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Characteristics
Cadherins are a family of calcium-dependent
transmembrane cell adhesion glycoproteins. In connecting cells they
comprise a part of the zonula adherens and desmosomes. Each type of
cadherin has a specific extracellular binding site and the proteins
preferentially interact with themselves in a homophilic manner.
Besides cell adhesion, the cadherins are involved in shape, motility
and proliferation of cells.
ECAD (syn. CD325), 120kDa, chromosome 16q22.1 (CDH1 gene), is a
critical regulator of epithelial junction formation. It interacts
with the cytoskeleton through a number of associated proteins: The
ECAD internal domain binds with alpha, beta, gamma, and p120
catenins to anchor the ECAD complex to the actin cytoskeleton of the
cell.
ECAD is expressed in virtually all epithelial cells with the
exception of adrenocortical cells. The expression in liver cells is
weaker than in most other epithelia. ECAD is also expressed in
melanocytes (adhering to squamous epithelial cells).
Mesothelial cells and granulosa cells are ECAD negative. Mesenchymal
cells and neural crest cells are mostly negative but some types may
show a weak reaction. Testicular germinative cells are weakly
positive.
Neoplasms
Decreased expression or function of ECAD appears
to be an important step in tumour progression. Compared to normal
tissues, ECAD expression may be down-regulated in malignant tumours,
and in highly invasive, poorly differentiated carcinomas ECAD may be
entirely lost, as a consequence of biallelic inactivation of CDH1
(by promoter methylation, mutation or allelic loss in any
combination). Somatic mutation of ECAD is associated with increased
activation of EGFR that may explain enhanced motility of tumor
cells.
Hereditary autosomal dominant diffuse-type gastric carcinoma usually
results from germline truncating mutations in the ECAD gene. These
patients also have an increased risk of lobular breast carcinoma.
Overall, 50 % - 90 % of carcinomas are positive with a strong
membranous reactivity. The following tumours are almost always
positive: adenocarcinoma of colorectum, stomach, pancreas, prostate,
endometrium, uterine cervix, and thyroid. Among ovarian carcinomas,
the mucinous type is almost always positive, while varying
positivity is seen in the other types.
Among breast carcinomas the ductal type (including the tubulolobular
subtype) is almost always positive (at least in part of the tumour)
while the lobular type is negative in 85 – 90 %. Decreased
expression in breast ductal carcinoma is associated with higher
frequency of lymph node metastases and shorter survival. In some of
these cases the down regulation of ECAD is transient, as the
metastases show a higher expression of the protein.
In urothelial carcinoma and squamous cell
carcinoma ECAD is found in most cases but the expressioni s often
reduced compared to normal cells.
Hepatocellular carcinoma and renal cell carcinoma are positive in
about half of the cases. Carcinoids are usually positive. Among
malignant mesotheliomas, about 30% are positive.
Most malignant melanomas stain for ECAD. However, the melanoma
metastases are frequently negative. Among sarcomas, ECAD positivity
is associated with an epithelioid growth pattern.
No positivity in seen in gliomas and virtually none in malignant
lymphomas. Seminomas are varying positive.
Application
Staining for ECAD may be useful for the
differentiation between ductal and lobular breast carcinomas.
ECAD positive malignant mesothelioma may be differentiated from
reactive mesothelial cells. However, ECAD staining cannot be
recommended in the differentiation between malignant mesothelioma
and adenocarcinoma.
Identification of ECAD may be useful for prognostic studies in
carcinomas but standards have not been established.
Visualization
Numerous mAbs are available. Good staining
results have been demonstrated with HECD-1 and NCH38. Heat induced
epitope retrieval is mandatory. An alkaline heating buffer is
recommendable.
Control: Liver tissue is useful. The liver cells should show
a strong membranous staining without cytoplasmic reaction.
Assessments
Run B5 2007
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