Although initiating mutations in the ret protooncogene have been found in familial and sporadic medullary thyroid carcinoma (MTC), the molecular events underlying subsequent tumor progression stages are unknown. We now report that changes in trk family neurotrophin receptor expression appear to be involved in both preneoplastic thyroid C cell hyperplasia and later tumor progression. 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 tumors, trkB expression was substantially reduced, while trkC expression was increased and often intense. In a cell culture model of MTC, exogenous trkB expression resulted in severely impaired tumorigenicity and was associated with 11-fold lower levels of the angiogenesis factor vascular endothelial growth factor. These results suggest that trk family receptor genes participate in MTC development and progression, and, in particular, that trkB may limit MTC tumor growth by inhibition of angiogenesis.The trk family of neurotrophin receptors, trkA, trkB, and trkC, and their neurotrophin ligands, promote the survival, growth, and differentiation of central nervous system neurons and other neural crest-derived cells (1). In cell culture, expression and stimulation of the trk family receptors can result in cell proliferation or differentiation, depending on the cell type. Expression of specific trk family members plays an important role in several human cancers. For two types of cancer, trk family expression is correlated with disease progression. In neuroblastoma, expression of trkA (2, 3) or trkC (4) correlates with good prognosis, and expression of trkB (5) correlates with poor prognosis. Several studies using neuroblastoma cell lines have suggested that trkA expression and activation can result in cell differentiation (6-8), while trkB activation can result in growth stimulation and increased invasion (5, 9). Similarly, in medulloblastoma, trkC expression has been found to correlate with good prognosis (10), and expression of trkC in medulloblastoma cell lines resulted in alterations in morphology consistent with cell differentiation (11).We have now examined the patterns and biology of trk family receptor expression in medullary thyroid carcinoma (MTC), a cancer that arises from the thyroid C cell. MTC can occur as a sporadic disease or as part of the autosomal dominant multiple endocrine neoplasia type 2 (MEN 2) syndromes (12). There are three related MEN 2 syndromes. In MEN 2A, patients develop MTC, pheochromocytoma, and parathyroid hyperplasia. In MEN 2B, patients develop MTC, pheochromocytoma, and mucosal neuromas. In familial medullary thyroid carcinoma, only MTC occurs. Each of these syndromes results from an inherited activating mutation in the ret tyrosine kinase gene. Like almost all cancers, MTC is a multistage disease. Thus, in the MEN 2 syndromes, the inherited ret mutation predisposes the individual to an i...