Endocrine Abstracts

Somatotroph adenomas (SA) causing acromegaly are histologically classified into densely (DG) and sparsely granulated (SG) subtypes. We¹ and others have shown that these histological subtypes may be clinically relevant. In short, SGSAs are generally found in younger, mainly female patients. They are larger at presentation, more invasive and show higher proliferation indices compared with DGSAs. Fibrous bodies (FBs) are the histological hallmark of SGSAs; they consist of accumulated cytokeratins, implying loss of normal cytoskeletal architecture and disrupted membrane attachment in SGSAs. The mechanisms linking FB formation with a more invasive phenotype are not known. Here we tested the hypothesis that a regulator of adherens junction integrity, p120, is associated with FB formation. We conducted a comprehensive assessment of the adherens junction complex by immunohistochemistry and found that total loss of membranous E-cadherin and α-, β- and γ- catenin in SGSAs is associated with redistribution of p120 from the membrane to FBs. Alternative splicing of p120 leads to short (epithelial) and long (mesenchymal) variants. Colocalisation experiments showed that the short, but not the long p120 isoform was found at FBs. Expression (mRNA and protein) of the two isoforms remained unchanged; however, ESRP1 mRNA (a splicing regulator that promotes the epithelial p120 variant) was expressed 80-fold higher in DGSAs than SGSAs. It is hypothesised that sequestration of the short isoform of p120 at the FB inhibits function in SGSA cells, mimicking aspects of epithelial-to-mesenchymal transition, a common phenomenon associated with a more invasive phenotype in neoplasms. Further characterisation of this mechanism in SGSAs may reveal novel pharmacologic targets for the treatment of SGSAs that are resistant to current therapy.

References: 1. Larkin et al. Eur J Endocrinol 2013 168 (4) 491–499.