Normal Cells: The Normal Neuroendocrine Prostate Prostatic neuroendocrine cells are intraglandular and intraductal hybrid epithelial/neural/endocrine cells which express/secrete serotonin and numerous peptides/neuropeptides. Prostatic neuroendocrine cells are generally widely scattered throughout the prostate with only an occasional cell per gland/duct, but are most consistently found in the periurethral ducts and verumontanum. A small percent of human prostates contain numerous neuroendocrine cells. Prostatic neuroendocrine cells are of the open and closed cell types. The open cell type has an apical cytoplasmic process which extends to the lumen and has long specialized surface microvilli. These cells resemble sensory cells such as olfactory and taste bud cells. Both types of neuroendocrine cells also have long branching dendrite-like processes which extend between nearby epithelial cells. In addition to physically communicating with non-neuroendocrine epithelial cells, neuroendocrine cells also appear to communicate with each other via these dendrite-like processes. Both afferent and efferent nerves innervate prostatic neuroendocrine cells. Ultrastructural studies have shown a wide range of neurosecretory granule morphology which correlates with the large number of known secretory products. Prostate Neuroendocrine Cell Products Chromogranins Serotonin Gastrin releasing peptide (bombesin) Calcitonin gene family Somatostatin Parathyroid hormone-related protein Neuropeptide Y Vascular endothelial growth factor Cholecystokinin Proadrenomedullin N-terminal peptide TSH-like peptide Histamine Receptors for neuroendocrine products have been found in normal and/or neoplastic prostate. Prostate Neuroendocrine Receptors (Normal Prostate and/or Cancer) Gastrin releasing peptide (GRPR) Serotonin (5HT1a) Somatostatin (SST 1-5) Calcitonin (hCTR-2) Cholecystokinin (CCK-a) Neuropeptide Y (NPY1 and NPY2) Evidence suggests that neuroendocrine cells regulate the growth, differentiation and secretory activity of the prostatic epithelium through paracrine, endocrine and neurocrine mechanisms. The open type may "taste" the glandular lumenal contents and adjust the epithelial secretions as needed via paracrine signals to adjacent epithelial cells, reflex neural loops or endocrine signaling to distant sites such as the hypothalamic/ pituitary axis or the testis. This hypothesized role for the prostatic neuroendocrine cell is based on the known actions of the prostatic peptides/ neuropeptides in other organ systems, the morphology of the cells, experimental studies, and analogy with the much more extensively studied neuroendocrine cells of the gastrointestinal, pancreatic, thyroid and pulmonary organ systems. These prostatic neuroendocrine cells are nearly identical to those in the gastrointestinal tract which play a major role in digestion, motility, satiety, food seeking behavior, etc. They are also closely related to lung neuroendocrine cells which regulate lung growth and differentiation via bombesin-like peptides. Figure 1: Low power photomicrograph showing a prostate with numerous neuroendocrine cells (Chromogranin immunocytochemistry). Figure 2: Higher power of an area from Figure 1, showing open (arrow) and closed prostatic neuroendocrine cells with dendritic processes (Chromogranin immunocytochemistry). Figure 3: Prostatic neuroendocrine cells in ductoglandular complex (Serotonin immunocytochemistry). Figure 4: Electron photomicrograph of an open type prostatic neuroendocrine cell with long apical cytoplasmic process extending to lumen. Note the tall specialized microvilli on the cell surface and the basally oriented neurosecretory granules. Figure 5: Electron photomicrograph of a closed type prostatic neuroendocrine cell filled with numerous large pleomorphic neurosecretory granules. Figure 6: Electron photomicrograph showing three contiguous prostatic neuroendocrine cells. Note the middle neuroendocrine cell appears to have a different neurosecretory granule morphology from those flanking it. Figure 7: Electron photomicrograph of a prostatic neuroendocrine cell with smaller round variably dense granules. Note an efferent nerve process invaginating into the cell at the lower left (arrow). Figure 8: Composite of range of ultrastructural granule morphology found in various prostatic neuroendocrine cells. All panels are at the same magnification. Figure 9: Mechanisms by which prostatic neuroendocrine cells may secrete serotonin and bioactive peptides. The most likely secretory pathway is paracrine to adjacent epithelial cells. There is also evidence of paracrine interaction with other neuroendocrine cells. Other possible routes of secretion are paracrine (stromal cells), endocrine (into blood stream), neurocrine (to adjacent afferent nerve endings), exocrine/lumencrine (into prostatic secretions). Figure 10: Pathways by which prostatic neuroendocrine cells may be regulated. These include via lumenal contents (essentially "tasting" lumenal secretions and then regulating the secretion of adjacent epithelial cells), paracrine by other prostatic neuroendocrine cells (and possibly stromal cells), via efferent nerves and the blood stream.