Roles of trk Family Neurotrophin Receptors in Medullary Thyroid Carcinoma Development and Progression

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 96; no. 8; pp. 4540 - 4545
• Main Authors: McGregor, Lisa M., McCune, Bryan K., Graff, Jeremy R., McDowell, Philip R., Romans, Katherine E., Yancopoulos, George D., Ball, Douglas W., Baylin, Stephen B., Nelkin, Barry D.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 13.04.1999; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: Animals; Antibodies; Biological Sciences; Carcinoma, Medullary - genetics; Carcinoma, Medullary - pathology; Carcinoma, Medullary - physiopathology; Cell culture techniques; Cell growth; Cell lines; Cellular biology; Disease Progression; Female; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Genes; Genetics; Humans; Hyperplasia; Ligands; Mice; Mice, Nude; Neurons; Pregnancy; Proto-Oncogene Proteins - genetics; Receptor Protein-Tyrosine Kinases - genetics; Receptor, Ciliary Neurotrophic Factor; Receptor, trkA; Receptor, trkC; Receptors; Receptors, Nerve Growth Factor - genetics; Thyroid gland; Thyroid Gland - cytology; Thyroid Gland - metabolism; Thyroid Gland - pathology; Thyroid Neoplasms - genetics; Thyroid Neoplasms - pathology; Thyroid Neoplasms - physiopathology; Transplantation, Heterologous; Tumor cell line; Tumor Cells, Cultured; Tumors
• DOI: 10.1073/pnas.96.8.4540
• ISSN: 0027-8424

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.