Roles of trk family neurotrophin receptors in medullary thyroid carcinoma development and progression

Although initiating mutations in the ret protooncogene have been found in f amilial and sporadic medullary thyroid carcinoma (MITC), the molecular even ts underlying subsequent tumor progression stages are unknown. We now repor t that changes in trk family neurotrophin receptor expression appear to be involved in both preneoplastic thyroid C cell hyperplasia and later tumor p rogression. Only a subset of normal C cells expresses trk family receptors, but, in C cell hyperplasia, the affected cells consistently express trkB, with variable expression of trkA and trkC. In later stages of gross MTC tum ors, trkB expression was substantially reduced, while trkC expression was i ncreased and often intense. In a cell culture model of MTC, exogenous trkB expression resulted in severely impaired tumorigenicity and was associated with Ii-fold lower levels of the angiogenesis factor vascular endothelial g rowth factor. These results suggest that trk family receptor genes particip ate in MTC development and progression, and, in particular, that trkB may l imit MTC tumor growth by inhibition of angiogenesis.