Follistatin impacts Tumor Angiogenesis and Outcome in Thymic Epithelial Tumors

Stefan Janik,Bernhard Moser,Ana-Iris Schiefer,Hendrik Jan Ankersmit,Balazs Dome,Cecilia Veraar,Thomas Raunegger,Walter Klepetko,Philipp Hacker,Christine Bekos,Leonhard Müllauer

doi:10.1038/s41598-019-53671-8

Abstract

Tumor angiogenesis is a key factor in the progression of thymic epithelial tumors (TETs). Activin A, a member of the TGFβ family, and its antagonist Follistatin are involved in several human malignancies and angiogenesis. We investigated Activin A and Follistatin in serum and tumor tissue of patients with TETs in relation to microvessel density (MVD), WHO histology classification, tumor stage and outcome. Membranous Activin A expression was detected in all tumor tissues of TETs, while Follistatin staining was found in tumor nuclei and cytoplasm. Patients with TETs presented with significantly higher Activin A and Follistatin serum concentrations compared to healthy volunteers, respectively. Follistatin serum concentrations correlated significantly with tumor stage and decreased to physiologic values after complete tumor resection. Follistatin serum concentrations correlated further with MVD and were associated with significantly worse freedom from recurrence (FFR). Low numbers of immature tumor vessels represented even an independent worse prognostic factor for FFR at multivariable analysis. To conclude, the Activin A - Follistatin axis is involved in the pathogenesis of TETs. Further study of Follistatin and Activin A in TETs is warranted as the molecules may serve as targets to inhibit tumor angiogenesis and tumor progression.

Highlights

Thymic epithelial tumors (TETs), comprising thymomas and thymic carcinomas (TCs) are extremely rare malignancies with an annual incidence of only 3.2 cases per million[1]
We investigated for the first time the role of Activin A and Follistatin serum concentrations and tumor expression in thymic epithelial tumors (TETs)
We found significantly elevated Activin A and Follistatin serum concentrations in patients with TETs compared to healthy volunteers

Summary

Introduction

Thymic epithelial tumors (TETs), comprising thymomas and thymic carcinomas (TCs) are extremely rare malignancies with an annual incidence of only 3.2 cases per million[1]. TCs represent a minor group of TETs that are not associated with paraneoplastic MG, which show a more aggressive tumor behavior with worse outcome and more recurrences compared to thymomas[7,8]. Surgical tumor resection represents the mainstay of therapy even in case of recurrent disease or in TETs with pleural metastases[11]. Activin A, a member of the TGFβ superfamily of cytokines, binds to type II activin receptors on the cell surface, which leads to recruitment and phosphorylation of type I activin receptors that results in intracellular phosphorylation and activation of Smad proteins. Follistatin has tumorigenic and proangiogenic functions, at least partially through antagonizing Activin A20,21

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Conclusion