The HGF Receptor c-Met Is Overexpressed in Esophageal Adenocarcinoma1 (original) (raw)
Related papers
The HGF Receptor c-Met Is Overexpressed in Esophageal Adenocarcinoma
Neoplasia, 2005
The hepatocyte growth factor (HGF) receptor, Met, has established oncogenic properties; however, its expression and function in esophageal adenocarcinoma (EA) remain poorly understood. We aimed to determine the expression and potential alterations in Met expression in EA. Met expression was investigated in surgical specimens of EA, Barrett's esophagus (BE), and normal esophagus (NE) using immunohistochemistry (IHC) and quantitative reverse transcriptase polymerase chain reaction. Met expression, phosphorylation, and the effect of COX-2 inhibition on expression were examined in EA cell lines. IHC demonstrated intense Met immunoreactivity in all (100%) EA and dysplastic BE specimens. In contrast, minimal immunostaining was observed in BE without dysplasia or NE specimens. Met mRNA and protein levels were increased in three EA cell lines, and Met protein was phosphorylated in the absence of serum. Sequence analysis found the kinase domain of c-met to be wild type in all three EA cell lines. HGF mRNA expression was identified in two EA cell lines. In COX-2 -overexpressing cells, COX-2 inhibition decreased Met expression. Met is consistently overexpressed in EA surgical specimens and in three EA cell lines. Met dysregulation occurs early in Barrett's dysplasia to adenocarcinoma sequence. Future study of Met inhibition as a potential biologic therapy for EA is warranted. Neoplasia (2005) 7, 75 -84
Cancer Genetics and Cytogenetics, 2006
Adenocarcinomas of the gastroesophageal junction (GEJ) show frequent high-level amplifications (HLA), but the underlying genes are not well defined. We have characterized genomic gain in 14 GEJ carcinomas by array-based comparative genomic hybridization (aCGH). The most frequent gains and amplifications were detected at 7q (57%), 8q (57%), 17q (64%), and 20q (79%), with minimally amplified regions at 7q21.1, 8q24.2, 17q12, and 20q13.2. Five HLA were detected on 7q, one on 8q, two on 17q, and three on 20q. HLA of 8q24 and 17q12 were related to MYC and ERBB2, respectively. The HLA on 7q21 was associated recurrently with ABCB1, whereas the amplified region on 20q13 implicated ZNF217, BCAS1, and CYP24. RNA expression analysis of 11 adenocarcinomas by reverse-transcription polymerase chain reaction was performed for cancerrelated genes residing at 7q21 (ABCB1, ABCB4, CDK6, HGF, DMTF1, SRI, TP53AP1) and 20q13 (ZNF217, BCAS1, CYP24, TNFRSF6B). The most frequently upregulated gene on 7q21 was HGF (45%), but there was no association with genomic amplification. The most frequently overexpressed gene at 20q13 was BCAS1 (27%), which was related to HLA of this region (P 5 0.006) in all three cases. We conclude that HLA occur often in GEJ adenocarcinomas. The gene responsible for the HLA of 7q21 requires further investigation, whereas BCAS1 is a good candidate for the frequent amplification of 20q13. Ó
Superficial and early cancers of the esophagus
Annals of the New York Academy of Sciences, 2014
The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on the evolution of Barrett's dysplasia to early cancer; the early detection of esophageal cancer in China; new technologies of treatment for dysplasia; the prognostic value of molecular markers expression in esophageal squamous cell carcinoma; the follow-up schedule after ablation of high-grade dysplasia; intramucosal cancers; and tubular widespread endoscopic esophageal submucosal dissection with high-dose steroid stricture prevention.
Journal of Cancer Research and Clinical Oncology, 1993
Adamantinoma of long bones is a rare bone tumour with (immuno-) histological features of epithelial cells, surrounded by various amounts of osteofibrous tissue. Recent studies have indicated that cells with an epithelial phenotype are most probably the malignant element. There is still debate as to whether the fibrous part should be designated as a benign neoplastic element of a biphasic tumour or as a reactive non-neoplastic tissue next to an epithelioid bone tumour. The expression of fibroblast growth factor type 2 (FGF-2), epidermal growth factor (EGF), and their respective receptors FGFR-1 and EGFR, as well as the proliferation marker Ki-67, was studied in both constituents of adamantinoma in serial sections of 25 cases by immunohistochemistry. Expression of FGF-2 and its receptor was present in both constituents of adamantinoma, but predominated in the epithelial component. Expression of EGF and its receptor was restricted to the epithelial component of adamantinoma. Comparing osteofibrous dysplasia (OFD)-like adamantinoma with classic epithelial cell-rich adamantinoma, the expression of FGF-2, EGF, and EGFR was more intense and in a higher percentage of cells in classic adamantinoma. Proliferative activity was found nearly exclusively in the epithelial component. These data further substantiate the hypothesis that epithelial cells constitute the proliferating tumour cell population responsible for the malignant behaviour of adamantinoma. The data indicate that during progression, the epithelial cells acquire expression of FGF-2, EGF, and EGFR, accompanied by a higher proliferative activity. Within the epithelial cell population, there exists an autocrine pathway of growth stimulation. Furthermore, these data point to an interaction between the epithelial and fibrous components, in which the epithelial cells additionally stimulate fibrous cell growth via a paracrine pathway involving FGF-2.
General morphological and biological features of neoplasms: integration of molecular findings.
