Cell proliferation and neoplastic progression in the adrenal medulla: Insights and questions from immunohistochemical studies

Adult rat chromaffin cells proliferate at a low rate throughout life and sh ow robust mitogenic responses to a variety of agents in vivo and in vitro. Prolonged treatment of rats with some of these agents leads to development of pheochromocytomas, probably by exacerbating an age-dependent proclivity. The rat adrenal medulla is thus a remarkable model for studies of mitogeni c signaling and neoplastic progression. Immunohistochemical approaches to t he study of this model have helped to overcome obstacles presented by heter ogeneity of the chromaffin cell population and complex relationships betwee n medulla, cortex and nerve supply. Current evidence suggests that these re lationships are important both in normal chromaffin cell turnover and in de velopment of pheochromocytomas. The prototypical mitogen for adult rat chro maffin cells in vitro is nerve growth factor (NGF), which, parodoxically, a rrests proliferation and causes neuronal differentiation of rat pheochromoc ytoma cells. Cell culture studies suggest that activation of phosphatidyl i nositol 3-kinase by NGF is a critical determinant of mitogenic specificity in normal chromaffin cells. Numerous unanswered questions concern differenc es between normal chromaffin cells and their neoplastic counterparts, diffe rences between chromaffin cells of rats and other species, and influences o f the in vitro environment on responses to trophic signals.