Cadherins
The cadherins are cell adhesion molecules. E-cadherin is the major Ca2+ dependent cell adhesion molecule of epithelial cells. Included in this family are desmoglein and desmocollins I and II. Desmosomal glycoprotein is a component of desmosomes with marked homology to cadherins.
Cadherins form part of a chain of regulators of cell adhesion, morphology and motility, and hence tumour invasiveness. Catenins are classified according to their molecular weight: a-; 102kD, b-; 88kD and g-; 80kD22. b-catenin and g-catenin have a high degree of sequence homology and interact with E-cadherin in mutually exclusive complexes22. b- or g- catenin links E-cadherin to a-catenin, that, in turn, links the E-cadherin-catenin complex to the actin cytoskeleton. b-catenin is a component of the wingless (wnt) signalling pathway which complexes with DNA-binding proteins and, as a result, regulates genes including c-myc, cyclin D1 and matrilysin.
The adenomatous polyposis coli (APC) protein competes with cadherins to form exclusive complexes with catenins4.
Both b-catenin and g-catenin contain the conserved armadillo repeat which is responsible for the binding to classical cadherin. p120-catenin is a substrate of the Src tyrosine kinase oncogene and also associates with E-cadherin and catenins; p120-catenin contains 11 armadillo repeats.
P-cadherin is a calcium dependent cellular adhesion molecule first identified in mouse placenta34. It is present in a range of cells, including myoepithelial cells.
Immunohistochemical expression
E-cadherin expression is reduced in 45% of cancers of various organs22. Expression by carcinomas is inversely proportional to the degree of differentiation. Loss of E-cadherin-mediated cell-cell adhesion is associated with the progression of many carcinomas2, including breast5, bladder6,12 and squamous head and neck carcinomas7. It is associated with high grade of hepatocellular carcinoma13. In gastric carcinoma, the results have been variable, with loss of E-cadherin expression correlating with poor differentiation: it has been shown to be associated with lymph node metastases and poor prognosis in advanced9,10 but not early gastric carcinoma8. Hereditary autosomal dominant diffuse-type gastric carcinoma usually results from germline truncating mutations in the E-cadherin gene21. Alterations of E-cadherin expression have also been reported in pre-invasive lesions, including colonic adenomas, cervical intraepithelial neoplasia gastric intestinal metaplasia8 and dysplastic Barrett's oesophagus. The E-cadherin-complex distribution is not a prognostic marker in neuroendocrine tumours of the lung4. In sarcomas, E-cadherin expression may be associated with epithelioid differentiation14, although epithelioid sarcoma does not express E-cadherin15.
Abnormal a-catenin expression has been reported in carcinomas of the stomach, colon, oesophagus, ovaries and breast22.
b-catenin expression is decreased in gastrointestinal16 and breast22 carcinomas but increased in various mesenchymal tumours, including desmoid tumours, osteosarcoma, synovial sarcoma, rhabdomyosarcoma and MFH17.
g-catenin and p120-catenin expression is associated with poor survival in bladder cancer23.
Expression of E-cadherin and of a-, b- & g- catenins did not prove markers of metastatic potential in colorectal tumours18.
E-cadherin expression is greater in primary melanoma than in metastases; there is a loss of cytoplasmic reactivity for a- and b-catenins in metastatic melanoma compared with primaries: nuclear expression of b- catenin is greater in deep primaries and metastases than in superficial primaries20.
Impaired E-cadherin or b-catenin expression is associated with nodal metastases in both typical36 and atypical37 pulmonary carcinoids.
In pancreatic endocrine tumours,
aberrant expression(normal expression of both e-cadherin and b-catenin is membranous; decreased, cytoplasmic or nuclear staining is regarded as abnormal.) of e-cadherin and b-catenin is associated with invasive tumour behaviour38.
Diagnostic utility
-
Differentiation of non-neoplastic mesothelial cells from mesothelial and carcinoma cells in effusions: positivity seen in reactive mesothlium; 0/16, mesothelioma; 16/16 and adenocarcinoma; 45/5231.
