transforming-growth-factor-alpha and Barrett-Esophagus

Barrett esophagus is a premalignant condition that may progress to adenocarcinoma. The risk of developing cancer has been estimated to be approximately 1 in 250 patient-years of observation; however, there appear to be subsets of patients at much higher risk. Risk stratification has previously been determined by histological identification of dysplasia. Several new biomarkers are being tested to help clinicians better determine the risk of cancer development. Although none of these biomarkers has been proven in a prospective study to predict the onset of cancer, they have been correlated with cancer development. Most of these are factors that have been associated with cancer development in other organs. These include assessment of cell proliferation, expression of cyclooxygenase 2, growth factors and oncogenes, secretory factors, cell cycle proteins, adhesion molecules, and aneuploidy and other genetic abnormalities. In addition to their role as potential cancer biomarkers, these factors have increasingly been reported as surrogate markers to monitor the effectiveness of conservative treatments for Barrett esophagus. In this article, biological markers are reviewed for their relevance in Barrett esophagus. Although most biological markers need to be evaluated further and, for most, prospective follow-up studies are lacking, at present abnormal ploidy status, P16 and P53 gene abnormalities, or allelic losses are the most extensively documented.

Topics: Barrett Esophagus; Biomarkers; Cyclooxygenase 2; Epidermal Growth Factor; ErbB Receptors; Esophageal Neoplasms; Female; Humans; Immunohistochemistry; Isoenzymes; Male; Membrane Proteins; Ornithine Decarboxylase; Precancerous Conditions; Prostaglandin-Endoperoxide Synthases; Sensitivity and Specificity; Transforming Growth Factor alpha

A wide variety of biologic events and mechanisms appear to have roles in the development and progression of Barrett's esophagus-associated neoplastic lesions. Figure 5 is a schematic depiction of these events. This is known as an infernogram (named after Dante's Inferno) (S. Kern, unpublished presentations, 1996). Events at the bottom rings of the inferno are high-frequency mutations; nearer to the top of the inferno are the less common events. The next several years promise many further discoveries of not only high-frequency and low-frequency events, but also their application. Some of the molecular alterations already studied show promise as markers for early cancer detection or prognostication. Eventually, applications of these discoveries should yield new and more effective means of preventing and treating the deadly complications of this troublesome premalignant condition.

Topics: Adenocarcinoma; Barrett Esophagus; DNA, Neoplasm; Esophageal Neoplasms; Esophagus; Genes, Tumor Suppressor; Heterozygote; Humans; Proto-Oncogenes; Transforming Growth Factor alpha; Transforming Growth Factor beta

Topics: Adenocarcinoma; Barrett Esophagus; Epidermal Growth Factor; ErbB Receptors; Esophageal Neoplasms; Growth Substances; Humans; Transforming Growth Factor alpha; Transforming Growth Factor beta

Accelerated cellular proliferation in Barrett's esophagus has been implicated in Barrett's elongation and malignant transformation. Therefore, growth factors may play important roles in the pathophysiology of Barrett's esophagus. Regenerating gene (REG), an epithelial growth factor, has been reported to link mucosal inflammation and subsequent carcinogenesis in the gastrointestinal tract. The aim of this study was to investigate whether REG is expressed in Barrett's esophagus and to elucidate the relationship between REG protein expression and clinicopathological factors of Barrett's esophagus.. Between July 2003 and June 2004, 266 patients with endoscopically and histologically proven Barrett's esophagus were enrolled in this study. Before endoscopic examination, all participants were requested to answer structured questionnaires on gastroesophageal reflux symptoms and drugs usage. Mucin phenotype, cyclooxygenase-2 expression, cellular proliferation, apoptosis and REG Ialpha protein expression were investigated in the biopsy samples taken from Barrett's esophagus. Clinicopathological factors that correlated with REG Ialpha protein expression in patients with Barrett's esophagus were evaluated using multivariate logistic regression analysis.. REG Ialpha protein expression was observed in 48 (18.0%) of 266 patients with Barrett's esophagus by immunohistochemistry. Newly developed squamous re-epithelialization of Barrett's esophagus at biopsy sites, presence of hiatal hernia and aging were shown to correlate with REG Ialpha protein expression.. The present study is the first to show REG expression in Barrett's esophagus. Expression of REG Ialpha was more frequently observed in patients who showed squamous re-epithelialization of Barrett's esophagus at biopsy sites.

