Strategies for molecular intervention in esophageal cancers and their precursor lesions
Thoracic Oncology Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Diseases of the Esophagus
(Impact Factor: 1.78).
02/1999; 12(3):181-5. DOI: 10.1046/j.1442-2050.1999.00044.x
Molecular analysis of malignant transformation in Barrett's epithelium provides insight into the temporal nature and significance of individual genetic events during multistep esophageal carcinogenesis. Potential targets for intervention in esophageal neoplasms include mutations involving retinoblastoma (Rb) and p53 tumor-suppressor pathways as well as tyrosine kinase cascades, which are known to promote cell cycle progression. Data from recent experiments provide the preclinical rationale for novel pharmacologic interventions in established esophageal cancers, and suggest strategies for chemoprevention in patients at risk for the development of these neoplasms.
Available from: Maria-Chiara Osterheld
- "As demonstrated in numerous previous studies for various types of invasive carcinoma    the cytofluorometric analysis of DNA content of early malignant lesions could also be associated with aberrant cell-cycle regulation. That is consecutive to mutations occurring in oncogenes and tumor suppressor genes, and that affect G1 checkpoints  . This step should be of major interest to stratify patients not only for treatment, but also for further molecular studies and development of new therapeutic strategies. "
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ABSTRACT: The purpose of this study was to explore the potential use of image analysis on tissue sections preparation as a predictive marker of early malignant changes during squamous cell (SC) carcinogenesis in the esophagus. Results of DNA ploidy quantification on formalin-fixed, paraffin-embedded tissue using two different techniques were compared: imprint-cytospin and 6 microm thick tissue sections preparation.
This retrospective study included 26 surgical specimens of squamous cell carcinoma (SCC) from patients who underwent surgery alone at the Department of Surgery in CHUV Hospital in Lausanne between January 1993 and December 2000. We analyzed 53 samples of healthy tissue, 43 tumors and 7 lymph node metastases.
Diploid DNA histogram patterns were observed in all histologically healthy tissues, either distant or proximal to the lesion. Aneuploidy was observed in 34 (79%) of 43 carcinomas, namely 24 (75%) of 32 early squamous cell carcinomas and 10 (91%) of 11 advanced carcinomas. DNA content was similar in the different tumor stages, whether patients presented with single or multiple synchronous tumors. All lymph node metastases had similar DNA content as their primary tumor.
Early malignant changes in the esophagus are associated with alteration in DNA content, and aneuploidy tends to correlate with progression of invasive SCC. A very good correlation between imprint-cytospin and tissue section analysis was observed. Although each method used here showed advantages and disadvantages; tissue sections preparation provided useful information on aberrant cell-cycle regulation and helped select the optimal treatment for the individual patient along with consideration of other clinical parameters.
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ABSTRACT: Barrett's esophagus is characterised by the presence of specialised intestinal metaplasia in the lower esophagus. Its importance is related primarily to its link with adenocarcinoma of the lower esophagus, often preceded by dysplastic changes. The incidence of this carcinoma has increased dramatically over the last few decades. Although modern treatments, particularly acid suppression with proton pump inhibitors, have been most useful in controlling the reflux symptoms associated with Barrett's esophagus, they have not reduced the incidence of adenocarcinoma of the esophagus. The same can be said about anti-reflux surgery. Surgical excision of Barrett's esophagus has been advocated when high-grade dysplasia is detected; this carries considerable morbidity and mortality, so alternative treatments are being developed. This update summarises recent information concerning newer treatments aimed at eradicating Barrett's esophagus. These vary from thermal coagulation (using electrocoagulation and heater probes) to lasers, photodynamic therapy and mechanical methods. Of these, photodynamic therapy using a porphyrin precursor (5-amino-laevulinic acid) seems to give the most consistent satisfactory results with a minimum of complications. However, persistence of some metaplastic cells beneath the neo-squamous layer remains a problem. Ongoing effective acid control (by medical or surgical therapy) is also essential to prevent recurrence of Barrett's esophagus. Future research is aimed at perfecting these methods. Ultimately, it may be possible to understand the molecular biology which could help to predict which patients are at greatest risk of developing dysplastic and carcinomatous changes.
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ABSTRACT: Aberrant expression of Ki67, p53 and RARbeta are characteristic of many tumor types including those of the oral cavity. Chemopreventive agents may act by modulating their expression to more normal levels.
The effects of 21 chemopreventive agents on the expression of Ki67, p53 and RARbeta were determined using a human in vitro model of normal, premalignant and malignant oral epithelial cell lines.
Ki67 and mutant p53 (mtp53) were overexpressed in both the premalignant and malignant cell lines, whereas expression of RARbeta was high in the normal, low in the premalignant and not detectable in the malignant cell lines. Most of the agents selectively inhibited the expression of Ki67 in the premalignant and malignant cell lines. Eight of the 21 agents increased, while four agents decreased, the levels of mtp53 protein in the premalignant cell line. In the malignant cell line, five of the agents increased, while ten agents decreased mtp53 protein levels. The agents increased RARbeta expression to near normal levels in the premalignant cell line.
The data suggest that the suppression of Ki67 and mtp53 are good indicators of the effectiveness of agents in premalignant and malignant oral cells, whereas the enhancement of RARbeta is a measure of effectiveness in premalignant oral cells.
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