The molecular and cellular origin of human prostate cancer

Abstract

Prostate cancer is the most commonly diagnosed male malignancy. Despite compelling epidemiology, there are no definitive aetiological clues linking development to frequency. Pre-malignancies such as proliferative inflammatory atrophy (PIA) and prostatic intraepithelial neoplasia (PIN) yield insights into the initiating events of prostate cancer, as they supply a background "field" for further transformation. An inflammatory aetiology, linked to recurrent prostatitis, and heterologous signalling from reactive stroma and infiltrating immune cells may result in cytokine addiction of cancer cells, including a tumour-initiating population also known as cancer stem cells (CSCs). In prostate tumours, the background mutational rate is rarely exceeded, but genetic change via profound sporadic chromosomal rearrangements results in copy number variations and aberrant gene expression. In cancer, dysfunctional differentiation is imposed upon the normal epithelial lineage, with disruption/disappearance of the basement membrane, loss of the contiguous basal cell layer and expansion of the luminal population. An initiating role for androgen receptor (AR) is attractive, due to the luminal phenotype of the tumours, but alternatively a pool of CSCs, which express little or no AR, has also been demonstrated. Indolent and aggressive tumours may also arise from different stem or progenitor cells. Castrate resistant prostate cancer (CRPC) remains the inevitable final stage of disease following treatment. Time-limited effectiveness of second-generation anti-androgens, and the appearance of an AR-neuroendocrine phenotype imply that metastatic disease is reliant upon the plasticity of the CSC population, and indeed CSC gene expression profiles are most closely related to those identified in CRPCs.

Metabolic heterogeneity signature of primary treatment-naïve prostate cancer

“…Whereas the genomic and transcriptomic heterogeneity of prostate cancer is well documented [26], less is known about metabolic heterogeneity of this malignancy and its relevance to malignant progression. Studies of the heterogeneity of prostate cancer, in particular hormone-naïve cancers, have been impeded by a lack of clinically relevant experimental models.…”

Establishment of a dog primary prostate cancer organoid using the urine cancer stem cells

“…Basal cells are regarded as stem cell components and are located at the basement membrane; they are identified by expression of CK5. The luminal cells are the secretory components of the gland, which express CK8 . To clarify which cells regulate tumor progression in dog PC, we performed the sorting of basal and luminal cells (Fig.…”

NRIP/DCAF6 stabilizes the androgen receptor protein by displacing DDB2 from the CUL4A-DDB1 E3 ligase complex in prostate cancer

“…For example, when overexpressed in cancers derived from basal epithelial cells, the AR functions as a tumor suppressor to inhibit the proliferation of basal cells and drive them into differentiation, resulting in the inhibition of prostate cancer metastasis [40, 42]. In contrast, the AR is a survival factor that promotes the proliferation of luminal cellsthat constitute more than 99% of prostate tumor epithelial cells [40, 43]. Here, we report that AR expression increased in prostate cancer tissues and support the proposed model of the AR as an oncogene in cancer.…”