Expression of RAGE and HMGB1 in thymic epithelial tumors, thymic hyperplasia and regular thymic morphology.
Recently, a role of the receptor for advanced glycation endproducts (RAGE) in myasthenia gravis was described. RAGE and its ligand high mobility group box 1 (HMGB1) play key roles in autoimmunity and cancer. To test whether these molecules are involved in patients with thymic abnormalities we applied immunohistochemical analysis in 33 cases of thymic epithelial tumors, comprising 27 thymomas and 6 thymic carcinomas, and 21 nonneoplastic thymuses. Both molecules were detected in neoplastic epithelial cells: RAGE staining was most intense in WHO type B2 thymomas and thymic carcinomas (p<0.001). HMGB1 nuclear staining was strongest in A and AB, and gradually less in B1 = B2>B3>thymic carcinoma (p<0.001). Conversely, HMGB1 cytoplasmic staining intensities were as follows: A and AB (none), B1 (strong), B2 (moderate), B3 and thymic carcinoma (weak); (p<0.001). Fetal thymic tissue showed a distinct expression of RAGE and HMGB1 in subcapsular cortical epithelial cells which was found in 50% of myasthenic patients. Furthermore RAGE and HMGB1 were expressed in thymocytes, macrophages, Hassall's corpuscles, thymic medulla, and germinal center cells in myasthenic patients. Immunohistochemistry results were complemented by systemic measurements (immunosorbent assay): serum levels of soluble RAGE were significantly reduced in patients with epithelial tumors (p = 0.008); and in invasive tumors (p = 0.008). Whereas RAGE was equally reduced in thymic hyperplasia and epithelial tumors (p = 0.003), HMGB1 was only elevated in malignancies (p = 0.036). Results were most pronounced in thymic carcinomas. Thus, RAGE and HMGB1 are involved in the (patho-)physiology of thymus, as evidenced by differentiated thymic and systemic expression patterns that may act as diagnostic or therapeutic targets in autoimmune disease and cancer.
Department of Thoracic Surgery, Division of Surgery, Medical University Vienna, Vienna, Austria.
Bernhard
B
Moser
Department of Thoracic Surgery, Division of Surgery, Medical University Vienna, Vienna, Austria.
Stefan
S
Janik
Department of Pathology, Medical University Vienna, Vienna, Austria.
Ana-Iris
AI
Schiefer
Department of Pathology, Medical University Vienna, Vienna, Austria.
Leonhard
L
Müllauer
Department of Thoracic Surgery, Division of Surgery, Medical University Vienna, Vienna, Austria; Christian Doppler Laboratory for the Diagnosis and Regeneration of Cardiac and Thoracic Diseases, Medical University Vienna, Vienna, Austria.
Christine
C
Bekos
Department of Pathology, Medical University Vienna, Vienna, Austria.
Anke
A
Scharrer
Department of Dermatology, Medical University Vienna, Vienna, Austria.
Michael
M
Mildner
Department of General and Thoracic Surgery, National Institute of Oncology, Budapest, Hungary.
Ferenc
F
Rényi-Vámos
Department of Thoracic Surgery, Division of Surgery, Medical University Vienna, Vienna, Austria.
Walter
W
Klepetko
Department of Thoracic Surgery, Division of Surgery, Medical University Vienna, Vienna, Austria; Christian Doppler Laboratory for the Diagnosis and Regeneration of Cardiac and Thoracic Diseases, Medical University Vienna, Vienna, Austria.
Hendrik Jan
HJ
Ankersmit
D000293:Adolescent; D000328:Adult; D005260:Female; D005333:Fetus / Q000378:metabolism; D015870:Gene Expression; D024243:HMGB1 Protein / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008297:Male; D008875:Middle Aged; D009157:Myasthenia Gravis / Q000378:metabolism / Q000473:pathology; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism* / Q000473:pathology*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D013950:Thymus Gland / Q000378:metabolism*; D013952:Thymus Hyperplasia / Q000378:metabolism* / Q000473:pathology; D013953:Thymus Neoplasms / Q000378:metabolism* / Q000473:pathology*; D055815:Young Adult
D024243:HMGB1 Protein; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic