Human prostate epithelium consists of two cell layers within which three cell types are recognized: basal, luminal and neuroendocrine cells, each of which has many phenotypic variants. Prostate cancers contain cells with similar phenotypes, but the patterns of growth and differentiation are altered to varying extents within each cancer.
An important concept is that the degree of differentiation is inversely proportional to the capacity for cell division. In normal prostate epithelial cells, there is a relatively strict division of labor, and cells that produce prostate-specific antigen (PSA) are unlikely to be proliferative. In contrast, one of the characteristics of prostate cancer is the blurring of this distinction.
In order to understand prostate cancer cell differentiation, it is first necessary to understand normal prostate epithelial cell growth and differentiation. Many studies of normal and abnormal prostate tissue derived from fetuses, boys, young men and older men have been published. However, few definitive conclusions have been reached.
The aim of this review is to summarize the literature describing the patterns of differentiation seen in human normal prostate epithelium and consider how these are altered in prostate cancer.
Prostate normal epithelial cell lineages
In the normal prostate epithelium, a nearly complete layer of basal, relatively undifferentiated cells is the progenitor of the luminal layer of columnar PSA-secreting cells1-3. Interspersed amongst these cells are scattered individual or small groups of neuroendocrine cells. It is thought that the stem cells reside in the basal layer, where the majority of cell division occurs.
A number of interrelated questions arise, including:
(1) What is the sequence of phenotypes during prostate epithelial cell differentiation?
(2) Is there, in some areas, a cell layer between the basal cells and the secretory cells?
(3) What is the phenotype of the cells transiting between the basal and luminal layers?
(4) Does prostate epithelium contain some cells with characteristics of both basal and luminal cells?
(5) What is the origin of the neuroendocrine cells?
(6) Is stem cell division monodirectional or can the prostate epithelial stem cell give rise to two populations of transit amplifying cells, one of which divides to give basal cells and one to luminal cells?
(7) What are the differences in the patterns of differentiation between the transition, central and peripheral zones of the human prostate?
(8) Which cell type(s) give rise to prostate cancer?
Study of these questions has been facilitated by the use of a number of markers, particularly cytokeratins (CKs). The classical lineage markers are CK5/14 (and p63) for basal cells, CK8/18 (and PSA, nuclear androgen receptor (AR), prostate-specific membrane antigen (PSMA) and prostatic acid phosphatase (PSAP)) for luminal cells and chromogranin A or CD56 for neuroendocrine cells. However, extending the range of markers studied has demonstrated that there are many other phenotypes present in both the basal and luminal layers.