This review highlights the importance of morphologymolecular correlations for a proper implementation of new markers. It covers both general aspects of tumorigenesis (which are normally omitted in papers analysing molecular pathways) and the general mechanisms for the acquired capabilities of neoplasms. The mechanisms are also supported by appropriate diagrams for each acquired capability that include overlooked features such as mobilization of cellular resources and changes in chromatin, transcription and epigenetics; fully accepted oncogenes and tumour suppressor genes are highlighted, while the pathways are also presented as activating or inactivating with appropriate colour coding. Finally, the concepts and mechanisms presented enable us to understand the basic requirements for the appropriate implementation of molecular tests in clinical practice. In summary, the basic findings are presented to serve as a bridge to clinical applications. The current definition of neoplasm is descriptive and difficult to apply routinely. Biologically, neoplasms develop through acquisition of capabilities that involve tumour cell aspects and modified microenvironment interactions, resulting in unrestricted growth due to a stepwise accumulation of cooperative genetic alterations that affect key mole-cular pathways. The correlation of these molecular aspects with morphological changes is essential for better understanding of essential concepts as early neoplasms ⁄ precancerous lesions, progression ⁄ dedifferentiation, and intratumour heterogeneity. The acquired capabilities include self-maintained replication (cell cycle dysregulation), extended cell survival (cell cycle arrest, apoptosis dysregulation, and replicative lifespan), genetic instability (chromosomal and microsatellite), changes of chromatin, transcription and epigenetics, mobilization of cellular resources, and modified microenvironment interactions (tumour cells, stromal cells, extracellular, endothelium). The acquired capabilities defining neoplasms are the hallmarks of cancer, but they also comprise useful tools to improve diagnosis and prognosis, as well as potential therapeutic targets. The application of these concepts in oncological pathology leads to consideration of the molecular test requirements (Molecular Test Score System) for reliable implementation; these requirements should cover biological effects, molecular pathway, biological validation, and technical validation. Sensible application of molecular markers in tumour pathology always needs solid morphological support.
Epidemiology – etiology – pathology Adenocarcinoma of the esophagus and the gastro-esophageal junction is reportedly the fasted rising malignancy. Esophageal carcinoma is ranking ninth in the list of most common cancers in the world. Esophageal carcinoma is a disease of the mid to late adulthood. It's late mortality is high with only 8% of patients surviving more than five years with a median survival of nine months. There are no differences in survival chances according to sex, racial background and histological type. There is a marked variation in incidence, more than for any other tumor, according to sex, geographical area, racial and economical background. The annual age adjusted incidence rate amongst males is varying from less than 5 cases per 100,000 inhabitants amongst whites in the U.S. to up to 12.5 per 100,000 in some regions of France (Normandy) and even more than 100 cases per 100,000 in parts of China (Linxian) or the Kaspian part of Iran. In most countries, esophageal carcinoma is twice-to four times more frequent in men as compared to women. Squamous cell carcinoma is five times as frequent in blacks as compared to Kaukasians. Today a clear rising incidence is noticed in parts of the world where this condition used to be rather occasional in the past e.g. Germany, Denmark and former Sovjet Union countries. This probably relates to an increased alcohol consumption. In Germany the cumulative risk has quadrupled in five yearly birth cohorts between 1915 and 1940. On the contrary there is a clear decreasing trend in Finland with an incidence in mortality decreasing about 10% every five years in both sexes. Also patterns of incidence of histological subtypes are showing some changes squamous cell carcinoma seemingly decreasing while on the other hand a sharp and fast increase of adenocarcinoma is noticed mainly in the Western World. In Burgundy (France) the incidence of squamous cell carcinoma remained stable between 1976 and 1983 but the incidence of adenocarcinomas sharply rized from 5.6% between 1976 and 1987, up to 20.1% in 1991 until 1993. In Norway the yearly increase of incidence of adenocarcinoma is estimated at 17% for the male population and 14% for the female population between 1983 and 1992. The increase of incidence of adenocarcinoma is estimated faster and bigger than for any other carcinoma over the last two decades and is currently estimated at a rise between 5 to 10% per year during the 1980 decade. Heavy smoking and drinking are considered as the two main risk factors to develop a squamous cell carcinoma. More than 95% of the patients with a squamous cell carcinoma are smokers and there is an increase with both the number of cigarettes smoked per day and the duration of smoking. Carotenoids, vitamins C and E may be involved as preventives of esophageal carcinogenesis. Randomized trials in China indicate that a supplement of these micro-elements significantly decreases mortality caused by esophageal carcinoma as compared to a population deprived of these supplements in their diet. Genetic predisposition is unusual. However 95% of patients with congenital palmar and plantar keratosis (tylosis) may develop esophageal carcinoma before age 65. Other predisposing conditions to esophageal carcinoma are: chronic inflammation (reflux?), achalasia, caustic injury and Plummer-Vinson syndrome. Little is known about the role of viruses (papilloma virus) which may be involved as agents favoring the progression from dysplasia to invasive carcinoma. Adenocarcinoma may also be related to smoking and alcohol abuse, but to a lesser extend than squamous cell carcinoma. Most adenocarcinomas (from 20% to 80%) seem to arise from specialized columnar metaplastic epithelium (Barrett). It is now accepted that the cancer risk is mostly related to the intestinal type of metaplasia with a 5% chance of apparition of cancer within 5 years. Esophageal carcinoma is considered to be the consequence of an accumulation of different mutations in different suppressor genes and protooncogenes. There is evidence of multiple chromosomal defects and deletions (13 Q, 5 Q, 18 Q, 3 P, 9 P, 17 Q). Often significant aneuploidy is noticed. P53 mutation seems to be an early event in the progression