Immunohistochemical Investigation of HER/AKT/mTOR Pathway and Cellular Adhesion Molecules in Urothelial Carcinomas.

Nikolaos Koletsas,Stavros Touloupidis,Nikolaos Papadopoulos,Thomas Zaramboukas,Maria Lambropoulou,Konstantinos Anagnostopoulos,Triantafyllia Koletsa,Spyros Choidas,Georgia Raptou

doi:10.1155/2017/6794150

Abstract

Background. Several investigators have suggested the possibility that the expression of both EGFR and HER2 could be utilized for molecularly targeted therapy in urinary bladder cancer. We tried to evaluate the expression of HER2 and EGFR and activation of the AKT/PTEN/mTOR pathway in urothelial carcinomas and if there is any association between them and cellular adhesion molecules (CAMs). Materials and Methods. Forty-one paraffin-embedded urothelial cancer tissue blocks were collected. Immunostains for HER2, EGFR, MIB1, phospho-AKT, PTEN, phospho-mTOR, e-cadherin, p-cadherin, and b-catenin were performed on tissue microarrays sections. The immunohistochemical results were correlated with clinicopathological parameters. Results. The overexpression of HER2 was found in 19.6% of the cases and it was associated with high grade tumors with a high mitotic index and phosphorylation of AKT and mTOR. Muscle-invasive tumors presented both cytoplasmic and nuclear losses of PTEN expression. There was no association between HER/AKT/mTOR pathway activation and CAM expression. Although cadherins were often coexpressed, only p-cadherin immunoreactivity was associated with tumor grade and high proliferative index. Conclusions. HER2 overexpression is found in a respective proportion of urothelial carcinomas. P-cadherin expression is associated with high grade UCs but it is not affected by HER2 overexpression or by activation of HER/AKT/mTOR pathway.

Highlights

Several investigators have suggested the possibility that the expression of both EGFR and HER2 could be utilized for molecularly targeted therapy in urinary bladder cancer
The dimerization of human epidermal growth factor receptors (HER) members leads to the activation of intracellular RAS/MEK/ERK [5] and PI3K/AKT/PTEN/ mTOR [6, 7] pathways which plays an important role in cell proliferation, angiogenesis, invasion, and metastasis
Two of the HER family members, HER1/EGFR and HER2, have been researched extensively in the context of various types of cancer. Apart from their role in tumor proliferation, infiltration, and metastatic potential [22], the increasing interest in them derives from being targets of newly developed and FDA approved therapies

Summary

Introduction

Several investigators have suggested the possibility that the expression of both EGFR and HER2 could be utilized for molecularly targeted therapy in urinary bladder cancer. We tried to evaluate the expression of HER2 and EGFR and activation of the AKT/PTEN/mTOR pathway in urothelial carcinomas and if there is any association between them and cellular adhesion molecules (CAMs). In urothelial carcinomas HER1 and HER2 expression has been implicated in tumor aggressiveness, poor outcome, or even pathogenesis [1,2,3,4] In recent years, their importance has been emphasized due to the development of targeted anti-HER therapy. The PI3K/AKT/PTEN/mTOR pathway is considered to be essential for cell growth, survival, cell motility, and angiogenesis [8,9,10,11] The activation of this pathway has been implicated in carcinogenesis or malignant potential of several cancers, including urothelial ones [12, 13]

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Results

Conclusion