Disruption of Prostate Epithelial Differentiation Pathways and Prostate Cancer Development

Abstract

One of the foremost problems in the prostate cancer (PCa) field is the inability to distinguish aggressive from indolent disease, which leads to difficult prognoses and thousands of unnecessary surgeries. This limitation stems from the fact that the mechanisms of tumorigenesis in the prostate are poorly understood. Some genetic alterations are commonly reported in prostate tumors, including upregulation of Myc, fusion of Ets genes to androgen-regulated promoters, and loss of Pten. However, the specific roles of these aberrations in tumor initiation and progression are poorly understood. Likewise, the cell of origin for PCa remains controversial and may be linked to the aggressive potential of the tumor. One important clue is that prostate tumors co-express basal and luminal protein markers that are restricted to their distinct cell types in normal tissue. Prostate epithelium contains layer-specific stem cells as well as rare bipotent cells, which can differentiate into basal or luminal cells. We hypothesize that the primary oncogenic cell of origin is a transient-differentiating bipotent cell. Such a cell must maintain tight temporal and spatial control of differentiation pathways, thus increasing its susceptibility for oncogenic disruption. In support of this hypothesis, many of the pathways known to be involved in prostate differentiation can be linked to genes commonly altered in PCa. In this article, we review what is known about important differentiation pathways (Myc, p38MAPK, Notch, PI3K/Pten) in the prostate and how their misregulation could lead to oncogenesis. Better understanding of normal differentiation will offer new insights into tumor initiation and may help explain the functional significance of common genetic alterations seen in PCa. Additionally, this understanding could lead to new methods for classifying prostate tumors based on their differentiation status and may aid in identifying more aggressive tumors.

Notch signaling in the prostate: critical roles during development and in the hallmarks of prostate cancer biology

“…The binding of NICD to the RBPJ complex displaces corepressor complexes and recruits coactivators, such as Mastermind-like protein (MAML) and histone acetyltransferase, to induce the expression of Notch downstream target genes, including Hes1, Hey1, cyclin D and others (Fischer and Gessler 2007;Iso et al 2003;Miele 2006). In order to achieve precise temporal Notch regulation, Notch-induced transcription is eliminated immediately after the activation by NICD degradation and by the suppression from Hes1 and Hey1 (Frank and Miranti 2013). This canonical Notch signaling pathway is crucial for regulating cell homeostasis, cellfate determination, cell proliferation and differentiation, as well as apoptosis in a variety of tissues (Fig.…”

“…The loss of basal cells and reduced matrix diversity marks the initiation of tumor formation in the prostate (Frank and Miranti 2013). It has been suggested that the accumulation of prostatic intraepithelial neoplasia (PIN) lesions may eventually lead to the development of adenocarcinoma (Lawson and Witte 2007).…”

Human prostate luminal cell differentiation requires NOTCH3 induction by p38-MAPK and MYC

“…NOTCH can negatively regulate integrin expression and is generally required for epithelial differentiation (Frank and Miranti, 2013;Koh et al, 2010;Mazzone et al, 2010). Additionally, MYC suppresses integrin α6 and β1 expression (Gebhardt et al, 2006), and was previously demonstrated to be required for prostate differentiation (Berger et al, 2014).…”

“…Moreover, many of the commonly altered genes in prostate cancer (e.g. MYC, AR, ERG and PTEN) are also implicated in differentiation (Frank and Miranti, 2013). We previously demonstrated that manipulation of differentiation regulators (MYC,PTEN and ING4) in normal human prostate epithelial cells results in tumor formation when grafted into a mouse prostate (Berger et al, 2014).…”

Induction of a heparin-stimulated serine proteinase in sex accessory gland tumors of the Lobund-Wistar rat

“…For example, the TMPRRSS2-ERG gene fusion has been found in about half of prostate cancer patients and amplification of the MYC oncogene and deletions of the tumor suppressor PTEN are commonly associated with a worse clinical prognosis. However, inconsistencies in results and outcomes limit understanding of their role in tumor progression and their clinical usefulness (Frank and Miranti, 2013;Lorente and De Bono, 2014;Helfand and Catalona, 2014). Advanced prostate cancer is commonly treated with androgen deprivation therapies, which after a period of remission progresses to castration-resistant prostate cancer and resistance to available cancer therapies.…”