Expression of RAGE and HMGB1 in Thymic Epithelial Tumors, Thymic Hyperplasia and Regular Thymic Morphology

Abstract

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.

Activation of the High-Mobility Group Box 1 Protein-Receptor for Advanced Glycation End-Products Signaling Pathway in Rats During Neurogenesis After Intracerebral Hemorrhage

“…20 RAGE is also expressed in neurons and glial cells of the brain, and its expression can be unregulated by activated astrocytes and microglia cells. 8 In a mouse model of ischemia/reperfusion injury in heart, HMGB1 binds to RAGE soon after injury and thereby activates proinflammatory pathways and exacerbates myocardial injury.…”

Cytoplasm estrogen receptor β5 as an improved prognostic factor in thymoma and thymic carcinoma progression

“…A large number of studies have reported that estrogen is involved in biological functions in human and animal organs through estrogen receptors, including ERα and ERβ (which has at least five isoforms, such as ERβ5) (22)(23)(24). At present, controversial findings exist on the expression of estrogen receptors in thymic tumors, since a number studies reported overexpression of ERβ in these tumors, whereas others studies obtained contradictory results (11,12,13,19).…”

“…To establish the negative controls, the same procedure was followed, without the primary antibody. A previously described scoring system was adopted (19), the tissue microarrays were digitized and cytoplasmic ERβ5 (cERβ5) or nuclear ERβ5 (nERβ5) immunoreactivity was scored between -and +++ (-, no staining; +, weak staining; ++, moderate staining; +++, strong staining). The percentage of tumor cells displaying staining for cERβ5 or nERβ5 was determined and calculated as the average of six high power fields per specimen.…”

Clinical Significance of HMGB1 Expression in Human Gastric Cancer

“…HMGB1, expressed in 55.6% of the colorectal cancer (CRC) patients, is significantly correlated with lymph node metastases and pathological stage (15). HMGBI expression is elevated in thymic epithelial tumors involved in the pathology and physiology of thymus (16). High expression ofHMGB 1 activates Tregs and Th2 polarization, promoting the immune evasion and the recurrence of HPV infection in cervical cancer (17).…”