C-MET receptor as potential biomarker and target molecule for malignant testicular germ cell tumors.

Katia Corano Scheri,Leendert H.J Looijenga,Luisa Gesualdi,Erica Leonetti,Angela Catizone,Giulia Ricci,Luigi Laino,J Wolter Oosterhuis,Mariano Bizzarri,Hans Stoop,Paola Grammatico,Renato Franco,Vincenzo Gigantino

doi:10.18632/oncotarget.25867

Abstract

Type II testicular germ cell tumors (TGCTs) represent the most frequent malignancy in Caucasian males (20–40 years). Even if diagnosed with disseminated disease, >80% of patients are cured; however, a small percentage of cases progress and result in death. It is commonly accepted that these cancers arise from a disturbed testicular embryonic niche that leads to the block of gonocyte differentiation. The subsequent development of the invasive seminomas and non-seminomas is due to a combination of genetic, epigenetic and microenvironment-based alterations (genvironment). Hepatocyte growth factor (HGF) is present in the testicular microenvironment, together with its receptor c-MET, from early embryonic development to an adult stage. In addition, c-MET is a well-known proto-oncogene involved in the onset and progression of various human cancers. Herein, we have investigated the expression and availability of HGF and c-MET in TCam-2, NCCIT and NT2D1 cells, which are type II (T)GCT representative cell lines, and the effect of c-MET activation/repression on the regulation of cancerous biological processes. We found that NT2D1 cells increase their proliferation, polarized migration, and invasion in response to HGF administration. NCCIT cells respond to HGF stimulation only partially, whereas TCam-2 cells do not respond to HGF, at least according to the investigated parameters. Interestingly, the immunohistochemical study of c-MET distribution in TGCTs confirm its presence in both seminoma and non-seminoma lesions with different patterns. Notably, we found the highest c-MET immunoreactivity in the epithelial elements of the various components of TGCTs: teratoma, yolk sac tumor and choriocarcinoma.

Highlights

Testicular germ cell tumors are a heterogeneous group of neoplasms with different histopathology and variable clinical course
Since Mesenchymal Epithelial Transition factor (c-MET) gene is located in the ch7q31 region, we decided to use fluorescence in situ hybridization (FISH) analysis to assess if GCT cell lines gained the c-MET gene
The c-MET fulllength protein content appears to be differently regulated in these (T)GCT cells, being more abundant in NT2D1 cells and less abundant in TCam-2 cells. - The (T)GCT cell line that expresses highest levels of full length c-MET protein, is the most sensitive to Hepatocyte growth factor (HGF) administration, as expected

Summary

Introduction

Testicular germ cell tumors are a heterogeneous group of neoplasms with different histopathology and variable clinical course. A genetic reprogramming of these cells gives rise to embryonal carcinoma cells, the stem cells of non-seminomas, malignant tumors that mimic embryonic development, both with possible embryonic (teratomas) and extra-embryonic differentiation (yolk sac tumors and choriocarcinomas) [2, 4, 5]. These cancers are mainly characterized by a good prognosis, since they are extraordinarily chemo- and radio-sensitive. In a small percentage of cases, a cisplatin-resistance exists, making cure difficult For this reason, TGCTs remain an important cause of mortality in young men. A deeper investigation of TGCT biology may allow an identification of novel biological therapies or novel predictive markers of an aggressive disease [6,7,8]

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