Neuronal Properties of Thyroid C-Cell Tumor Lines

Abstract

Thyroid C-cells present a paradoxical phenotype of neuronal properties in multiple endocrine neoplasia type 2 (MEN 2). The neuronal phenotype is in contrast to the primarily endocrine nature of the parental C-cells. What can account for this transdifferentiation? In this chapter, we will try to answer that question by comparing the neuronal features of C-cell lines with those of normal C-cells treated with nerve growth factor. From that perspective, we will then present a model proposing that ret tyrosine kinase activity is responsible for the neuronal properties in C-cell tumors. Interestingly, the neuronal phenotype is partly reversible. Overexpression of the ras oncogene or treatment with glucocorticoids inhibits both cell growth and induces a more endocrine state. An attractive hypothesis is that these agents might be decreasing ret activity, although this remains to be tested. The utility of thyroid C-cell lines for identification of differentiation and growth genes will be exemplified by description of a novel splice product of the G_sα transcript that is selectively expressed in a subset of neuroendocrine and neuronal cells. Finally, the applicability of C-cell lines for studying fundamental transcriptional control mechanisms will be described using the calcitonin/CGRP gene as a model. In summary, the induction and repression of neuronal properties in C-cell tumors provide a useful system for studying the genetic mechanisms underlying gene expression and differentiation in MEN 2.