Vitamin D3, lactose, and xylitol stimulate chromaffin cell proliferation in the rat adrenal medulla.

Chronic consumption by rats of diets rich in sugars or sugar alcohols leads to an increased incidence of pheochromocytomas. This relationship is hypothesized to be based on altered Ca2+ homeostasis due to increased intestinal Ca2+ absorption. Other agents associated with pheochromocytomas in rats in long-term toxicity studies have been shown to increase chromaffin cell proliferation, leading to the suggestion that the tumors occur secondarily to increased chromaffin cell turnover. We have demonstrated marked stimulation of chromaffin cell proliferation by vitamin D3, a potent stimulus to Ca2+ absorption not previously associated with adrenal medullary toxicity. This effect is detectable during the first week of dietary supplementation and persists throughout a 4-week time course. Lactose and xylitol, representative of sugars and sugar alcohols associated with pheochromocytomas, are also mitogenic but to a lesser extent, with their effects first detectable during Week 4 of dietary supplementation. Vitamin D3, its active metabolite calcitriol, lactose, and xylitol all fail to stimulate proliferation of rat chromaffin cells in vitro. The mitogenic effects of these agents may be mediated presynaptically in vivo. The data suggest that altered Ca2+ homeostasis may increase chromaffin cell proliferation and support the hypothesis that diets containing high concentrations of sugars and sugar alcohols cause pheochromocytomas in rats secondarily by this mechanism.

Mitogen-activated protein kinase and mitogen-activated kinase phosphatase-1 expression in the Noble rat model of sex hormone-induced prostatic dysplasia and carcinoma.

Our recent studies have implicated the TGF-alpha/epidermal growth factor receptor pathway in the genesis of testosterone (T) and estradiol-17 beta (E2)-induced dysplasia in the dorsolateral prostate (DLP) of Noble rats. This pathway was also found to be markedly up-regulated in the androgen-independent transplantable carcinoma that arose from the DLP of a Noble rat. In the current study, we investigated the expression of mitogen-activated protein kinase (MAP-kinase) and mitogen-activated kinase phosphatase-1 (MKP-1), key downstream regulators of growth factor-activated signal transduction in the DLP of castrated, castrated T-supplemented, and T+E2-treated rats and in the androgen-independent transplantable carcinoma. Both MAP-kinase and MKP-1 expression in the DLP were found to be dependent on androgen stimulation. Immunoblots of DLP from T+E2 treated rats demonstrated a selective decline in MKP-1 levels with no alteration in MAP-kinase expression. These findings suggest that the dual hormone treatment induces changes in the signal transduction pathway, which favors the protracted mitogenic action of MAP-kinase. In situ hybridization and immunohistochemistry findings corroborated the immunoblot data but also revealed that both MAP-kinase and MKP-1 were strongly expressed in severely dysplastic lesions, which may indicate the presence of transformed cells in these foci. In this regard, both proteins were strongly expressed in samples of the androgen-independent transplantable carcinoma. Taken together, results from this and our recent study suggest that alterations in a growth factor-MAP-kinase pathway may be important events in the initiation and progression of prostatic carcinoma.