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, bladder^6,12 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 advanced^9,10 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 lung^4. 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.

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

 ¹ Han, A. C., Peralta-Soler, A., Knudsen, K. A., Wheelock, M. J., Johnson, K. R., Salazar, H. Differential expression of N-cadherin in pleural mesotheliomas and E- cadherin in lung adenocarcinomas in formalin-fixed, paraffin-embedded tissues. Hum Pathol 1997;28(6):641-5.

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.

⁸ Blok, P., Craanen, M. E., Dekker, W., Tytgat, G. N. Loss of E-cadherin expression in early gastric cancer. Histopathology 1999;34:410-415

⁹ Yonemura, Y., Ninomiya, I., Kaji, M., Sugiyama, K., Fujimura, T., Tsuchihara, K., Kawamura, T., Miyazaki, I., Endou, Y., Tanaka, M. et al. Decreased E-cadherin expression correlates with poor survival in patients with gastric cancer. Anal Cell Pathol 1995;8:177-190

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.

¹¹ Leers, M. P., Aarts, M. M., Theunissen, P. H. E-cadherin and calretinin: a useful combination of immunochemical markers for differentiation between mesothelioma and metastatic adenocarcinoma. Histopathology 1998;32:209-216.

¹² Ross, J. S., del Rosario, A. D., Figge, H. L., Sheehan, C., Fisher, H. A., Bui, H. X. E-cadherin expression in papillary transitional cell carcinoma of the urinary bladder. Hum Pathol 1995;26:940-944.

¹³ Cancer Lett 1991;52:131-5

¹⁴ Smith MEF, Cowley GP, Dogan A et al. E-cadherin is a differentiation antigen of normal Schwann cells and is expresed in epithliod Schwann cell tumours. J Pathol 1994;173:181A

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.

¹⁶ Takayama, T., Shiozaki, H., Shibamoto, S. et al. Beta-catenin expression in human cancers. Am J Pathol 1996;148:39-46.

¹⁷ Iwao, K., Miyoshi, Y., Nawa, G., Yoshikawa, H., Ochi, T., Nakamura, Y. Frequent beta-catenin abnormalities in bone and soft-tissue tumors. Jpn J Cancer Res 1999;90:205-9.

¹⁸ El-Bahrawy, M. A., Poulsom, R., Jeffery, R., Talbot, I., Alison, M. R. The expression of E-cadherin and catenins in sporadic colorectal carcinoma. Human Pathol 2001;32:1216-1224.

¹⁹ Abutaily AS, Collins JE, Roche WR. Cadherins, catenins and APC in pleural malignant Mesothelioma. Pathological Society, July 2002, abstract no 37.

²⁰ Ali-Khan AS, Intzedy L, Pignatelli M. Expression of E-cadherin and associated molecules in malignant melanoma. Pathological Society, July 2002, abstract no 163.

²¹ Sobrinho-Simoes, M. and Oliveira, C. Different types of epithelial cadherin alterations play different roles in human carcinogenesis. Adv Anat Pathol 2002;9:329-37.

²² Nakopoulou, L., Gakiopoulou-Givalou, H., Karayiannakis, A.J., Giannopoulou, I., Keramopoulos, A., Davaris, P. and Pignatelli, M. Abnormal alpha-catenin expression in invasive breast cancer correlates with poor patient survival. Histopathology 2002;40:536-46.

²³ Shimazui, T., Schalken, J.A., Giroldi, L.A., Jansen, C.F., Akaza, H., Koiso, K., Debruyne, F.M. and Bringuier, P.P. Prognostic value of cadherin-associated molecules (alpha-, beta-, and gamma-catenins and p120cas) in bladder tumors. Cancer Res 1996;56:4154-8.

²⁴ Abutaily, A.S., Addis, B.J. and Roche, W.R. Immunohistochemistry in the distinction between malignant mesothelioma and pulmonary adenocarcinoma: a critical evaluation of new antibodies. J Clin Pathol 2002;55:662-8.

²⁵ Peralta Soler, A., K. A. Knudsen, et al. (1995). "The differential expression of N-cadherin and E-cadherin distinguishes pleural mesotheliomas from lung adenocarcinomas." Hum Pathol 26(12): 1363-9.

²⁶ Han, A. C., M. R. Filstein, et al. (1999). "N-cadherin distinguishes pleural mesotheliomas from lung adenocarcinomas: a ThinPrep immunocytochemical study." Cancer 87(2): 83-6.

²⁷ Thirkettle, I., P. Harvey, et al. (2000). "Immunoreactivity for cadherins, HGF/SF, met, and erbB-2 in pleural malignant mesotheliomas." Histopathology 36(6): 522-8.

²⁸ Davidson, B., S. Nielsen, et al. (2001). "The role of desmin and N-cadherin in effusion cytology: a comparative study using established markers of mesothelial and epithelial cells." Am J Surg Pathol 25(11): 1405-12.

²⁹ Simsir, A., P. Fetsch, et al. (1999). "E-cadherin, N-cadherin, and calretinin in pleural effusions: the good, the bad, the worthless." Diagn Cytopathol 20(3): 125-30.

³⁰ Ordonez, N. G. (2003). "The immunohistochemical diagnosis of mesothelioma: a comparative study of epithelioid mesothelioma and lung adenocarcinoma." Am J Surg Pathol 27(8): 1031-51.

³¹ Kitazume, H., K. Kitamura, et al. (2000). "Cytologic differential diagnosis among reactive mesothelial cells, malignant mesothelioma, and adenocarcinoma: utility of combined E- cadherin and calretinin immunostaining." Cancer 90(1): 55-60.

³² Ordonez, N. G. (2000). "Value of thyroid transcription factor-1, E-cadherin, BG8, WT1, and CD44S immunostaining in distinguishing epithelial pleural mesothelioma from pulmonary and nonpulmonary adenocarcinoma." Am J Surg Pathol 24(4): 598-606.

³³ Laskin, W. B. and M. Miettinen (2002). "Epithelial-type and neural-type cadherin expression in malignant noncarcinomatous neoplasms with epithelioid features that involve the soft tissues." Arch Pathol Lab Med 126(4): 425-31.

³⁴ Kovacs, A. and R. A. Walker (2003). "P-cadherin as a marker in the differential diagnosis of breast lesions." J Clin Pathol 56(2): 139-41.

³⁵ King JE, Thatcher N, Pickering CA, et al. Sensitivity and specificity of immunohistochemical markers used in the diagnosis of epithelioid mesothelioma: a detailed systematic analysis using published data. Histopathology 2006; 48:223-32

This page last revised 16.2.2006.

©SMUHT/PW Bishop