LGD) increased the risk of developing HGD/EAC compared with no dysplasia (HR 3.6; 95% confidence interval (CI): 1.6 - 8.1). Aneuploidy (HR 3.5; 95% CI: 1.3-9.4), strong Ki67 overexpression (HR 5.2; 95% CI: 1.5-17.6), and moderate p53 overexpression (HR 6.5; 95% CI: 2.5-17.1) were also associated with an increased risk of developing HGD/EAC, independent of the histological result. A multivariable analysis showed that in the presence of LGD, p53 overexpression, and to a lesser extent, Ki67 overexpression remained important risk factors for neoplastic progression, whereas aneuploidy was no longer predictive. CONCLUSIONS p53 overexpression and, to a lesser extent, Ki67 overexpression could predict neoplastic progression in BE irrespective of the histological result. These markers may be useful for identifying patients at an increased risk of developing EAC, either alone or used as a panel.
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Delgado JS, Mustafi R, Yee J, Cerda S, Chumsangsri A, Dougherty U, Lichtenstein L, Fichera A, Bissonnette M. Sorafenib triggers antiproliferative and pro-apoptotic signals in human esophageal adenocarcinoma cells. Dig Dis Sci 2008; 53:3055-64. [PMID: 18512153 DOI: 10.1007/s10620-008-0294-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2008] [Accepted: 04/10/2008] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND PURPOSE Current therapies offer scant benefit to patients with advanced esophageal adenocarcinoma. We investigated the effects of Sorafenib, a multifunctional kinase inhibitor, on several growth regulatory pathways that control cell growth and survival in SEG-1 cells derived from Barrett's adenocarcinoma. METHODS SEG-1 cells were exposed to acidified medium or taurocholic acid, with and without pre-incubation with Sorafenib. Cyclin D1 and E, c-Myc, and Bcl-2 expression levels as well as STAT3 activations were determined by Western blotting. Cyclin D1 mRNA was measured by real-time PCR. Apoptosis was assessed by TUNEL assay. RESULTS Sorafenib significantly inhibited SEG-1 cell proliferation stimulated by acid or bile acid treatments and reduced cell survival. This drug significantly reduced the up-regulations of cyclin D1, cyclin E, c-Myc, and Bcl-2 as well as the activation of STAT3 in SEG-1 cells. CONCLUSIONS These results support a rational basis for future clinical studies to assess the therapeutic benefit of Sorafenib in esophageal adenocarcinoma.
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Affiliation(s)
- Jorge-Shmuel Delgado
- Section of Gastroenterology, Department of Medicine, The University of Chicago Medical Center, MC 4076. 5841 S. Maryland Ave, Chicago, IL, 60637, USA.
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Martinez J, Palomino J, Samaniego R, Sepulveda JM, Cabello A, Ricoy JR. Retinoblastoma (Rb) tumor‐suppressor pathway alterations in meningeal hemangiopericytomas: High E2F transcription factor 1 expression and loss of Rb expression. Cancer 2008; 113:166-74. [DOI: 10.1002/cncr.23532] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Mizoguchi Y, Ogawa K, Futakuchi M, Takahashi S, Hirose M, Shirai T. Differences in Expression Patterns of Cell Cycle Regulators after Cessation of Genotoxic and Non-genotoxic Carcinogen Treatment in the Rat Forestomach. J Toxicol Pathol 2008. [DOI: 10.1293/tox.21.77] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Affiliation(s)
- Yasumoto Mizoguchi
- Department of Experimental Pathology and Tumor Biology Nagoya City University Graduate School of Medical Sciences
| | - Kumiko Ogawa
- Department of Experimental Pathology and Tumor Biology Nagoya City University Graduate School of Medical Sciences
| | - Mitsuru Futakuchi
- Department of Experimental Pathology and Tumor Biology Nagoya City University Graduate School of Medical Sciences
| | - Satoru Takahashi
- Department of Experimental Pathology and Tumor Biology Nagoya City University Graduate School of Medical Sciences
| | - Masao Hirose
- Department of Experimental Pathology and Tumor Biology Nagoya City University Graduate School of Medical Sciences
- Food Safety Commission, Cabinet Office Government of Japan
