Abstract
Germ cell tumors (GCTs) are the most common malignancies in young men. Most patients with GCT can be cured with cisplatin-based combination chemotherapy, even in metastatic disease. In case of therapy resistance, prognosis is usually poor. We investigated the potential of N-cadherin inhibition as a therapeutic strategy. We analyzed the GCT cell lines NCCIT, NTERA-2, TCam-2, and the cisplatin-resistant sublines NCCIT-R and NTERA-2R. Effects of a blocking antibody or siRNA against N-cadherin on proliferation, migration, and invasion were investigated. Mouse xenografts of GCT cell lines were analyzed by immunohistochemistry for N-cadherin expression. All investigated GCT cell lines were found to express N-cadherin protein in vitro and in vivo. Downregulation of N-cadherin in vitro leads to a significant inhibition of proliferation, migration, and invasion. N-cadherin-downregulation leads to a significantly higher level of pERK. N-cadherin-inhibition resulted in significantly higher rates of apoptotic cells in caspase-3 staining. Expression of N-cadherin is preserved in cisplatin-resistant GCT cells, pointing to an important physiological role in cell survival. N-cadherin-downregulation results in a significant decrease of proliferation, migration, and invasion and stimulates apoptosis in cisplatin-naive and resistant GCT cell lines. Therefore, targeting N-cadherin may be a promising therapeutic approach, particularly in cisplatin-resistant, therapy refractory and metastatic GCT.
Highlights
Germ cell tumors (GCTs) are the most common malignancies in young men between 15–40 years
N-cadherin protein expression was found in all GCT-cell lines examined, namely NCCIT, NTERA-2, and their cisplatin-resistant sublines, as well as in TCam-2 cells
In xenografts, expression of N-cadherin was higher in NTERA-2 and NCCIT, whereas the expression was lower in TCam-2 xenografts, showing an opposite pattern to the expression results found by Western Blotting
Summary
Germ cell tumors (GCTs) are the most common malignancies in young men between 15–40 years. The incidence of GCT has been constantly increasing over the last 40 years [1]. Distinction of the different histological subtypes is essential for the therapeutic management. Non-seminomas can be further subdivided into embryonic carcinomas (EC), yolk sac tumors (YS), chorionic carcinomas (CC), and teratomas (TER) [2]. Seminomas and non-seminomas have a common precursor called intratubular germ cell neoplasia (IGCNU) [3]. Patients with metastatic GCTs can be cured in about 80% of cases by using cisplatin-based combination chemotherapy [4, 5]. Patients with multiple relapses have an unfavorable prognosis, and long-term survival can be achieved in only 10–15% of these patients [6, 7].
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