Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor involved in such cellular processes as adipogenesis, inflammation, atherosclerosis, cell cycle control, apoptosis, and carcinogenesis. PPAR gamma gene mutations have been found in 4 of 55 sporadic colon cancers, and a chimeric PAX8-PPAR gamma 1 gene frequently generates a chromosomal translocation in thyroid follicular carcinomas, implicating PPAR gamma in tumor suppression. We investigated whether PPAR gamma is involved in the growth regulation of normal and tumor thyroid cells. We found no mutations in PPAR gamma exons 3 and 5 in human thyroid carcinoma cell lines and tissues. Moreover, 1 cell line (NPA) of 6 analyzed did not express PPAR gamma. Treatment of NPA with PPAR gamma agonists did not induce any inhibitory effect. Conversely, PPAR gamma agonists and PPAR gamma overexpression led to a drastic reduction of the cell growth rate in PPAR gamma-expressing thyroid carcinoma cells. Restoration of PPAR gamma expression in NPA cells induced cell growth inhibition; PPAR gamma agonists induced further inhibition. Growth inhibition induced by PPAR gamma agonists or by PPAR gamma gene overexpression in thyroid carcinoma cells was associated with increased p27 protein levels and apoptotic cell death. Should these data be confirmed, PPAR gamma could be a novel target for innovative therapy of thyroid carcinoma, particularly anaplastic carcinomas, which represent one of the most aggressive tumors in mankind and are unresponsive to conventional therapy.

Monomeric human pancreatic RNase, devoid of any biological activity other than its RNA degrading ability, was engineered into a dimeric protein with a cytotoxic action on mouse and human tumor cells, but lacking any appreciable toxicity on mouse and human normal cells. This dimeric variant of human pancreas RNase selectively sensitizes to apoptotic death cells derived from a human thyroid tumor. Because of its selectivity for tumor cells, and because of its human origin, this protein represents a potentially very attractive, novel tool for anticancer therapy.

The tall-cell variant (TCV) of papillary thyroid carcinoma (PTC), characterized by tall cells bearing an oxyphilic cytoplasm, is more clinically aggressive than conventional PTC. RET tyrosine kinase rearrangements, which represent the most frequent genetic alteration in PTC, lead to the recombination of RET with heterologous genes to generate chimeric RET/PTC oncogenes. RET/PTC1 and RET/PTC3 are the most prevalent variants. We have found RET rearrangements in 35.8% of TCV (14 of 39 cases). Whereas the prevalences of RET/PTC1 and RET/PTC3 were almost equal in classic and follicular PTC, all of the TCV-positive cases expressed the RET/PTC3 rearrangement. These findings prompted us to compare RET/PTC3 and RET/PTC1 in an in vitro thyroid model system. We have expressed the two oncogenes in PC Cl 3 rat thyroid epithelial cells and found that RET/ PTC3 is endowed with a strikingly more potent mitogenic effect than RET/PTC1. Mechanistically, this difference correlated with an increased signaling activity of RET/PTC3. In conclusion, we postulate that the correlation between the RET/PTC rearrangement type and the aggressiveness of human PTC is related to the efficiency with which the oncogene subtype delivers mitogenic signals to thyroid cells. Follicular-cell-derived thyroid tumors are divided into four main types: benign adenomas, well differentiated (papillary or follicular), poorly differentiated, and undifferentiated (anaplastic) carcinomas. Papillary thyroid carcinoma (PTC) is the most common thyroid carcinoma. It is defined on the basis of the architectural pattern and/or distinctive nuclear features, ie, ground glass appearance and longitudinal grooves with cytoplasm invaginations.