Previous studies have demonstrated that the rapid involution of the rat ventral prostate following castration involves the death of the androgen-dependent epithelial cells present within the gland and that this death is the result of a series of discrete biochemical steps. The degradation of genomic DNA into nucleosomal-sized fragments is an early event in this process and is catalyzed by calcium magnesium-dependent endonuclease activity. The morphologic correlation of the involution process involves a series of structural changes which are collectively referred to as apoptosis. The apoptotic process describes the earliest apparent signs of morphologic change exhibited by the dying cells through their eventual complete destruction and deletion from the tissue. The temporal relationship between these recently described biochemical events and the morphologic changes of the apoptotic process were compared in the present study, in order to test the cause versus effect nature of DNA fragmentation in the programmed death of androgen dependent prostatic cells following castration. These studies demonstrated that the early elevation of the Ca+2 Mg+2-dependent endonuclease activity and the fragmentation of DNA into nucleosomal oligomers occurs within prostatic glandular epithelial cells and probably does not involve the direct participation of extraprostatic cells which may subsequently migrate into the gland. Once the DNA is initially cleaved into the nucleosomal oligomers, the subsequent participation of lysosomal enzymes act in a less restricted fashion to degrade both the nucleosomal DNA as well as the cytoplasmic elements and the cell becomes morphologically apoptotic. As the elevations in Ca+2 Mg+2-dependent endonuclease activity and DNA fragmentation are initiated at a time well before the cell is morphologically dead, as defined by apoptosis, these changes in DNA metabolism must not be the consequences of cell death but instead are early causal events in an active process of programmed cell death.

Relationship between DNA fragmentation and apoptosis in the programmed cell death in the rat prostate following castration.

In the epithelium of secretory acini of the prostate two different cell types can be discriminated on the basis of localization, morphology, and degree of differentiation, the luminal and basal cells. The possibility of a developmental relationship between basal and luminal cells has been a subject of interest in several studies. According to the stem cell model at least three cell types, i.e., stem, amplifying, and transit cells, can be discriminated in the epithelium of prostate secretory acini. We previously reported that in the process of degeneration and regeneration in normal rat prostate a population of cells could be identified as candidates for the amplifying cells. These cells showed a keratin expression profile intermediate between those of basal and luminal cells. We now show, by using keratin antibodies, that also in normal human prostate at least three subpopulations of cells can be identified, one of them putatively representing amplifying cells as defined in the stem cell model. Furthermore, these antibodies were used to obtain a better insight into the different cell types involved in the etiology and progression of prostatic carcinoma. Both primary and hormone-independent prostatic tumors were investigated. Our results indicated that the candidate stem cell population was absent in prostatic carcinoma. Unlike earlier reports on the unique presence of cells with luminal characteristics in prostatic carcinoma, we identified also a population of cells coexpressing basal and luminal cell-type cytokeratins in primary and hormone-independent prostatic carcinoma. Since amplifying cells are defined in the stem cell model as precursors of transit (luminal) cells in the hierarchical pathway of prostatic epithelium differentiation, we postulate that on the basis of the keratin expression profile this subpopulation is most likely the target for neoplastic transformation.

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Colocalization of basal and luminal cell-type cytokeratins in human prostate cancer.

The role of the different epithelial compartments during degeneration and regeneration of the rat prostate is examined on basis of intermediate filament protein (IFP) expression pattern. With the monoclonal antibodies RCK 103 and RGE 53, directed against specific keratins, it was possible to differentiate between the basal (RCK 103+) and luminal (RGE 53+) cells of the prostatic epithelium. After testosterone deprivation, by orchiectomy, an extensive and rapid cell loss was observed which appeared to affect mainly the luminal cells. In the process of prostate regeneration, induced by testosterone administration, using silastic implants, the luminal compartment rapidly regained its normal thickness. A heterogeneous population of morphologically luminal cells was observed showing keratin expression patterns intermediate between basal and luminal cells. These findings support the idea of a relationship between basal and luminal cells as being members of the same lineage of differentiation.

Differential expression of keratins in the basal and luminal compartments of rat prostatic epithelium during degeneration and regeneration.

Publisher Summary This chapter discusses the secretory proteins of the prostate and the seminal vesicles with particular emphasis on the human glands. The male accessory sex glands vary considerably in mammals with respect to their topographical location, size, morphology, and functions, thus reflecting that the diversity of species-specific requirements of these glands for reproduction is due to differences in environment and sexual habits. Secretions from highly developed and specialized accessory sex glands—for example, in rodents, are responsible for the formation of the so called “copulatory plug.” The important groups of proteins characterized are the transglutaminases, the calcium transport modifiers, and the growth factors. Transglutaminase is an enzyme that triggers multifarious biological responses, such as receptor stabilization or polymerization of seminal secretory proteins during the formation of the copulatory plug in rodents, and in immune defense mechanisms. This enzyme is an anchor protein and is released in an apocrine secretion mode from the dorsal prostate and the coagulating gland and may serve as a tool in scrutinizing the special mode of secretion.

Protein secretion and secretory processes in male accessory sex glands.

The rat ventral prostate is a complex gland composed of numerous ducts The epithelial cells that line the lumen of the ducts are surrounded by stromal cells The epithelial cells display a characteristic morphology that is dependent on their anatomical location within the ducts; the cells that line the lumen in the region of the ducts close to the urethra (the proximal region) are cuboidal, while those in the distal regions of the ducts are tall columnar cells We have examined the regional expression of two genes that are expressed in the prostate: prostate steroid-binding protein (PSBP; a marker for androgen-dependent protein synthesis) and TRPM-2 (a marker for programmed cell death) We have demonstrated that the expression of PSBP, in the presence of androgens, and TRPM-2, in the absence of androgens, is restricted to the luminal epithelial cells in the distal regions of the prostatic ducts Neither of the genes is expressed in the proximal regions of the ducts In view of the probable effects of the

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Ductal heterogeneity of cytokeratins, gene expression, and cell death in the rat ventral prostate.

The ultrastructure of the basal cells of rat lateral and ventral prostate and of dog prostate has been studied. Basal cells from both species appear as undifferentiated cells, characterised by a lack of cytoplasmic organelles and a poorly developed Golgi complex and endoplasmic reticulum. The presence of cytoplasmic filaments and micropinocytosis is not considered to be sufficient evidence to assume any similarity to myoepithelium, as has been previously suggested. Basal cells are instead considered to be precursors of secretory epithelial cells.

F. Sinowatz

Papers

The ultrastructure of basal cells of rat and dog prostate.