-
Differentiation of non-neoplastic mesothelial cells from carcinoma cells in effusions. (E-cadherin expression is up-regulated in the ovarian tumour cells in the effusion by comparison with the solid tumours)3:
|
E-cadherin immunoreactivity
|
Staining extent: percentages of cells with membranous staining)
|
|
|
0%
|
1-5%
|
6-25%
|
26-75%
|
76-100%
|
|
Primary ovarian carcinoma
|
3% (1/36)
|
39% (14/36)
|
36% (13/39)
|
8% (3/36)
|
14% (5/36)
|
|
Metastatic ovarian carcinoma
|
3% (3/61)
|
54% (33/61)
|
22% (13/61)
|
11% (7/61)
|
10% (6/61)
|
|
Ovarian carcinoma cells in effusion
|
6% (4/67)
|
9% (6/67)
|
10% (7/67)
|
10% (7/67)
|
65% (43/67)
|
|
Reactive mesothelial cells in effusion
|
98% (51/52)
|
0
|
2% (1/52)
|
0
|
0
|
-
E-cadherin may be less valuable in differentiating mesothelial cells from carcinoma cells in other tumours that exhibit loss of cell cohesion, such as lobular breast and gastric carcinomas, where there is a higher frequency of mutation3.
-
Differentiation of mesothelioma from adenocarcinoma:
|
N-cadherin
|
adenocarcinoma
|
mesothelioma
|
|
Peralta-Soler 1995 (monoclonal 13A9, on frozen sections)25
|
3/16(positivity seen in only a few cells)
|
19/19
|
|
Han 19971
|
0/13
|
12/13
|
|
Han 1999 (monoclonal 13A9, on cytological preparations)26
|
0/8
|
4/4(cell-cell membrane staining)
|
|
Simsir 1999 (on cytological preparations)29
|
14/29
|
9/26
|
|
Thirkettle 2000 (monoclonal 13A9)27
|
not studied
|
26/29
|
|
Davidson 2001 (3B9 Zymed, on cytological preparations)28
|
47/98(positivity was seen in 34/48 serous ovarian carcinomas, 3/3 primary peritoneal carcinomas, 3/16 breast carcinomas, 1/6 endometrial carcinomas)
|
12/12
|
|
Abutaily 200224
|
9/35(mainly cytoplasmic staining)
|
32/41(8/11 epithelioid, 18/23 mixed and 6/7 sarcomatoid)
|
|
Laskin 200233
|
not studied
|
14/20
|
|
Ordonez 2003(3B9 Zymed)30
|
15/50(All cases were pulmonary adenocarcinomas. 6 cases showed positivity of 50-75% of cells, 3 cases 25-50%, 4 cases 1-25% and 2 cases <1% of cells)
|
44/60(epithelioid mesotheliomas: staining was membranous, in 11 cases >75% of cells stained, in 14 cases 50-75% of cells stained), in 13 cases 25-50% of cells stained, in 5 cases 1-25% of cells stained and in 1 case <1% of cells stained)
|
|
Overall
|
35% (88/249)
|
77% (172/224)
|
A systematic review of five studies (consisting of 151 epithelioid mesotheliomas and 121 pulmonary adenocarcinomas) reported sensitivities and specificities of n-cadherin for epithelioid mesothelioma of 78% and 84%35.