Topics: Aged; Aging; Barrett Esophagus; Biopsy; Esophagitis, Peptic; Female; Helicobacter Infections; Helicobacter pylori; Hernia, Hiatal; Humans; Immunohistochemistry; Lithostathine; Male; Middle Aged; Predictive Value of Tests; Transforming Growth Factor alpha; Transforming Growth Factor beta

Topics: Barrett Esophagus; ErbB Receptors; Humans; Oncogene Proteins v-erbB; Signal Transduction; Transforming Growth Factor alpha

A retrospective study of surgically resectable esophageal cancers was undertaken to determine the relationship between angiogenesis score and growth factor expression with tumor size, histology, degree of differentiation, depth of invasion, nodal disease, and the presence of Barrett's esophagus. The office and hospital charts of 27 patients who had esophageal resection for carcinoma between 1990 and 1995 at Rush-Presbyterian-St. Luke's Medical Center were reviewed. Data collection included patient demographics, survival, tumor size, histology, differentiation, depth of invasion, nodal metastases, and the presence of Barrett's esophagus. The pathology specimens were immunostained for von Willebrand factor (factor VIII-related antigen). Immunostaining was also performed for vascular endothelial growth factor and transforming growth factor alpha. Twenty normal esophageal specimens served as controls. Angiogenesis score was determined by counting vessels under conventional light microscopy at x200 magnification, and growth factor expression was graded on a scale of 1 to 4. Cancers had higher angiogenesis and growth factor expression than controls (P = 0.01). Patient age, tumor size, histology, differentiation, depth of invasion, and Barrett's esophagus did not correlate with angiogenesis score or tumor growth factor expression. Lymph node status did correlate with both angiogenesis score and growth factor expression (P < or = 0.02). We conclude that high angiogenesis score and growth factor expression correlate with the presence of lymph node metastases. This may help select patients for preoperative radiation and chemotherapy or determine the extent of surgery performed for esophageal carcinoma.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Barrett Esophagus; Biomarkers, Tumor; Carcinoma; Endothelial Growth Factors; Esophageal Neoplasms; Esophagectomy; Female; Humans; Lymphatic Metastasis; Lymphokines; Male; Middle Aged; Neovascularization, Pathologic; Prognosis; Retrospective Studies; Statistics, Nonparametric; Survival Analysis; Transforming Growth Factor alpha; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; von Willebrand Factor

Overexpression of transforming growth factor alpha (TGF-alpha) and epidermal growth factor receptor (EGFR) occurs in Barrett's esophagus, particularly the specialized type, which is at an increased risk for malignant transformation. We performed this study to evaluate the immunohistochemical expression and prognostic significance of these growth factors, as well as MiB-1, the Ki-67 proliferation-associated nuclear antigen, in Barrett's-associated neoplasia. Monoclonal antibodies for TGF-alpha, EGFR, and MiB-1 were evaluated in 25 cases of Barrett's-associated adenocarcinoma (BAA) and in adjacent areas of Barrett's metaplasia and dysplasia. The data were correlated with the pathologic features (grade, stage, depth of invasion, lymph node metastasis) and the clinical outcome of the patients. Of the BAAs, 100% and 64% were positive for TGF-alpha and EGFR, respectively. TGF-alpha and EGFR expression did not correlate with any of the pathologic features of the tumors. By univariate analysis, a higher degree of EGFR immunostaining was significantly associated with poorer patient survival (P = 0.004). After stratified analysis, however, EGFR expression correlated with poor survival only in patients with pathologic Stage II cancer (P = 0.03). There was significant (P < 0.001) increase in the MiB-1 proliferation index (PI) associated with neoplastic progression: Barrett's metaplasia, 22.0% +/- 6.4; dysplasia, 56.5% +/- 21.6; and BAA, 70.0% +/- 17.7. In a separate comparison of the luminal (upper half) and basal (lower half) crypt MiB-1 PI, dysplastic epithelium revealed a significant increase in the luminal crypt MiB-1 PI in comparison with Barrett's metaplastic epithelium (50.7 +/- 24.6 versus 1.2 +/- 1.9, P < 0.001). EGFR expression might have prognostic value for patients with BAA, particularly those with Stage II cancer. The MiB-1 PI pattern supports the metaplasia-dysplasia-adenocarcinoma pathogenetic sequence in these tumors. Furthermore, the pattern of MiB-1 immunostaining might help to distinguish dysplastic from regenerative metaplastic epithelium of Barrett's esophagus in uncertain cases.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antigens, Nuclear; Barrett Esophagus; Biomarkers; Biomarkers, Tumor; ErbB Receptors; Esophageal Neoplasms; Female; Humans; Immunohistochemistry; Ki-67 Antigen; Male; Middle Aged; Nuclear Proteins; Prognosis; Transforming Growth Factor alpha