| | - Tomoyuki Shirai
- Department of Experimental Pathology and Tumor Biology Nagoya City University Graduate School of Medical Sciences
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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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Zhang H, Jin Y, Chen X, Jin C, Law S, Tsao SW, Kwong YL. Papillomavirus type 16 E6/E7 and human telomerase reverse transcriptase in esophageal cell immortalization and early transformation. Cancer Lett 2006; 245:184-94. [PMID: 16488074 DOI: 10.1016/j.canlet.2006.01.005] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2005] [Revised: 01/09/2006] [Accepted: 01/09/2006] [Indexed: 12/20/2022]
Abstract
Infection with high-risk human papillomavirus (HPV) has been implicated in the pathogenesis of esophageal squamous cell carcinoma, and up-regulation of telomerase in esophageal adenocarcinoma. We immortalized normal esophageal epithelial cells by over-expression of the HPV16 E6/E7 and human telomerase reverse transcriptase (hTERT) genes. HPV16 E6/E7-induced immortalization was accompanied by reduced RB and p53, but increased p16 and p21, protein expression. hTERT-immortalized cells had unaffected RB and p53, but significantly decreased p16 and p21, protein expression. Aurora-A protein was also up-regulated in E6E7 immortalized cells, and to a less extent in hTERT immortalized cells. Fluorescence in situ hybridization showed that the Aurora-A gene locus was amplified in E6E7 immortalized cells, which might account in part for the Aurora-A over-expression. These molecular changes led to an abrogation of the G2 checkpoint. E6E7 and hTERT immortalized esophageal cells recapitulated many of the molecular changes observed in esophageal carcinomas, where RB and p53 are frequently down-regulated. However, down-regulation of p16 and p21 occurred frequently in esophageal cancer, owing to aberrant gene promoter methylation. We showed in the immortalized cells that aberrant methylation had not yet set in, suggesting that promoter methylation might not be necessary for cellular immortalization. In addition to supporting the role of HPV and telomerase in esophageal carcinogenesis, our cell lines may also be useful in vitro models for further studies of esophageal carcinogenesis.
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Affiliation(s)
- Hao Zhang
- Department of Medicine, University of Hong Kong, Professorial Block, Queen Mary Hospital, Pokfulam Road, Hong Kong, China
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Chang MS, Lee HS, Lee BL, Kim YT, Lee JS, Kim WH. Differential protein expression between esophageal squamous cell carcinoma and dysplasia, and prognostic significance of protein markers. Pathol Res Pract 2005; 201:417-25. [PMID: 16136747 DOI: 10.1016/j.prp.2005.04.005] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
The aim of the current study was to evaluate the protein expression involved in the progression from dysplasia to invasive esophageal squamous cell carcinomas and to analyze the prognostic value of markers. Immunohistochemistry was performed for cell cycle regulators [p53, p21, p27, p16, cyclin D1, Rb], apoptosis-related proteins [Fas, Fas-L, FADD, TRAIL, DR4, DR5, caspase-8, caspase-3, bcl-2, Bax], tumor suppressor proteins [beta-catenin, E-cadherin, FHIT, Smad 4, VHL, PTEN, KAI-1], and oncoproteins [c-myc, COX-2, EGFR]. Caspase-3, TRAIL, Fas-L, Fas, Smad 4, VHL, E-cadherin, and EGFR revealed significant differences between dysplasia and their corresponding invasive cancer portion in 25 cases. In a total of 118 cases of invasive cancer, proteins with frequent (> or = 60% of the cases) alterations were p53 (overexpression in 64% of SCCs), p27 (loss in 91%), p16 (loss in 81%), and FHIT (loss in 75%). Early clinical stage and bcl-2 immunopositivity were related to the survival rate of patients. In conclusion, caspase-3, TRAIL, Fas-L, Fas, Smad 4, VHL, E-cadherin, and EGFR may be involved in the progression from dysplasia to invasive esophageal SCCs. Clinical stage and bcl-2 are independent prognostic factors throughout the multivariate analysis.
