The HGF Receptor c-Met Is Overexpressed in Esophageal Adenocarcinoma (original) (raw)
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The HGF Receptor c-Met Is Overexpressed in Esophageal Adenocarcinoma1
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.
Pathology and Molecular Biology
Diffuse Gastric Cancer
The Cancer Genome Atlas (TCGA) (2014), based on dysregulated pathways and candidate driver genes, has divided gastric cancer (GC) cases into four subtypes: Epstein-Barr virus (EBV)-infected tumors, microsatellite instability (MSI) tumors, genomically stable (GS) tumors, and chromosomal instability (CIN) tumors. The main characteristics of this classification are described in what follows. According to the TCGA, around 50% of GC cases may be classified as chromosomally unstable, featuring marked aneuploidy, high somatic copy number alterations (SCNA), including focal amplification of receptor tyrosine kinases, such as ERBB2, EGFR, ERBB3, FGFR2, MET, KRAS, and VEGFA, as well as cell cycle mediators, such as CCNE1, CCND1, and CDK6, most of them amenable to targeted therapies. In addition, DNA hypomethylation and a high frequency of TP53 mutation may also be detected [1]. Another 9% of cases may be classified as positive for EBV, an alteration that may be accompanied by phosphatidylinositol-4,5bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations, DNA hypermethylation, including cyclin-dependent kinase inhibitor, also known as p16 INK4A (CDKN2A) silencing. Other alterations are amplifications of Janus kinase 2 (JAK2), CD274 (also known as PD-L1), and programmed cell death 1 ligand 2, also known as PD-L2 (PDCD1LG2), that may be accompanied by mRNA increased expression, indicating implication of immune signaling. Another 20% of GC cases may be classified as microsatellite unstable tumors, showing elevated mutation rates, including mutations of genes encoding targetable oncogenic signaling proteins. In most of these cases, the mismatch repair defect is more likely due to an epigenetic hypermethylation in the MLH1 promoter region. In addition, microsatellite unstable GCs are generally intestinal-type tumors, according to Lauren's classification. Finally,