MET expression during prostate cancer progression.

Esther I Verhoef,Hein F.B.M Sleddens,Berdine Van Der Steen,Maria J De Herdt,Kimberley Kolijn,A Marije Hoogland,Geert J.L.H Van Leenders,Leendert H.J Looijenga

doi:10.18632/oncotarget.8829

Esther I Verhoef, Hein F.B.M Sleddens + Show 6 more

Open Access

https://doi.org/10.18632/oncotarget.8829

Copy DOI

Journal: Oncotarget	Publication Date: Apr 18, 2016
Citations: 19	License type: cc-by

Affiliation: Erasmus University Rotterdam

Abstract

Tyrosine-kinase inhibitors of the hepatocyte growth factor receptor MET are under investigation for the treatment of hormone-refractory prostate cancer (HRPC) metastasis. Analysis of MET protein expression and genetic alterations might contribute to therapeutic stratification of prostate cancer patients. Our objective was to investigate MET on protein, DNA and RNA level in clinical prostate cancer at various stages of progression.Expression of MET was analyzed in hormone-naive primary prostate cancers (N=481), lymph node (N=40) and bone (N=8) metastases, as well as HRPC (N=54) and bone metastases (N=15). MET protein expression was analyzed by immunohistochemistry (D1C2 C-terminal antibody). MET mRNA levels and MET DNA copy numbers were determined by in situ hybridization.None of the hormone-naive primary prostate cancer or lymph node metastases demonstrated MET protein or mRNA expression. In contrast, MET protein was expressed in 12/52 (23%) evaluable HRPC resections. RNA in situ demonstrated cytoplasmic signals in 14/54 (26%) of the HRPC patients, and was associated with MET protein expression (p=0.025, χ2), in absence of MET amplification or polysomy. MET protein expression was present in 7/8 (88%) hormone-naive and 10/15 (67%) HRPC bone metastases, without association of HRPC (p=0.37; χ2), with MET polysomy in 8/13 (61%) evaluable cases.In conclusion, MET was almost exclusively expressed in HRPC and prostate cancer bone metastasis, but was not related to MET amplification or polysomy. Evaluation of MET status could be relevant for therapeutic stratification of late stage prostate cancer.

Highlights

The tyrosine-kinase receptor MET and its ligand hepatocyte growth factor (HGF) play important roles in stromal-epithelial interactions in a diversity of tissues
MET protein expression was observed in preexistent basal and atrophic luminal glandular epithelium, which served as internal positive controls, and was variably expressed in both normal and tumor-associated endothelial cells (Figure 1A)
Recent phase II and III studies have demonstrated that treatment of metastasized hormone-refractory prostate cancer (HRPC) patients with Cabozantinib led to reduced tumor load on bone scans and in soft tissues together with prolonged progressionfree survival [15]

Summary

Introduction

The tyrosine-kinase receptor MET and its ligand hepatocyte growth factor (HGF) play important roles in stromal-epithelial interactions in a diversity of tissues. Upon secretion by mesenchymal cells HGF targets the MET receptor, contributing to embryogenesis, tissue development, proliferation and differentiation [1,2,3]. Over-expression and hyper-activation of MET has been found in various cancer types and is often associated with poor outcome, or a role in development and metastasis of cancer [4,5,6,7,8,9]. In prostate cancer MET is predominantly expressed in cells with an intermediate phenotype and enhanced at the tumor perimeter. Activation of MET in prostate cancer cell line DU145 results in cell migration, invasion and the acquisition of a stem-like phenotype [10,11,12]

Objectives

Methods

Results

Conclusion