Distinct roles for members of the trk neurotrophin receptor family in the biology of medullary thyroid carcinoma

Medullary thyroid carcinoma (MTC) is a neoplasm of the C-cells of the thyroid. Patients who have a genetic predisposition to develop MTC provide a model to study MTC progression. This progression can include development of an aggressive, metastatic disease that ultimately kills the patient. The goal of this thesis is to determine what molecular events may underlie the development and progression of MTC tumors by investigating a potential role for the trk family of neurotrophin receptors.;To begin this work, I evaluated trkC as a candidate gene for inherited forms of MTC by cloning the human homolog of trkC and mapping it to chromosome 15q24-q25. It is not the gene responsible for inherited MTC, which maps to chromosome 10 and is now known to be the ret proto-oncogene.;To further investigate a role for the trk family in MTC, immuno-histochemical analyses were performed. The trkB neurotrophin receptor was expressed in normal and hyperplastic C-cells and this expression was diminished in MTC. In contrast, expression of the trkC neurotrophin receptor was never detected in normal C-cells, but demonstrated increasing staining with tumor development, including markedly strong staining in the cells of the most aggressive tumors. The trkA neurotrophin receptor demonstrated no staining in normal C-cells and variable levels of staining in the progression of MTC.;In the context of these in vivo expression patterns, a cell culture model was developed. Expression and activation of trkA or trkC in a cultured MTC line resulted in increased cell growth in vitro and increased tumor growth when the expressing cells were injected into nude mice. In contrast, although the cells expressing trkB demonstrated increased cell growth in vitro, little to no tumor development occurred when the trkB expressing cells were injected into nude mice. These results suggest a model for tumor development of MTC in which loss of growth control due to a decrease in expression of one trk family member, trkB, along with a gain in growth potential by an increase in the expression of a different trk family member, trkC, are critical events in tumor initiation, tumor progression, or both.