79 research outputs found
Establishment of cell lines from adenocarcinomas of the esophagus and gastric cardia growing in vivo and in vitro
E-cadherin promotes intraepithelial expansion of bladder carcinoma cells in an in vitro model of carcinoma in situ
High-grade transitional cell carcinomas (TCCs) of the urinary bladder are
frequently associated with carcinoma in situ, which may replace large
areas of the mucosa of the urinary tract. The invasive component of TCCs
often reveals a loss of expression of the cell-cell adhesion molecule
E-cadherin, but the role of E-cadherin in the development and expansion of
intraepithelial neoplasia is unknown. To study the underlying mechanism of
intraepithelial expansion (IEE), we have developed an IEE assay. Human TCC
cell lines were investigated in this IEE assay for their capacity to
replace the surrounding normal murine urothelial cells. In vitro IEE
appeared to be prominent in three (SD, RT112, and 1207) of the four
E-cadherin-positive cell lines. Although the two E-cadherin-negative cell
lines (T24 and J82) were able to penetrate surrounding normal urothelium
as single cells, they largely lacked the capacity of IEE. These results
prompted us to investigate whether the cell-cell adhesion molecule
E-cadherin is an important determinant for IEE. T24 cells that were
transfected with full-length mouse E-cadherin cDNA displayed an enhanced
IEE rate. Transfection did not influence their proliferative capacity,
their pattern and level of integrin expression, or their ability to expand
in the absence of surrounding urothelium. The data suggest that
E-cadherin-mediated cohesiveness is an important factor in the IEE of
bladder carcinoma cells. These observations argue for a dual, paradoxical
role of E-cadherin in bladder tumorigenesis. On the one hand, E-cadherin
promotes the expansion of intraepithelial neoplasia; on the other hand,
its loss correlates with invasive behavior
Neuroendocrine Cells in Barrett's Mucosa and Adenocarcinomas of the Gastroesophageal Junction
Mitochondrial D310 mutation as clonal marker for solid tumors
Patients with multiple tumors, either synchronous or metachronous, can have metastatic disease or suffer from multiple independent primary tumors. While proper diagnosis of these patients is important for prognosis and treatment, this can be challenging using only clinical and histological criteria. The aim of the present study was to evaluate the value of mitochondrial D310 mutation analysis in diagnostic questions regarding tumor clonality for a wide range of tumor types. Sanger sequencing of D310 was performed on a diagnostic cohort of 382 patients with 857 tumors that were previously analyzed using routine molecular analysis on genomic DNA. The D310 mononucleotide repea
Comparative genomic hybridization of cancer of the gastroesophageal junction: deletion of 14Q31-32.1 discriminates between esophageal (Barrett's) and gastric cardia adenocarcinomas
Incidence rates have risen rapidly for esophageal and gastric cardia
adenocarcinomas. These cancers, arising at and around the gastroesophageal
junction (GEJ), share a poor prognosis. In contrast, there is no consensus
with respect to clinical staging resulting in possible adverse effects on
treatment and survival. The goal of this study was to provide more insight
into the genetic changes underlying esophageal and gastric cardia
adenocarcinomas. We have used comparative genomic hybridization for a
genetic analysis of 28 adenocarcinomas of the GEJ. Eleven tumors were
localized in the distal esophagus and related to Barrett's esophagus, and
10 tumors were situated in the gastric cardia. The remaining seven tumors
were located at the junction and could not be classified as either
Barrett-related, or gastric cardia. We found alterations in all 28
neoplasms. Gains and losses were distinguished in comparable numbers.
Frequent loss (> or = 25% of all tumors) was detected, in decreasing order
of frequency, on 4pq (54%), 14q (46%), 18q (43%), 5q (36%), 16q (36%), 9p
(29%), 17p (29%), and 21q (29%). Frequent gain (> or = 25% of all tumors)
was observed, in decreasing order of frequency, on 20pq (86%), 8q (79%),
7p (61%), 13q (46%), 12q (39%), 15q (39%), 1q (36%), 3q (32%), 5p (32%),
6p (32%), 19q (32%), Xpq (32%), 17q (29%), and 18p (25%). Nearly all
patients were male, and loss of chromosome Y was frequently noted (64%).