Adenocarcinomas of the gastro-esophageal junction (GEJ) and those arising in Barrett's esophagus (BE) are increasing in the West and have a poorer prognosis than distal stomach cancers. This has been attributed mainly to anatomical location, but biological factors such as growth-regulatory molecules have been implicated. We have investigated the expression of one of these factors, TGF alpha, and its precursor prepro TGF alpha in 82 adenocarcinomas of GEJ (32 resected specimens and 50 biopsies) as well as in 48 BE biopsies without tumor, by immunohistochemistry and by Western-blot analysis. TGF alpha staining was shown in the cytoplasm and membrane of cells. Western blot confirmed that most immunoreactivity was against mature TGF alpha (5.6 kDa), but higher-molecular-weight bands were also identifiable, suggesting some reactivity with prepro protein. TGF alpha expression was more extense and intense in intestinal metaplasia and cancer. The tubular histological type of adenocarcinoma was more often positive than the signet-ring type. Primary tumors with lymph-node metastases also had increased TGF alpha expression. We conclude, therefore, that there is differential regulation of the expression of TGF alpha and its precursors during esophageal tumorigenesis.

Topics: Adenocarcinoma; Barrett Esophagus; Blotting, Western; Epithelium; Esophageal Neoplasms; Gastric Fundus; Gastric Mucosa; Humans; Immunohistochemistry; Intestinal Mucosa; Lymphatic Metastasis; Myocardium; Protein Precursors; Transforming Growth Factor alpha

The conventional assessment of the premalignant potential of Barrett's oesophagus is unsatisfactory. However, it has recently been shown that abnormalities of growth-regulatory peptides and their receptors may be important in the pathogenesis of this condition. In an attempt to improve the diagnostic and prognostic criteria we have studied 21 consecutive patients with Barrett's oesophagus and 7 others with adenocarcinoma of the oesophagus. In each patient biopsy specimens were taken from the columnarlined oesophagus or the adenocarcinoma and from the gastric cardiac mucosa for routine histologic evaluation. Immediately adjacent specimens were taken from both the Barrett's mucosa or adenocarcinoma and from the gastric mucosa for flow-cytometric study. The latter samples were disaggregated and labelled with antibodies to epidermal growth factor (EGF), transforming growth factor alpha (TGF-alpha), and epidermal growth factor receptor (EGF-R). The flow cytometer selected cells labelled with each antibody and expressed them as a percentage of the total number of disaggregated cells (average, 5500 cells). Epidermal growth factor receptors were expressed in a greater number of cells from Barrett's mucosa, with the intestinal type or those with dysplasia, than in gastric cardiac mucosa (p less than 0.05). All seven adenocarcinoma had many more cells expressing EGF, TGF-alpha, and EGF-R than normal gastric mucosa (p less than 0.01). We conclude that flow-cytometric evaluation of EGF-R can help in the understanding of the pathogenesis of Barrett's oesophagus.

