Strategies for molecular intervention in esophageal cancers and their precursor lesions
ABSTRACT 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.
- SourceAvailable from: Maria-Chiara Osterheld
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- "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. "
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.Cancer Detection and Prevention 02/2006; 30(3):276-83. DOI:10.1016/j.cdp.2006.05.001 · 2.52 Impact Factor
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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.Biomedecine [?] Pharmacotherapy 09/2000; 54(7):362-7. DOI:10.1016/S0753-3322(01)80002-0 · 2.11 Impact Factor
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ABSTRACT: Although MAGE-3 has been detected in approximately 40% of lung and esophageal cancers, expression of this cancer testis antigen appears to be below the threshold for immune recognition in patients with these malignancies. The aim of this study was to determine if the demethylating agent, 5-Aza-2'-deoxycytidine (DAC) and if the histone deacetylase inhibitor Depsipeptide FR901228 (DP) could enhance MAGE-3 expression in lung and esophageal cancer cells. Eleven lung and esophageal cancer lines and cultured normal human bronchial epithelial (NHBE) cells were exposed to normal media (NM), DAC, DP, or combination DAC/DP at varying concentrations and exposure durations. MAGE-3 expression was evaluated by quantitative RT-PCR (TaqMan) and immunohistochemistry techniques. Trypan blue exclusion techniques were used to examine the proliferation of cancer cells after drug exposure. Relative to untreated controls, MAGE-3 expression was enhanced 32-fold (range 3.9 to 110) by DAC alone (0.1 micromol/L x 72 h), 2.1-fold (0.4 to 4.2) by DP alone (25 ng/mL x 6h), and 57-fold (4.6 to 209) by sequential DAC/DP exposure. Increased MAGE-3 mRNA copy numbers coincided with enhanced protein levels in these cells. MAGE-3 expression persisted after drug exposure. Flow cytometry confirmed the presence of functional HLA class I expression in these cells. Sequential DAC/DP treatment mediated pronounced growth inhibition in cancer cells but not NHBE. Sequential DAC/DP treatment may be a novel strategy to simultaneously augment MAGE-3 expression and induce growth arrest in thoracic malignancies.The Annals of Thoracic Surgery 02/2001; 71(1):295-301; discussion 301-2. DOI:10.1016/S0003-4975(00)02421-8 · 3.63 Impact Factor