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Activation of Wnt/?-catenin signaling in a subpopulation of murine prostate luminal epithelial cells induces high grade prostate intraepithelial neoplasia.

ABSTRACT: Wnt/?-catenin signaling is important for prostate development and cancer in humans. Activation of this pathway in differentiated luminal cells of mice induces high-grade prostate intraepithelial neoplasia (HGPIN). Though the cell of origin of prostate cancer has yet to be conclusively identified, a castration-resistant Nkx3.1-expressing cell (CARN) may act as a cell of origin for prostate cancer.To activate Wnt/?-catenin signaling in CARNs, we crossed mice carrying tamoxifen-inducible Nkx3.1-driven Cre to mice containing loxP sites in order to either conditionally knock out adenomatous polyposis coli (Apc) or constitutively activate ?-catenin directly. We then castrated and hormonally regenerated these mice to target the CARN population.Loss of Apc in hormonally normal mice induced HGPIN; however, after one or more rounds of castration and hormonal regeneration, Apc-null CARNs disappeared. Alternatively, when ?-catenin was constitutively activated under the same conditions, HGPIN was apparent.Activation of Wnt/?-catenin signaling via Apc deletion is sufficient to produce HGPIN in hormonally normal mice. Loss of Apc may destabilize the CARN population under regeneration conditions. When ?-catenin is constitutively activated, HGPIN occurs in hormonally regenerated mice. A second genetic hit is likely required to cause progression to carcinoma and metastasis.

SUBMITTER: Valkenburg KC

PROVIDER: S-EPMC4175140 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Activation of Wnt/β-catenin signaling in a subpopulation of murine prostate luminal epithelial cells induces high grade prostate intraepithelial neoplasia.

Valkenburg Kenneth C KC Yu Xiuping X De Marzo Angelo M AM Spiering Tyler J TJ Matusik Robert J RJ Williams Bart O BO

The Prostate 20140829 15

<h4>Background</h4>Wnt/β-catenin signaling is important for prostate development and cancer in humans. Activation of this pathway in differentiated luminal cells of mice induces high-grade prostate intraepithelial neoplasia (HGPIN). Though the cell of origin of prostate cancer has yet to be conclusively identified, a castration-resistant Nkx3.1-expressing cell (CARN) may act as a cell of origin for prostate cancer.<h4>Methods</h4>To activate Wnt/β-catenin signaling in CARNs, we crossed mice carr ...[more]

PMID: 25175604

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Project description:Lo-MYC and Hi-MYC mice develop prostatic intraepithelial neoplasia (PIN) and prostatic adenocarcinoma as a result of MYC overexpression in the mouse prostate. However, prior studies have not determined precisely when, and in which cell types, MYC is induced. Using immunohistochemistry (IHC) to localize MYC expression in Lo-MYC transgenic mice, we show that morphological and molecular alterations characteristic of high grade PIN arise in luminal epithelial cells as soon as MYC overexpression is detected. These changes include increased nuclear and nucleolar size and large scale chromatin remodeling. Mouse PIN cells retained a columnar architecture and abundant cytoplasm and appeared as either a single layer of neoplastic cells or as pseudo-stratified/multilayered structures with open glandular lumina-features highly analogous to human high grade PIN. Also using IHC, we show that the onset of MYC overexpression and PIN development coincided precisely with decreased expression of the homeodomain transcription factor and tumor suppressor, Nkx3.1. Virtually all normal appearing prostate luminal cells expressed high levels of Nkx3.1, but all cells expressing MYC in PIN lesions showed marked reductions in Nkx3.1, implicating MYC as a key factor that represses Nkx3.1 in PIN lesions. To determine the effects of less pronounced overexpression of MYC we generated a new line of mice expressing MYC in the prostate under the transcriptional control of the mouse Nkx3.1 control region. These "Super-Lo-MYC" mice also developed PIN, albeit a less aggressive form. We also identified a histologically defined intermediate step in the progression of mouse PIN into invasive adenocarcinoma. These lesions are characterized by a loss of cell polarity, multi-layering, and cribriform formation, and by a "paradoxical" increase in Nkx3.1 protein. Similar histopathological changes occurred in Hi-MYC mice, albeit with accelerated kinetics. Our results using IHC provide novel insights that support the contention that MYC overexpression is sufficient to transform prostate luminal epithelial cells into PIN cells in vivo. We also identified a novel histopathologically identifiable intermediate step prior to invasion that should facilitate studies of molecular pathway alterations occurring during early progression of prostatic adenocarcinomas.

Project description:BackgroundVulval intraepithelial neoplasia (VIN) is a pre-malignant condition of the vulval skin; its incidence is increasing in women under 50 years. VIN is graded histologically as low grade or high grade. High grade VIN is associated with infection with human papilloma virus (HPV) infection and may progress to invasive disease. There is no consensus on the optimal management of high grade VIN. The high morbidity and high relapse rate associated with surgical interventions call for a formal appraisal of the evidence available for less invasive but effective interventions for high grade VIN.ObjectivesTo evaluate the effectiveness and safety of medical interventions for high grade VIN.Search strategyWe searched the Cochrane Gynaecological Cancer Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 3), MEDLINE and EMBASE (up to September 2010). We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field.Selection criteriaRandomised controlled trials (RCTs) that assessed medical interventions, in adult women diagnosed with high grade VIN.Data collection and analysisTwo review authors independently abstracted data and assessed risk of bias. Where possible the data were synthesised in a meta-analysis.Main resultsFour trials met our inclusion criteria: three assessed the effectiveness of topical imiquimod versus placebo in women with high grade VIN; one examined low versus high dose indole-3-carbinol in similar women. Meta-analysis of three trials found that the proportion of women who responded to treatment at 5 to 6 months was much higher in the group who received topical imiquimod than in the group who received placebo (relative risk (RR) = 11.95, 95% confidence interval (CI) 3.21 to 44.51). A single trial showed similar results at 12 months in (RR = 9.10, 95% CI 2.38 to 34.77). Only one trial reported adverse events, which were more common in the imiquimod group. One trial found no significant differences in quality of life (QoL) or body image between the imiquimod and placebo groups.Authors' conclusionsImiquimod appears to be effective, but its safety needs further examination. Its use is associated with side effects which are tolerable, but more extensive data on adverse effects are required. Long term follow-up should be mandatory in view of the known progression of high grade VIN to invasive disease. Alternative medical interventions, such as cidofovir, should be explored.

Dataset Information

Activation of Wnt/?-catenin signaling in a subpopulation of murine prostate luminal epithelial cells induces high grade prostate intraepithelial neoplasia.

Publications

Activation of Wnt/β-catenin signaling in a subpopulation of murine prostate luminal epithelial cells induces high grade prostate intraepithelial neoplasia.

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