Induction of abnormal development and differentiation in cultured mammary glands by cyclic adenine nucleotide and prostaglandins.

Abstract

Squamous (epidermoid) metaplasia is a common abnormality of development and differentiation, in which various epithelia are replaced by cells resembling those of the epidermis. The metaplastic cells differentiate into flattened cells that frequently form keratotic flakes and whorls. The cells may regress, remain benignly squamous, or progress to epidermoid carcinoma1. Squamous metaplasias have previously been brought about by mechanical injury2, vitamin A deficiency3,4 and chemical carcinogens5–7. In search of the physiological mediators of abnormal development and differentiation in oncogenesis, we have now discovered that the combination of dibutyryl cyclic AMP, prostaglandins (PGs) E1, E2 and B1, and papaverine (Pap) induces squamous metaplasia with keratin production in the epithelium of cultured mammary glands. The three inducers may act synergistically to elevate the level of intracellular cyclic adenine nucleotide. Removal of these inducers causes the regression of the metaplastic cells. Retinoid does not block the induction of this squamous metaplasia, even though retinoid has previously prevented and reversed the squamous metaplasias caused by vitamin A deficiency or chemical carcinogens in other organs4,8. The findings suggest that cyclic adenine nucleotide and the PGs may mediate the squamous metaplasias present in many abnormal, transformed and malignant tissues, and possibly also the normal development and differentiation of epithelia into keratin-producing, stratified squamous cells, as in skin.