Combining Cadherin Expression with Molecular Markers Discriminates Invasiveness in Growth Hormone and Prolactin Pituitary Adenomas

Abstract

Although growth hormone (GH)- and prolactin (PRL)-secreting pituitary adenomas are considered benign, in many patients, tumour growth and/or invasion constitute a particular challenge. In other tumours, progression relies in part on dysfunction of intercellular adhesion mediated by the large family of cadherins. In the present study, we have explored the contribution of cadherins in GH and PRL adenoma pathogenesis, and evaluated whether this class of adherence molecules was related to tumour invasiveness. We have first established, by quantitative polymerase chain reaction and immunohistochemistry, the expression profile of classical cadherins in the normal human pituitary gland. We show that the cadherin repertoire is restricted and cell-type specific. Somatotrophs and lactotrophs express mainly E-cadherin and cadherin 18, whereas N-cadherin is present in the other endocrine cell types. This repertoire undergoes major differential modification in GH and PRL tumours: E-cadherin is significantly reduced in invasive GH adenomas, and this loss is associated with a cytoplasmic relocalisation of cadherin 18 and catenins. In invasive prolactinomas, E-cadherin distribution is altered and is accompanied by a mislocalisation of cadherin 18, β-catenin and p120 catenin. Strikingly, de novo expression of N-cadherin is present in a subset of adenomas and cells exhibit a mesenchymal phenotype exclusively in invasive tumours. Binary tree analysis, performed by combining the cadherin repertoire with the expression of a subset of known molecular markers, shows that cadherin/catenin complexes play a significant role in discrimination of tumour invasion.

E‐cadherin expression is associated with somatostatin analogue response in acromegaly

“…Our results are in agreement with previous studies indicating that lower membranous E-cadherin levels are associated with aggressive features in pituitary tumours. 14,17,20 Importantly, our results revealed that loss of membranous E-cadherin localization is associated with poor response to SSAs in acromegaly patients, in line with a previous study. 14 Intriguingly, we observed a negative association between E-cadherin and SSTR5 expression in GH-producing tumours.…”

“…14,[17][18][19][20] However, the association between the loss of E-cadherin expression and aggressiveness of GH-producing tumours has yielded conflicting results. 14,[17][18][19][20] E-cadherin expression levels are also correlated with GH-producing tumour histological subtypes. Thus, whereas high E-cadherin expression levels are found in densely granulated somatotroph adenomas (DGSAs) tumours, low or absent E-cadherin expression is observed in sparsely granulated somatotroph adenomas (SGSAs).…”

“…However, not all pituitary cells were positive for E-cadherin, in agreement with previous studies. 20 Data are presented as median with interquartile ranges (IQR). ULN, upper limit of normal for age-and gender-matched IGF1 levels.…”

Expression of E-cadherin, Slug and NCAM and its relationship to tumor invasiveness in patients with acromegaly

“…The results are quite controversial regarding the role of these markers in the invasiveness of pituitary adenomas. Some studies indicate an association of markers with tumor invasiveness ( 6 , 7 , 9 ), while others do not recognize this association ( 10 – 12 ).…”

Germline Mutations in CDH23, Encoding Cadherin-Related 23, Are Associated with Both Familial and Sporadic Pituitary Adenomas

“…16,17 Deregulated expression and activity of some cadherin proteins are frequently observed in human PAs and are inferred to contribute to the pathogenesis of PAs. [18][19][20] In addition, CDH23 forms heterodimers and functions closely with protocadherin-related 15 (PCDH15), whose encoding gene is located near a genetic susceptibility locus for pituitary adenoma according to our previous work. 7 These findings further suggest mutations in CDH23 as a potential genetic risk factor for this familial PA.…”