General Process of Induction of Squamous Metaplasia by Cyclic Adenine Nucleotide and Prostaglandins: Mouse Prostate Glands1

Squamous metaplasia ¡sa common abnormality of cellular development and differentiation in the epithelia of many organs, including the prostate gland in humans. Agents known to elevate the level of intracellular cyclic adenine nucleotide have been found to direct various kinds of epithelial cells onto a pathway of epidermoid (squamous) development and a differ entiation marked by keratin production. We report here that the mixture of the cyclic adenine nucleotide; A/6,O2'-dibutyryladenosine cyclic 3':5'-monophosphate (0.1 mW); prostaglandins E,, E2, and Bt (each 5 jug/ml); and papaverine (1 /IM) induces extensive squamous metaplasia and keratin production in the epithelial cells of mouse ventral prostate glands cultured for 3 weeks. The components of the mixture act synergistically. A 10-fold higher concentration of A/6,O2'-dibutyryladenosine cyclic 3':5'-monophosphate (1 HIM) alone is as effective as is the mixture. The presence of either the retinoid, retinylidene dimedone, or the phorbol ester, phorbol-12,13-didecanoate, at 1 fiM completely prevents the induction of squamous metapla sia. The results suggest that cyclic adenine nucleotide and indirectly prostaglandins E, and E2 may play important roles in the spontaneous and exogenously induced production of squa mous metaplasia. These same inducing agents have also been found in other studies to bring about squamous metaplasia and keratinization in culture in the mammary glands of mice and the breast tissue of humans, as well as to accelerate normal epidermization in chick embryo skin. The findings in prostate gland, mammary glands, and skin derived from embryonic or adult animals and humans, spanning three species and two classes of vertebrates, suggest that cyclic adenine nucleotide augmented by prostaglandins Et and E2 may act generally on diverse types of epithelia to bring about normal and metaplastic squamous cell development and a differentiation marked by keratin production.