High-throughput tissue microarray analysis used to evaluate biology and prognostic significance of the E-cadherin pathway in non-small-cell lung cancer.
OBJECTIVE
E-cadherin (E-cad) and its associated intracellular molecules, catenins, are critical for intercellular epithelial adhesion and are often expressed in non-small-cell lung carcinomas (NSCLCs). We constructed tissue microarrays (TMAs) to investigate the expression of cadherins and catenins and their prognostic significance in NSCLC.


METHODS
Tumor tissue samples from 193 patients with stages I to III NSCLC were obtained from the University of Colorado Cancer Center and Johns Hopkins Medical Institutions. Viable tumor was sampled in triplicate for the TMAs, and slides were stained by immunohistochemistry with antibodies against E-cad, N-cadherin, alpha (alpha)-, beta (beta)-, and gamma (gamma)-catenin, p120, p27, and adenomatous polyposis coli (APC) gene product. Clinical data were collected by the tumor registries. Patients were followed for a median period of 51 months (range, 18 to 100 months).


RESULTS
Absent or severely reduced membranous expression for E-cad, alpha-, beta-, and gamma-catenin, and p120 were observed in 10%, 17%, 8%, 31%, and 61% of the cases, respectively. Tumor cell dedifferentiation correlated with reduced expression for E-cad, beta-catenin, gamma-catenin, and p120 in squamous cell carcinomas but not in adenocarcinomas. There was an inverse correlation between nodal metastasis and expression of E-cad and gamma-catenin. Besides the traditional clinical prognostic variables, E-cad and alpha-, beta-, and gamma-catenin expression were of positive prognostic value in univariate survival analyses. In multivariate analysis, E-cad expression was the only independent prognostic factor for survival in addition to age, node status, tumor status, and pathologic surgical margins.


CONCLUSIONS
Reduced expression of E-cad and catenins is associated with tumor cell dedifferentiation, local invasion, regional metastasis, and reduced survival in NSCLC. E-cad is an independent prognostic factor for NSCLC survival.
Bremnes
R M
RM
Department of Pathology, Division of Medical Oncology, University of Colorado Cancer Center, Denver, CO, USA. roy.bremnes@rito.no
Veve
R
R
Gabrielson
E
E
Hirsch
F R
FR
Baron
A
A
Bemis
L
L
Gemmill
R M
RM
Drabkin
H A
HA
Franklin
W A
WA
D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015820:Cadherins / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D051177:Catenins; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D008875:Middle Aged; D009124:Muscle Proteins; D009367:Neoplasm Staging; D010750:Phosphoproteins / Q000378:metabolism; D011379:Prognosis; D015996:Survival Rate; D000095002:Delta Catenin
D025601:Adenomatous Polyposis Coli Protein; D015820:Cadherins; D051177:Catenins; D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D009124:Muscle Proteins; D010750:Phosphoproteins; C058992:Tagln protein, mouse; D000095002:Delta Catenin