Prognostic Value of Apoptosis-Inducing Factor (AIF) in Germ Cell Tumors.

Katarina Letkovska,Vera Miskovska,Katarína Kalavska,Jozef Mardiak,Katarina Rejlekova,Silvia Schmidtova,Samuel Horak,Zuzana Cierna,Michal Mego,Veronika Liskova,Pavel Janega,Michal Chovanec,Pavel Babal

doi:10.3390/cancers13040776

Katarina Letkovska, Vera Miskovska + Show 11 more

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https://doi.org/10.3390/cancers13040776

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Abstract

Simple SummaryGerm cell tumors (GCTs) are the most common solid malignancies in young men. GCTs are extraordinary sensitive to chemotherapy and represent a model of curable cancer. However, in a small proportion of patients the disease progresses or relapses despite administration of salvage chemotherapy. Apoptosis is a form of programmed cell death that occurs in multicellular organisms. It is well established that dysregulation of apoptosis plays an important role in pathogenesis of malignant diseases and may be associated with tumor progression and resistance to cytotoxic treatment. This study aimed to evaluate expression of apoptosis inducing factor (AIF) in GCTs. We observed lower AIF expression in GCTs compared to normal testicular tissue. We also showed prognostic significance of AIF in GCTs. AIF downregulation might represent one of the mechanisms of inhibition of apoptosis with subsequent facilitation of cell survival and metastatic dissemination of GCTs and perhaps could serve as a potential therapeutic target. Apoptosis is a strictly regulated process essential for preservation of tissue homeostasis. This study aimed to evaluate expression of apoptosis inducing factor (AIF) in testicular germ cell tumors (GCTs) and to correlate expression patterns with clinicopathological variables. Formalin-fixed and paraffin-embedded specimens of non-neoplastic testicular tissue and GCTs obtained from 216 patients were included in the study. AIF expression was detected by immunohistochemistry, scored by the multiplicative quickscore method (QS). Normal testicular tissue exhibits higher cytoplasmic granular expression of AIF compared to GCTs (mean QS = 12.77 vs. 4.80, p < 0.0001). Among invasive GCTs, mean QS was the highest in embryonal carcinoma, yolk sac tumor and seminoma, lower in teratoma and the lowest in choriocarcinoma. No nuclear translocation of AIF was observed. Nonpulmonary visceral metastases were associated with lower AIF expression. Metastatic GCTs patients with high AIF expression had better overall survival compared to patients with low AIF expression (HR = 0.26, 95% CI 0.11–0.62, p = 0.048). We observed significantly lower AIF expression in GCTs compared to normal testicular tissue, which is an uncommon finding in malignant tumors. AIF downregulation might represent one of the mechanisms of inhibition of apoptosis and promotion of cell survival in GCTs.

Highlights

Testicular tumors represent a heterogenous group of neoplastic diseases accounting for approximately 1% of all malignant tumors in men
While cisplatin resistant cells NTERA-2 showed significant higher apoptosis inducing factor (AIF) expression when compared to sensitive cells (p = 0.00118), in seminoma cell line TCam-2 significant higher AIF expression on mRNA level was detected in sensitive cells (p = 0.00369) (Figure 1)
There were no differences in AIF expression on protein level between cisplatin sensitive or resistant germ cell tumors (GCTs) cell lines, nor between cell lines derived from different histological subtype of GCTs (Figure 2 and Supplementary Figure S1)

Summary

Introduction

Testicular tumors represent a heterogenous group of neoplastic diseases accounting for approximately 1% of all malignant tumors in men. Germ cell tumors (GCTs) are the most common type [1]. Prognosis of GCTs is influenced by multiple factors, including histologic diagnosis of the tumor, its primary location, location of metastases, and clinical stage of the disease. Through identification of these parameters, patients with metastatic GCTs are categorized into ‘good’, ‘intermediate’ and ‘poor’ prognosis. This system proposed by International Germ Cell Cancer Collaborative Group (IGCCCG) in 1997 is beneficial for risk-based decisions in therapy [6,7]. In small proportion of patients the disease progresses or relapses despite administration of salvage chemotherapy [9,10,11,12]

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