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Affiliation(s)
- Mee Soo Chang
- Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea
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Dong B, Xie YQ, Chen K, Wang T, Tang W, You WC, Li JY. Differences in biological features of gastric dysplasia, indefinite dysplasia, reactive hyperplasia and discriminant analysis of these lesions. World J Gastroenterol 2005; 11:3595-600. [PMID: 15962383 PMCID: PMC4315969 DOI: 10.3748/wjg.v11.i23.3595] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [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 investigate the differences in biological features of gastric dysplasia (Dys), indefinite dysplasia (IDys) and reactive hyperplasia (RH) by studying the biomarker alterations in cell proliferation, cell differentiation, cell cycle control and the expression of house-keeping genes, and further to search for markers which could be used in guiding the pathological diagnosis of three lesions.
METHODS: Expressions of MUC5AC, MUC6, adenomatous polyposis coli (APC), p53, Ki-67, proliferation cell nuclear antigen (PCNA) and EGFR were studied by immunohistochemistry with a standard Envision technique in formalin-fixed and paraffin-embedded specimens from 43 RH, 35 IDys, 35 Dys and 36 intestinal type gastric carcinomas (IGC). In addition, Bayes discriminant analysis was used to investigate the value of markers studied in differential diagnosis of RH, IDys, Dys and IGC.
RESULTS: The MUC5AC and MUC6 antigen expressions in RH, IDys, Dys and IGC decreased gradually (MUC5AC: 86.04%, 77.14%, 28.57%, 6.67%; MUC6: 65.15%, 54.29%, 20.00%, 25.00%, respectively). The expressions of the two markers had no significant difference between RH and IDys, but were all significantly higher than those of the other two lesions (MUC5AC: χ2 = 27.607, 38.027 and 17.33, 26.092; MUC6: χ2 = 16.54, 12.665 and 9.282, 6.737, P<0.01). There was no significant difference between RH and IDys, Dys and IGC in MUC6 expression. The APC gene expression in the four lesions had a similar decreasing tendency (RH 69.76%, IDys 68.57%, Dys 39.39%, IGC 22.86%), and it was significantly higher in the first two lesions than in the last two (χ2 = 7.011, 16.995 and 14.737, 19.817, P<0.05). The p53 expression in RH, IDys, Dys and IGC was 6.98%, 20%, 57.14% and 50%, respectively. There was no significant difference between RH and IDys or Dys and IGC, but the p53 expression in RH and IDys was significantly lower than that in Dys and IGC (χ2 = 7.011, 16.995 and 14.737, 19.817, P<0.01). The Ki-67 label index was significantly different among four lesions (RH: 0.298±8.92%, IDys: 0.358±9.25%, Dys: 0.498±9.03%, IGC: 0.620±10.8%, P<0.001). Positive immunostaining of PCNA was though observed in all specimens, significant differences were detected among four lesions (F = 95.318, P<0.01). In addition, we used Bayes discriminant analysis to investigate molecular pathological classification of the lesions, and obtained the best result with the combination of MUC5AC, Ki-67 and PCNA. The overall rate of correct classification was 67.4% (RH), 68.6% (IDys), 70.6% (Dys) and 84.8% (IGC), respectively.
CONCLUSION: Dys has neoplastic biological characteristics, while RH and IDys display hyperplastic characteristics. MUC5AC and proliferation-related biomarkers (Ki-67, PCNA) are more specific in distinguishing Dys from RH and IDys.