Recurrent high-level amplifications (> 10% of all tumors) were seen at
8q23-24.1, 15q25, 17q12-21, and 19q13.1. Minimal overlapping regions could
be determined at multiple locations (candidate genes are in parentheses):
minimal regions of overlap for deletions were assigned to 3p14 (FHIT,
RCA1), 5q14-21 (APC, MCC), 9p21 (MTS1/CDKN2), 14q31-32.1 (TSHR), 16q23,
18q21 (DCC, P15) and 21q21. Minimal overlapping amplified sites could be
seen at 5p14 (MLVI2), 6p12-21.1 (NRASL3), 7p12 (EGFR), 8q23-24.1 (MYC),
12q21.1, 15q25 (IGF1R), 17q12-21 (ERBB2/HER2-neu), 19q13.1 (TGFB1, BCL3,
AKT2), 20p12 (PCNA), 20q12-13 (MYBL2, PTPN1), and Xq25. The distribution
of the imbalances revealed similar genetic patterns in the three GEJ tumor
groups. However, loss of 14q31-32.1 occurred significantly more frequent
in Barrett-related adenocarcinomas of the distal esophagus, than in
gastric cardia cancers (P = 0.02). The unclassified, "pure junction" group
displayed an intermediate position, suggesting that these may be in part
gastric cardia tumors, whereas the others may be related to
(short-segment) Barrett's esophagus. In conclusion, this study has, fist,
provided a detailed comparative genomic hybridization-map of GEJ
adenocarcinomas documenting new genetic changes, as well as candidate
genes involved. Second, genetic divergence was revealed in this poorly
understood group of cancers
High frequency of loss of heterozygosity in vulval intraepithelial neoplasia (VIN) is associated with invasive vulval squamous cell carcinoma (VSCC)
Vulval intraepithelial neoplasia (VIN) is thought to be the premalignant phase of human papillomavirus (HPV)-associated vulval squamous cell carcinoma (VSCC). Various molecular events have been suggested as markers for progression from VIN to VSCC, but loss of heterozygosity (LOH) in vulval neoplasia has rarely been studied in this context. We performed LOH analysis by polymerase chain reaction (PCR) amplification of polymorphic microsatellite markers at 6 chromosomal loci (17p13-p53, 9p21-p16, 3p25, 4q21, 5p14 and 11p15). The presence of HPV was assessed using consensus PCR primers and DNA sequencing. To examine any association between LOH and the presence of invasive disease, we analyzed 43 cases of lone VIN III, 42 cases of lone VSCC and 21 cases of VIN with concurrent VSCC. HPV DNA was detected in 95% of lone VIN III samples and 71% of lone VSCC samples. Fractional regional allelic loss (FRL) in VIN associated with VSCC was higher than in lone VIN (mean FRL 0.43 vs. 0.21, p < 0.005). LOH at 3p25 occurred significantly more frequently in HPV-negative VSCC than in HPV-positive VSCC (58% vs. 22%, p < 0.04). These data suggest that genetic instability in VIN, reflected by LOH, may increase the risk of invasion. In addition, molecular events differ in HPV-positive and -negative VSCC and 3p25 may be the site of a tumor suppressor gene involved in HPV-independent vulval carcinogenesis
Allelic imbalance of 7q32.3-q36.1 during tumorigenesis in Barrett's esophagus
Malignant transformation of Barrett's esophagus is characterized by three
distinct premalignant stages: intestinal metaplasia (MET), low- (LGD), and
high-grade dysplasia (HGD). We reported recently an increase in the
frequency of loss of 7q33-q35 between LGD and HGD as determined by
comparative genomic hybridization (P. H. J. Riegman et al., Cancer Res.,
61: 3164-3170, 2001). Now the 7q32.3-q36.1 region was additionally
characterized by allelotype analysis with 11 polymorphic markers in 15
METs, 20 LGDs, 20 HGDs, and 20 Barrett's adenocarcinomas from different
patients. Low percentages of imbalance were determined in METs and LGDs,
7% and 10%, respectively, whereas HGDs and Barrett's adenocarcinomas
revealed high percentages of loss, 75% and 65%, respectively. This
difference in frequency between LGDs and HGDs appeared highly significant:
P = 0.00007. The majority of imbalances were found at D7S2439 and D7S483,
located on 7q36.1. These data suggest that markers from this area can be
used as a diagnostic tool in Barrett's esophagus, i.e., to distinguish
between watchful waiting and active treatment
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