Plasma Cytokines Correlated With Disease Characteristics, Progression-Free Survival, and Overall Survival in Testicular Germ-Cell Tumor Patients

Abstract

Background

Cytokines are the communicators of immune system and are involved in all immune responses. The aim of this study was to assess the correlation among plasma cytokines, patient and tumor characteristics, and clinical outcome in chemonaive testicular germ-cell tumor (TGCT) patients.

Patients and Methods

This study included 92 metastatic chemotherapy-naive TGCT patients treated with platinum-based chemotherapy from July 2010 to March 2014. Plasma was isolated before first administration of chemotherapy, and the concentration of 51 plasma cytokines were analyzed using multiplex bead arrays.

Results

At a median follow-up of 33.2 months (range, 0.1-54.8 months), 10.9% of patients experienced disease progression, and 7.6% died. Several cytokines were associated with different baseline clinicopathologic features. Elevated plasma levels of interferon (IFN)-α2, interleukin (IL)-2Rα, IL-16, hepatocyte growth factor (HGF), and monocyte chemotactic protein (MCP)-3 were significantly associated with worse progression-free survival and overall survival (OS). Moreover, elevated levels of stem-cell growth factor (SCGF)-β were also associated with worse OS. Patients with elevated levels of all 6 cytokines experienced significantly worse outcomes compared to patients who had fewer than 6 cytokines elevated (hazard ratio = 12.06; 95% confidence interval, 7.39-19.49; P = .002 for progression-free survival, and hazard ratio = 39.65; 95% confidence interval, 25.03-62.18; P < .00001 for OS, respectively). Results were independent of International Germ Cell Cancer Collaborative Group criteria.

Conclusion

We found a correlation among progression free-survival, OS, and circulating cytokines in TGCT. This suggests the existence an association between plasma cytokines and baseline clinicopathologic features in TGCT. Plasma cytokines could be used for identification of high-risk patients who are candidates for new therapeutic approaches.

Introduction

Testicular germ-cell tumors (TGCT) are the most common malignancy among young men aged between 15 and 35 years.¹ Cisplatin-based chemotherapy is the mainstay treatment of TGCT; however, approximately 20% of the patients fail to be cured after the first-line treatment.² To improve patient outcome, we must identify these patients by relevant, easily accessible biomarkers and recognize pathways involved in tumor progression.

Cytokines, as the communicators of the immune system, play a crucial role in all phases of cancer pathogenesis. Some cytokines have a tumor suppressor effect, while in advanced cancer, cytokines promote growth, attenuate apoptosis, and facilitate invasion and metastasis.3, 4, 5 They can act directly as growth and angiogenic factors, or they can function through effect on several types of cells, such as tumor-associated macrophages. Tumor cells themselves express chemokine receptors, which possibly support tumor-cell survival and invasion. Attraction of neutrophils may also play a key role in triggering and sustaining the inflammatory cascade.⁶ Recruiting Th2 effectors and regulatory T cells by chemokines may help tumor escape from the immune system.7, 8

The association between high levels of circulating cytokines and poor outcome has been described in many cancer types, including breast, gastric, prostate, head and neck, renal cell, colorectal, and hematologic malignancies.4, 9, 10 Cytokines are involved in both normal testicular function and tumorigenesis. Anti-inflammatory cytokines of the transforming growth factor (TGF)-β family are implicated in testicular development. Leukemia inhibitory factor and pro-inflammatory cytokines including IL (interleukin)-1, IL-6, and tumor necrosis factor (TNF) have direct effects on spermatogenic cell differentiation and testicular steroidogenesis.11, 12, 13 LIX (lipopolysaccharide-induced CXC chemokine) plays a role in the maintenance of spermatogonial stem cells after puberty,¹⁴ while insulin growth factor (IGF)-1 enhances testosterone production in Leydig cells, guarantees Sertoli cell homeostasis, and stimulates spermatogonia production.¹⁵ IGF-2 participates in embryonic and fetal development, and it can enhance the proliferation of spermatogonia in vitro; however, its postnatal function is not yet clear.¹⁶

Cytokines are also involved in pathogenesis of TGCT. Stem-cell factor (SCF), with its receptor (c-kit) and stromal-cell–derived factor (SDF)-1 with corresponding receptors CXCR4 and CXCR7, have been implicated in primordial germ-cell migration, proliferation, and survival.17, 18 Elevated intratumoral level of CXCR4 compared to nonseminoma or normal testis potentially reflect the higher proportion of dysfunctional germ cells within seminomas.¹⁸ Pure seminoma but not nonseminoma also showed a strong immunohistochemical reaction for both SCF and c-kit protein on the surface of the tumor cells.¹⁹ Vascular endothelial growth factor (VEGF) expression predicted metastasis in seminomas, and HST-1 (a member of the fibroblast growth factors) expression was associated with nonseminomas and with tumor stage.²⁰ Data have shown that IGF-1/insulin-like growth factor receptor (IGFR), and SDF-1/CXCR4 signaling pathways are important mediators of TGCT pathogenesis, as they are involved in many metastatic processes, such as cell proliferation, migration, and angiogenesis.15, 21, 22, 23 Moreover, IGF-2, fibroblast growth factor (FGF)-8, and FGF-9 have a prosurvival effect on teratoma/teratocarcinoma.15, 24, 25

Peripheral blood is easily accessible and enables repeated examination during the course of the disease. Plasma cytokines have showed clinical usefulness in numerous studies in different types of cancer; however, the prognostic value of plasma cytokines in TGCT remains to be investigated. The aim of this study was to assess the association among plasma cytokines, baseline clinicopathologic features, and clinical outcome in chemonaive TGCT patients. This exploratory analysis of 51 plasma cytokines was performed to assess potential cytokines involved in TGCT pathogenesis.