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Affiliation(s)
- Bin Dong
- Department of Pathology, Peking University School of Oncology, Beijing Institute for Cancer Research, Beijing Cancer Hospital, Beijing 100036, China
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Bahnassy AA, Zekri ARN, Abdallah S, El-Shehaby AMR, Sherif GM. Human papillomavirus infection in Egyptian esophageal carcinoma: correlation with p53, p21, mdm2, C-erbB2 and impact on survival. Pathol Int 2005; 55:53-62. [PMID: 15693850 DOI: 10.1111/j.1440-1827.2005.01804.x] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The etiological role of human papillomavirus (HPV) in esophageal carcinoma (EC) in relation to p53, mdm2, p21(waf), c-erbB2 and the overall survival (OS) rate was investigated. Tumor and normal tissues from 50 EC were evaluated by polymerase chain reaction and InnoLiPA for HPV. Single strand conformation polymorphism/sequencing were used to detect p53 gene mutations. Immunohistochemistry was performed to determine p53, mdm2, p21(waf)and c-erbB2 expression. Human papillomavirus was detected in 54% of tumors and in 24% of normal tissues. p53, mdm2 and c-erbB2 overexpression was detected in 68%, 70% and 60% of tumors and in 14%, 16% and 10% of normal samples, whereas loss of p21(waf) was evident in 64% of tumors. p53 mutations were detected in 20% of cases. Exon 8 and 5 showed the highest mutation rate (40% each), followed by exons 6 and 7 (10% each). There was a significant correlation between HPV and p53, mdm2, c-erbB2 overexpression. The OS was significantly associated with overexpression of p53 and loss of p21(waf). Human papillomavirus infection is frequent in Egyptian EC. Both p53-dependent and p53-independent pathways seem to be involved in HPV-associated EC. mdm2 and c-erbB2 are possible targets for HPV in the p53-independent pathway. However, only advanced stage and aberrant expression of p53 and p21(waf) are independent prognostic markers.
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Affiliation(s)
- Abeer A Bahnassy
- Department of Pathology, National Cancer Institute, Kaser El-Aini School of Medicine, Cairo University, Fom El-Khalig, Cairo 11796, Egypt
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Huang JX, Yan W, Song ZX, Qian RY, Chen P, Salminen E, Toppari J. Relationship between proliferative activity of cancer cells and clinicopathological factors in patients with esophageal squamous cell carcinoma. World J Gastroenterol 2005; 11:2956-9. [PMID: 15902736 PMCID: PMC4305667 DOI: 10.3748/wjg.v11.i19.2956] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [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 assess whether the molecular markers of malignant tumors could improve the understanding of tumor charact-eristics, and to observe the characteristics of expression of cell cycle markers Ki-67 and cyclin A in esophageal carcinoma and to analyze the relationship between proliferative activity of cancer cells and clinicopathological factors.
METHODS: Seventy of surgically resected esophageal squamous cell carcinoma (SCC) were examined by immun-ohistochemistry utilizing commercially available antibodies. Nuclear staining was regarded as a positive result. At least 50 fields in each tumor and non-tumor section were evaluated at a medium power (×200) to determine the proportion of tumor cells and the staining intensity of nuclei in the entire sections.
RESULTS: Ki-67 and cyclin A were only expressed in base cells of normal esophageal mucosa. The positive immuno-staining of nuclei of SCC was significantly higher than that in normal esophageal mucosa (t = 13.32 and t = 7.52, respectively, P<0.01). The distribution of positively stained was more diffuse and stronger in poorly differentiated SCC. Both Ki-67 and cyclin A expressions were related to histological grades of tumors (t = 3.5675 and t = 3.916; t = 2.13, respectively, P<0.05) but not to the sex and age of the patients, tumor size, lymphatic invasion, location, or stage grouping.
CONCLUSION: The proliferative activity of cancer cells may be understood by immunohistochemistry of Ki-67 and cyclin A in Chinese patients with esophageal SCC. These cell cycle markers may serve as an indicator of cancer cell proliferation rate. The overexpression of cell cycle markers Ki-67 and cyclin A suggests the poor SCC differentiation in patients with esophageal carcinoma.
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Affiliation(s)
- Jun-Xing Huang
- Department of Oncology and Pathology, The People's Hospital of Taizhou, Taizhou 225300, Jiangsu Province, China.
