Sequential changes in cadherin-catenin expression associated with the progression and heterogeneity of primary oesophageal squamous carcinoma.

Abstract

Maintenance of an adhesive function for cadherins requires appropriate membranous cellular expression and intact cadherin-catenin complexes. In normal squamous mucosa of the oesophagus there is membranous co-expression of E- and P-cadherin (E-cad, P-cad) in the basal compartment, whereas suprabasal stratification is associated with preservation of E-cad expression but loss of P-cad. Immunohistochemical staining of squamous dysplasia/carcinoma in situ shows a striking increase in the proportion of cells within the epithelial compartment showing co-expression of E- and P-cad with strong appropriate membranous expression of beta and gamma catenin. Strong membranous co-expression of E- and P-cad and beta catenin is seen on keratinocytes at the periphery of islands of invasive better-differentiated squamous carcinoma with keratinisation, mimicking normal mucosa. Beta catenin may be phosphorylated with implied loss of cadherin binding. Membranous cadherin and catenin expression is significantly down-regulated in poorly differentiated squamous carcinoma. No beta catenin mutations were demonstrated in squamous carcinomas following DNA extraction and sequencing, nor was any nuclear cadherin seen. Changes in cadherin-catenin complexes with cellular phenotype is well demonstrated in spindle cell carcinomas with a shift of cadherin expression from membranous to cytoplasmic between the epithelioid and spindle cell components of the tumour and with loss of expression in the sarcomatoid elements. In conclusion, we demonstrate an increased expression of P-cadherin early in tumourigenesis with loss of cadherin-catenin complexes in poorly differentiated invasive carcinomas. Cadherin/catenin expression may govern both the phenotype and biology of oesophageal squamous carcinomas.