Endocrine Abstracts

Introduction: Adrenocortical carcinoma (ACC) is an aggressive tumour with unsatisfactory treatment options in advanced disease. Activation of epithelial to mesenchymal transition (EMT) has been described as causative of metastatic spread in human cancers. New drugs were developed targeting EMT with a focus on FGF/FGFR signalling. We here asked whether EMT is relevant in ACC.

Methods: We analysed 6 normal adrenal glands (NAG), 40 adrenocortical adenomas (ACA) and 55 ACC. Epithelial and mesenchymal markers were analysed by IHC. Expression of FGFR1-4 was quantified using RNAscope and qRT-PCR was employed to quantify expression of 92 FGF-FGFR pathway genes. Isoform switching between FGFR isoforms IIIb (epithelial) and IIIc (mesenchymal) was assessed by qRT-PCR.

Results: Surprisingly, all adrenal tissues lacked E-cadherin expression while N-cadherin was present in both normal and neoplastic adrenal tissues but was significantly lower in malignant vs benign tissues (0.88 vs 1.64, P = 0.007). SLUG had a uniformly high nuclear expression in all adrenal tissues. FGFR2 mRNA was expressed at lower levels in ACC compared to ACA (3.1 vs 5.2 mRNA copies/cell, P = 0.005) whereas FGFR1 (8.2 vs 1.7, P = 0.0001) and FGFR4 (5.5 vs 2.1, P = 0.0004) were significantly higher in ACC. FGF/FGFR pathway analysis confirmed differential FGFR expression and revealed decreased expression of FGF7, FGF17 and mitogen associated protein kinases in tumors compared with NAG. Again surprisingly, all adrenal tissues had higher expression of IIIc vs IIIb isoform for FGFR. A brief comparison between adrenocortical tissues versus known epithelial tumors as well as mesenchymal tumors shows that in terms of the common markers, adrenal tissues are more mesenchymal than epithelial.

Conclusions: Normal but also tumoral adrenocortical tissues exhibit consistent expression of proteins considered to reflect mesenchymal differentiation. However, significant changes in expression of mesenchymal markers suggest their relevance in adrenocortical tumorigenesis and progression. Receptor tyrosine kinases FGFR1 and 4 may be also a suitable treatment target for advanced ACC.