https://orcid.org/0000-0001-9893-5485
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ABSTRACT
Background
Thymic epithelial tumors (TETs) are rare malignancies with unique association to the autoimmune disease myasthenia gravis (MG). Heat shock proteins (HSPs) harbor great potential as cancer biomarkers and HSP inhibitors approach clinical cancer therapy.
Methods
To explore HSP pathophysiology, we assessed sera (immunoassays) and tissues (immunohistochemistry) of TETs (and thymic tissues) for HSP27, phosphorylated (p)HSP27, HSP70 and HSP90α expression in 114 TETs and 26 non-thymomatous MG patients undergoing extended thymectomy.
Results
Serum concentrations of HSP90α were significantly increased in patients with thymic carcinomas, thymomas, thymic neuroendocrine tumors and non-thymomatous MG compared to patients who underwent thymectomy revealing regular thymic morphology or controls. In thymoma patients, high serum HSP90α represented a significantly worse prognostic factor for free-from-recurrence, and complete tumor resection led to decreased levels. The expression of HSP90 in nuclei and cytoplasm of tumor cells and non-neoplastic lymphocytes varied with WHO histological subtype. HSP90 was expressed in centroblasts of thymic germinal centers in MG patients. Higher pHSP27 serum concentrations were observed in seropositive MG and those not treated with steroids.
Conclusions
HSP data suggest high potential for HSPs as TET cancer biomarkers or as candidates for targeted therapy. Caution is warranted in TET patients with associated MG overexpressing HSPs.
Abbreviations
| AChR | = | Acetylcholine receptor |
| ChT | = | Chemotherapy |
| CSS | = | Cause specific survival |
| ELISA | = | Enzyme-linked immunosorbent assay |
| ESTS | = | European Society of Thoracic Surgeons |
| FFR | = | Freedom from recurrence |
| FTH | = | Follicular thymic hyperplasia |
| HSP | = | Heat shock protein |
| IHC | = | Immunohistochemistry |
| IASLC | = | International Association for the Study of Lung Cancer |
| ITMIG | = | International Thymic Malignancies Interest Group |
| MG | = | Myasthenia gravis |
| MGFA | = | Myasthenia Gravis Foundation of America |
| MNT | = | Micronodular thymoma |
| NPV | = | Negative Predictive Value |
| OS | = | Overall survival |
| pHSP27 | = | Phosphorylated heat shock protein 27 |
| PPV | = | Positive Predictive Value |
| regT | = | Regular thymus (benign thymic pathology) |
| RChT | = | Radio- and chemotherapy |
| RT | = | Radiotherapy |
| TC | = | Thymic carcinoma |
| TET | = | Thymic epithelial tumor |
| TNET | = | Thymic neuroendocrine tumor |
| TNM | = | Tumor Nodes and Metastasis |
| TTH | = | True thymic hyperplasia |
| WHO | = | World Health Organization |
Acknowledgments
We want to thank the research laboratories ARGE Moser and ARGE Ankersmit (FOLAB Chirurgie – Department of Surgery, Medical University Vienna) for funding of the study.
Disclosure of potential conflicts of interest
No potential conflicts of interest were disclosed.
Supplementary material
Supplemental data for this article can be accessed on the publisher’s website.
Author contributions statement
Study design and supervision: BM, JT, CB. Contributed to data collection: JT, CB, CV, SJ, AS, LM, WK, MD, HJA, and BM. Experimental test: JT, CB, AS and PB. Analyzed the data: JT, CB, CV, ML, HJA, and BM. Wrote the paper: JT, CB HJA, and BM.