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Merola E, Claudio PP, Giordano A. p53 and the malignant progression of Barrett's esophagus. J Cell Physiol 2005; 206:574-7. [PMID: 16110481 DOI: 10.1002/jcp.20475] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Barrett's esophagus (BE) is a metaplastic disorder in which specialized columnar epithelium replaces healthy squamous epithelium (intestinal metaplasia). Even though its pathophysiology and the steps of its neoplastic progression are not completely understood, BE can be considered as a complication of gastroesophageal reflux disease (GERD). Given that esophageal adenocarcinoma, which is continually increasing in the Western world, still has a poor prognosis and suffers from late diagnosis, and because BE is a precancerous lesion, there is a strong need for good molecular markers of malignant progression in Barrett's metaplasia (BM). The aim of this review is to examine the published data regarding the role that assessment of p53 may play in the management of BE, trying to understand if it may be a useful marker to early diagnose BE malignant transformation.
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Affiliation(s)
- Elettra Merola
- Sbarro Institute for Cancer Research and Molecular Medicine, Department of Biology, Temple University, Center for Biotechnology, Philadelphia 19122-6099, USA
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Tsuda H, Bandera CA, Birrer MJ, Hashiguchi Y, Berkowitz RS, Mok SC. Cyclin E Amplification and Overexpression in Clear Cell Adenocarcinoma of the Ovary. Oncology 2004; 67:291-9. [PMID: 15557791 DOI: 10.1159/000081330] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2004] [Accepted: 03/11/2004] [Indexed: 11/19/2022]
Abstract
OBJECTIVE The purpose of this study is to compare DNA, mRNA and protein levels of the cyclin E between clear cell (CC) and serous (SC) ovarian carcinomas, and evaluate the relationship between cyclin E and p53 status. METHOD We examined the DNA, mRNA and protein levels of cyclin E and the protein level of p53 in 44 CCs and 39 SCs using microdissected tissues. RESULTS Relative cyclin E mRNA expression was significantly higher in CC (3.62, 95% CI, 2.24-4.99) than in SC (1.75, 95% CI, 1.05-2.45; p = 0.0098). The percentage of positive nuclear staining of cyclin E was significantly higher in CC (48.3, 95% CI, 40.4-56.1) than SC (25.3, 95% CI, 17.4-33.3; p = 0.0001). The mRNA and protein expression of cyclin E was significantly correlated (r = 0.66, p < 0.0001). However, the correlation between relative DNA copy number and relative mRNA expression was not significant (r = -0.063; p = 0.66). Percentage of positive nuclear staining of cyclin E was significantly higher in p53 positive cases (51.8, 95% CI, 40.0-63.5) than p53 negative cases (36.2, 95% CI, 28.2-44.2; p = 0.028). CONCLUSIONS Cyclin E expression is significantly higher in CC than in SC. Cyclin E expression is significantly related with p53 positivity.
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Affiliation(s)
- Hiroshi Tsuda
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
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Zuo LF, Lin PZ, Qi FY, Guo JW, Liu JH. Flow cytometric analysis of DNA, telomerase content and multi-gene expression in esophageal epithelial dysplasia. World J Gastroenterol 2003; 9:2409-12. [PMID: 14606066 PMCID: PMC4656511 DOI: 10.3748/wjg.v9.i11.2409] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [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 investigate the alteration of molecular events and the early carcinogenesis mechanism of esophageal epithelial cells in the high incidence area of esophageal cancer.
METHODS: Esophageal epithelial cells of esophageal cancer patients were collected from the high incidence area in China. Content of DNA and telomerase as well as multi-gene expressions such as p53, p21 and cyclin D1 in esophageal precancer cells were quantitatively analysed by flow cytometry (FCM) with indirect immunofluorescence technique and DNA propidium iodide fluorescence staining.
RESULTS: FCM analysis results showed the DNA content increased significantly and the heteroploid rate was 87.9% in occurred carcinogenesis. P53 protein accumulation and ras p21 increase were seen in the early carcinogenesis of the esophagus. The positive rate of p53 and ras p21 was 100% (5/5, 4/4 respectively) in the cancer group. Telomerase and oncogene cyclin D1 were over- expressed in all of the cancer patients.
