While it is clear that prostate cancer arises from the epithelial compartment, the identification of the specific epithelial cell subtype which the carcinogenic process initiates has only recently been the focus of study. Currently, the precursor for most peripheral zone prostatic carcinomas is thought to be high-grade prostatic intraepithelial neoplasia (HGPIN) (McNeal and Bostwick 1986). It is believed that HGPIN arises from low-grade PIN, which in turn is thought to stem from normal prostate epithelium. The cell type of origin for HGPIN, however, is still incompletely understood. A widely held view of carcinogenesis is that the common carcinomas generally arise in self-renewing tissues in which dividing cells acquire somatic genetic alterations in growth regulatory genes. In normal human prostate epithelium, most cell divisions take place in the basal cell compartment where the tissue stem and presumably the transit amplifying cells reside (Bonkhoff etal. 1994;
1998). The majority of secretory luminal cells do not normally proliferate and are the terminally differentiated cells that perform the androgen-regulated differentiated functions of the prostate, such as prostate-specific antigen (PSA) production and secretion. Both prostate cancer and HGPIN cells possess many phenotypic and morphological features of secretory luminal cells (i.e., cytokeratin 8 and 18, PSA, hK2, PSMA, and AR expression), yet they also contain features of the basal transit amplifying cell compartment such as c-MET expression, DNA replication and extensive self renewal (De Marzo etal. 1998; Meeker etal. 2002; van Leenders et al. 2002; Verhagen et al. 1992) (Fig.12.2). Thus, in carcinoma these stem-cell and transit amplifying cell-like features have been shifted up from the basal into the secretory luminal compartment (De Marzo etal. 1998a; Meeker etal. 2002). It has been postulated that the cell of origin for prostate cancer is an intermediate, prostatic epithelial cell, presumably derived from the basal transit amplifying population which undergoes the initial malignant molecular changes allowing gene expression and morphologic features of both basal and secretory luminal cells (De Marzo et al. 1998a; De Marzo et al. 1998b; Meeker et al. 2002; van Leenders et al. 2002; Verhagen etal. 1992).
The site of these phenotypically intermediate, initiated cells appears not to be random within the prostate. Instead, they are enriched in sites of focal glandular atrophy where the luminal epithelial cells, atrophic in appearance, are quite proliferative and often surrounded by inflammation within the gland. Therefore, these sites have been termed "proliferative inflammatory atrophy" (PIA)(De Marzo etal.
1999). Based upon the following lines of evidence, these PIA lesions are proposed to be an intermediate transition stage to HGPIN and/or early prostatic carcinoma: 1.) Compared with normal-appearing epithelium, PIA is highly proliferative. 2.) PIA
contains many proliferating cells in the luminal layer, which is similar to PIN. 3.) Many of the luminal cells in PIA have decreased expression of the p27Kip1 cyclin-dependent kinase inhibitor even though they express AR. 4.) PIA contains many cells with phenotypic features of "intermediate cells," which have been proposed as the target cells for carcinogenesis in the prostate. 5.) PIA contains very few cells undergoing apoptosis, with many cells in the luminal layer expressing bcl-2.6.) PIA shows increased expression in the carcinogen-detoxifying enzyme, glutathione-S-transferase Pi (GSTP1), and GST alpha in many of the cells, consistent with a stress response to an increased oxidative burden. 7.) Finally, PIA shows frequent morphologic transitions to PIN and frequently occurs adjacent to small cancers (De Marzo etal. 2001).
Based on these findings, a new model of prostate carcinogenesis has been proposed whereby chronic and acute inflammation, in conjunction with dietary and other environmental factors, targets prostate epithelial cells for injury and destruction. Increased proliferation occurs as a regenerative response to lost epithelial cells; it occurs in cells with a transit amplifying or intermediate phenotype (Meeker etal. 2002; van Leenders etal. 2002). In this process, GSTP1 expression is elevated in many of the cells in PIA as a genome protective measure. Although elevated in many of the cells in PIA, GSTP1 expression is eventually lost in some cells as the result of aberrant methylation of the CpG island of the GSTP1 gene promoter (Lin etal. 2001). Indeed, such aberrant methylation of the GSTP1 promoter is one of the earliest molecular abnormalities characteristic of prostate cancer cells. This heritable epigenetic alteration places these cells at increased risk for the accumulation of additional genetic damage, with acceleration of the neoplastic process toward PIN (Lin etal. 2001). One of these additional genetic changes involves telomerase shortening by PIN cells. This appears to increase their genetic instability, driving further genetic damage and producing invasive cancers (Meeker etal. 2002).
During the initiation of prostate carcinogenesis, there are distinct "hard wiring" changes in the AR signaling pathways. Normally the proliferating transit amplifying cells in the basal epithelial layer do not express the androgen receptor or express only low levels of AR. As discussed, during their maturation, these cells eventually express higher levels of AR. Once a critical AR level is reached, the occupancy of AR by its ligand inhibits proliferation of these cells and induces their differentiation into secretory luminal cells. In contrast, the intermediate type of proliferating cells in PIA variably express higher levels of AR and such AR expression is further enhanced in proliferating cells in HGPIN (De Marzo et al. 2001). Associated with this enhanced expression of the AR is the decreased expression of ERp by HGPIN cells (Fixemer et al. 2003). This indicated that "hard wiring" changes occur in the AR/ERp signaling pathways even at this early stage of cancer development since now AR expressing/ERp negative cells are proliferating and not growth arrested.
These changes produce a "gain of function" ability by AR so that it now engages the molecular signaling pathways directly, stimulating the proliferation and survival of these initiated prostatic cells. Unlike the paracrine situation in the normal prostate in which such growth regulation is initiated by AR binding to genomic sequences in the nuclei of stromal cells, during prostatic carcinogenesis genomic AR binding within the transformed cells itself activates this growth regulation. Due to these "hard wiring" changes, there is a conversion from paracrine to autocrine AR signaling pathways in invasive prostate cancer (Gao and Isaacs 1998; Gao etal. 2001). These "gain of function" hard wiring changes pathologically allow androgen/AR complexes to bind to and enhance expression of survival and proliferation genes which physiologically are not affected by these complexes in either normal transit amplifying or secretory luminal cells (Gao and Isaacs 1998; Gao etal. 2001). In addition, such gain of function AR oncogenic signaling no longer represses but instead stimulates Skp2 expression. Such Skp2 enhanced expression results in downregu-lation of p27Kip1 protein, enhancing proliferation of these cancer cells (Yang et al. 2002).
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