Topics: Adenocarcinoma; Adult; Aged; Autoantigens; Barrett Esophagus; Epidermal Growth Factor; ErbB Receptors; Esophageal Neoplasms; Flow Cytometry; Humans; Middle Aged; Nuclear Proteins; Proliferating Cell Nuclear Antigen; Transforming Growth Factor alpha

This study was designed to correlate mucosal proliferation in Barrett's oesophagus with expression of a growth promoting peptide, transforming growth factor alpha (TGF alpha). Oesophageal mucosa was studied from 50 patients with oesophageal disease who had been treated by oesophagectomy. Histological analysis showed a range of oesophageal pathology - 18 patients had gastric type Barrett's mucosa, 18 had intestinal type Barrett's mucosa, and 14 had oesophageal adenocarcinomas. Sections were stained immunohistochemically for proliferating cell nuclear antigen (PCNA) (an index of cellular proliferation) and TGF alpha. PCNA immunostaining was seen mainly in the basal cells of the neck/foveolar epithelial compartment of the glands in Barrett's oesophagus. However, in mucosa with high grade dysplasia, the proliferative compartment extended upwards into the superficial layers of the glands. At least 2000 cells were counted in each patient to determine the proportion with PCNA immunoreactivity (PCNA labelling index). The labelling index was highest in adenocarcinoma (25%) and in Barrett's intestinal type mucosa with high grade dysplasia (26%) compared with intestinal type mucosa with no significant dysplasia (20%) and Barrett's gastric type mucosa (12%). There was a significant positive correlation between PCNA labelling indices and TGF alpha expression in Barrett's mucosa (p less than 0.01). In glands showing high grade dysplasia, TGF alpha immunoreactivity was seen in the same regions of the glands as PCNA immunoreactivity, indicating the possibility of involvement of TGF alpha in (pre) neoplastic proliferation in Barrett's oesophagus.

Topics: Adenocarcinoma; Autoantigens; Barrett Esophagus; Cell Count; Esophageal Neoplasms; Esophagus; Humans; Mitosis; Nuclear Proteins; Precancerous Conditions; Proliferating Cell Nuclear Antigen; Transforming Growth Factor alpha

Topics: Barrett Esophagus; ErbB Receptors; Flow Cytometry; Humans; Transforming Growth Factor alpha; Tumor Suppressor Protein p53

Topics: Barrett Esophagus; Epidermal Growth Factor; Humans; Saliva; Transforming Growth Factor alpha

1. In order to assess potential abnormalities in the control of mucosal proliferation, 30 patients with Barrett's oesophagus were studied in order to evaluate the presence and distribution of epidermal growth factor, transforming growth factor-alpha and epidermal growth factor receptor to determine the Ki-67 labelling index in the affected oesophageal mucosa. Serial sections were analysed immunohistochemically. Ten of the patients had adenocarcinoma in the Barrett's mucosa and the other 20 had differing histological types of Barrett's mucosa (10, intestinal-type; 10, fundic- or cardiac-type). 2. The expression of transforming growth factor-alpha, epidermal growth factor and epidermal growth factor receptor was increased and the Ki-67 labelling index was higher in Barrett's mucosa compared with normal gastric mucosa. The 'intestinal-type' of Barrett's mucosa had the greatest expression of transforming growth factor-alpha, epidermal growth factor receptor and the highest Ki-67 labelling index compared with the other types of Barrett's metaplasia. Five cases of 'intestinal-type' Barrett's metaplasia had especially high Ki-67 labelling indices and these patients over-expressed both transforming growth factor-alpha and epidermal growth factor receptor. The patients with adenocarcinomas in the Barrett's mucosa also over-expressed transforming growth factor-alpha and epidermal growth factor receptor, but not epidermal growth factor, compared with normal gastric mucosa. 3. In conclusion, both normal gastric mucosa and Barrett's mucosa have potential autocrine growth regulatory mechanisms, but Barrett's mucosa has increased expression of both of the measured ligands and of the epidermal growth factor receptor.

Topics: Adenocarcinoma; Adult; Aged; Barrett Esophagus; Epidermal Growth Factor; ErbB Receptors; Esophageal Neoplasms; Female; Gastric Mucosa; Humans; Male; Middle Aged; Mucous Membrane; Transforming Growth Factor alpha