|
E-cadherin
|
adenocarcinoma
|
mesothelioma
|
|
Peralta-Soler 1995 (monoclonal E9, on frozen sections)25
|
16/16(primary lung adenocarcinomas)
|
8/19(staining was faint or focal)
|
|
Han 1997 (monoclonal E9)1
|
13/14
|
1(focal)/14
|
|
Leers 1998 (monoclonal HECD1, Takara)11
|
20/21(various sites of origin; 17 cases >10% of cells, 3 cases 1% to 10% of cells staining)
|
3/20(2 cases >10% of cells, 1 case 1% to 10% of cells staining)
|
|
Han 1999 (monoclonal 36 Transduction Laboratories, on cytological preparations)26
|
8/8
|
4/4
|
|
Simsir 1999 (monoclonal Transduction Laboratories, on cytological preparations)29
|
28/29(various sites of origin)
|
12/26
|
|
Thirkettle 200027
|
not studied
|
14/25(epithelioid or mixed mesotheliomas; focal positivity)
|
|
Kitazume 2000 (monoclonal HECD1, Takara, on cytological preparations)31
|
45/52
|
9/9
|
|
Ordonez 2000 (clone 5H9, Caltag)32
|
109/135(40 pulmonary and 95 various extrapulomonary sites of origin)
|
3/50
|
|
Davidson 2001 (HECD1 Zymed, on cytological preparations)28
|
90/98
|
10/12
|
|
Laskin 2002(HECD1 Zymed)33
|
not studied
|
4/20(all histological types)
|
|
Abutaily 200224
|
35/35(membranous staining)
|
9/41(5/11 epithelioid, 4/23 mixed and 0/7 sarcomatoid)
|
|
Ordonez 2003(HECD1 Zymed)30
|
44/50(All cases were pulmonary adenocarcinomas. 7 cases showed positivty of 50-75% of cells, 20 cases 25-50%, 8 cases 1-25% and 9 cases <1% of cells)
|
24/60(epithelioid mesotheliomas: staining was membranous, in 3 cases >75% of cells stained, in 2 cases 50-75% of cells stained), in 5 cases 25-50% of cells stained and in 14 cases 1-25% of cells stained.)
|
|
Overall
|
89% (408/458)
|
34% (101/300)
|
A systematic review of seven studies (consisting of 183 pulmonary adenocarcinomas and 218 epithelioid mesotheliomas) reported sensitivities and specificities of e-cadherin for pulmonary adenocarcinoma of 86% and 82%35.
E-cadherin may be preferentially expressed in epithelioid mesothelioma (48%) by comparison with sarcomatoid mesothelioma (7%)19. Nuclear b-catenin expression is seen in 17% of mesotheliomas, irrespective of the presence of E-cadherin19.
P-cadherin may be useful in the assessment of invasion in breast neoplasia, by demonstration of the presence or absence of myoepithelial cells.
References
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2 Y Ohene-Abuakwa et al. Expression of the E-cadherin/catenin (a-, b-, g-) complex correlates with the macroscopic appearance of early gastric cancer. J Pathol 2000;192:433-439.
3 B Davidson et al. E-cadherin and a-, b-, and g-catenin protein expression is up-regulated in ovarian carcinoma cells in serous effusions. J Pathol 2000;192:460-469.
4 CE Clavel et al. Expression of the E-cadherin-catenin complex in lung neuroendocrine tumours. J Pathol 2001;194:20-26.
5 Lipponen, P., Saarelainen, E., Ji, H., Aaltomaa, S., Syrjanen, K. Expression of E-cadherin (E-CD) as related to other prognostic factors and survival in breast cancer. J Pathol 1994;174:101-109.
6 Bringuier, P. P., Umbas, R., Schaafsma, H. E., Karthaus, H. F., Debruyne, F. M., Schalken, J. A. Decreased E-cadherin immunoreactivity correlates with poor survival in patients with bladder tumors. Cancer Res 1993;53:3241-3245
7 Mattijssen, V., Peters, H. M., Schalkwijk, L., Manni, J. J., van 't Hof-Grootenboer, B., de Mulder, P. H., Ruiter, D. J. E-cadherin expression in head and neck squamous-cell carcinoma is associated with clinical outcome. Int J Cancer 1993;55:580-585.
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10 Gabbert, H. E., Mueller, W., Schneiders, A., Meier, S., Moll, R., Birchmeier, W., Hommel, G. Prognostic value of E-cadherin expression in 413 gastric carcinomas. Int J Cancer 1996;69:184-189.
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13 Cancer Lett 1991;52:131-5
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15 Smith, M. E., Brown, J. I., Fisher, C. Epithelioid sarcoma: presence of vascular-endothelial cadherin and lack of epithelial cadherin. Histopathology 1998;33:425-431.
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38 Chetty R, Serra S,Asa SL Loss of membrane localization and aberrant nuclear E-cadherin expression correlates with invasion in pancreatic endocrine tumors. Am J Surg Pathol 2008; 32:413-9
This page last revised 14.5.2008.
©SMUHT/PW Bishop