CONCLUSION: Increased DNA content and heteroploid rate, accumulation of p53 protein, and over-expression of p21, telomerase and cyclin D1 proteins were early molecular events during the development of esophageal cancer.
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Affiliation(s)
- Lian-Fu Zuo
- Hebei Provincial Tumor Institute, Shijiazhuang 050011, Hebei Province, China.
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Xing Y, Ning Y, Ru LQ, Wang LD. Expressions of PCNA, p53, p21 WAF-1 and cell proliferation in fetal esophageal epithelia: Comparative study with adult esophageal lesions from subjects at high-incidence area for esophageal cancer in Henan, North China. World J Gastroenterol 2003; 9:1601-3. [PMID: 12854173 PMCID: PMC4615514 DOI: 10.3748/wjg.v9.i7.1601] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [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 characterize the expression of p53, p21WAF-1 and proliferation-cell-nuclear-antigen (PCNA) in fetal esophageal epithelia and to determine the role of these genes in proliferation of fetal and adult esophageal epithelial cells.
METHODS: Immunohistochemical avdin-biotin peroxidase complex (ABC) method was applied to 31 cases of fetal esophageal specimens and 194 cases of adult esophageal specimens to detect the expression of p53, p21WAF-1 and PCNA in fetal and adult esophageal epithelia.
RESULTS: Both the PCNA positive immunostaining cell number and PCNA positive immunostaining rate in fetal esophageal epithelia (506 ± 239) were significantly higher than those in adults, including normal epithelia (200 ± 113) and epithelia with basal cell hyperplasia (BCH) (286 ± 150) (P < 0.05, t test). However, the number of PCNA positive immunostaining cells in adult esophageal dysplasia (719 ± 389) and squamous cell carcinoma(SCC) (1261 ± 545) was apparently higher than that in fetal esophageal epithelia (506 ± 239) (P < 0.05, t test). The positive immunostaining rate of P53 was 10% (3/31) in fetal esophageal epithelia, which was significantly lower than that in adult normal esophageal epithelia (50%), adult epithelia with basal cell hyperplasia (62%), dysplasia (73%) and squamous cell carcinoma (86%) (P < 0.05, Fisher's exact test). No p21WAF-1 positive immunostaining cells were observed in fetal esophageal epithelia. However, p21WAF-1 positive immunostaining cells were observed in adult esophagus with 39% (11/28) in normal, 38% (14/37) in BCH, 27% (3/11) in DYS and 14% (1/7) in SCC.
CONCLUSION: PCNA could act as an indicator accurately reflecting the high proliferation status of fetal esophageal epithelium. p53 may play an important role in growth and differentiation of fetal esophageal epithelium. p21WAF-1 may have no physiological function in development of fetal esophageal epithelium.
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Affiliation(s)
- Ying Xing
- Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
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Uys P, van Helden PD. On the nature of genetic changes required for the development of esophageal cancer. Mol Carcinog 2003; 36:82-9. [PMID: 12557264 DOI: 10.1002/mc.10100] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
It is clear that genetic mutations are necessary for the development of cancer, but the exact number required is not clear, with estimates ranging from one critical hit (e.g., p53) to dozens or perhaps even hundreds of expression changes (by microarray analysis) or chromosomal aberrations. We have used a mathematical model to estimate the critical number of mutations required for the development of esophageal cancer (EC) and to test for the likelihood of an EC major susceptibility gene. Our results suggest that six or seven mutations are required for the development of EC and that there is no evidence of a major susceptibility gene. This does not exclude the possibility that gene-environment interactions may not confer susceptibility or risk. The gradual accumulation of aberrant gene function also can explain the progression of pathologic states seen in the esophagus, from early dysplasia through mild to severe dysplasia and, finally, to cancer, as illustrated in our model.
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Affiliation(s)
- Pieter Uys
- MRC Centre for Molecular and Cellular Biology and Department of Medical Biochemistry, University of Stellenbosch, Tygerberg, South Africa
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