Expression of the autoimmune regulator gene (AIRE) and the presence of CD25⁺/forkhead box p3 (FoxP3)⁺ T regulatory (T_reg) cells were investigated in histologically normal adult thymi and in thymomas using immunohistochemistry and quantitative real-time polymerase chain reaction (PCR). In the normal thymus staining for AIRE was detected in the nucleus of some epithelial-like cells located in the medulla; in thymomas AIRE-positive cells were extremely rare and could be detected only in the areas of medullary differentiation of two B1 type, organoid thymomas. RNA was extracted from 36 cases of thymoma and 21 non-neoplastic thymi obtained from 11 myasthenic (MG⁺) and 10 non-myasthenic (MG^–) patients. It was found that AIRE is 8·5-fold more expressed in non-neoplastic thymi than in thymomas (P = 0·01), and that the amount of AIRE transcripts present in the thymoma tissue are not influenced by the association with MG, nor by the histological type. A possible involvement of AIRE in the development of MG was suggested by the observation that medullary thymic epithelial cells isolated from AIRE-deficient mice contain low levels of RNA transcripts for CHRNA 1, a gene coding for acetylcholine receptor. Expression of human CHRNA 1 RNA was investigated in 34 human thymomas obtained from 20 MG^– patients and 14 MG⁺ patients. No significant difference was found in the two groups (thymoma MG⁺, CHRNA1 = 0·013 ± 0·03; thymoma MG-, CHRNA1 = 0·01 ± 0·03). In normal and hyperplastic thymi CD25⁺/Foxp3⁺ cells were located mainly in the medulla, and their number was not influenced by the presence of MG. Foxp3⁺ and CD25⁺ cells were significantly less numerous in thymomas. A quantitative estimate of T_reg cells revealed that the levels of Foxp3 RNA detected in non-neoplastic thymi were significantly higher (P = 0·02) than those observed in 31 cases of thymomas. Our findings indicate that the tissue microenvironment of thymomas is defective in the expression of relevant functions that exert a crucial role in the negative selection of autoreactive lymphocytes.

The MET oncogene encodes for Met protein, a trans-membrane tyrosine kinase identified as the high affinity receptor for hepatocyte growth factor (HGF). Immunohistochemical studies have demonstrated that Met protein is intensely expressed in tumor cells of >95% cases of thyroid papillary carcinoma. High density of Met protein in tumor cells is the result of increased transcription of a normal MET gene, probably due to a combination of intracellular and extracellular signals. Over-expression of Met protein is more pronounced at the invading front of the tumor and can profoundly affect the tumorigenesis of papillary carcinoma of the thyroid. In fact, Met protein-positive papillary carcinoma cells are highly responsive to hepatocyte growth factor (HGF), which is effective in stimulating tumor cell adhesion, migration and invasiveness. In addition, HGF stimulation of papillary carcinoma of the thyroid (PTC) cells causes up-regulation of COX-2 and down-regulation of CD82/KAI-1; both these molecules have a major role in controlling tumor cell invasiveness. Finally, HGF stimulation of tumor cells may significantly affect the tumor microenvironment. In fact, HGF induces tumor cells to release chemokines active in the recruitment of dendritic cells, and is involved in regulating the production of proangiogenic factors.