Molecular pathogenesis of human prostate basal cell hyperplasia

Abstract

Background Understanding the molecular pathogenesis of distinct phenotypes in human benign prostatic hyperplasia (BPH) is essential to improving therapeutic intervention. Current therapies target smooth muscle and luminal epithelia for relief of lower urinary tract symptoms (LUTS) due to BPH, but basal cell hyperplasia (BCH) remains untargeted. The incidence of has been reported at 8–10%, but a molecular and cellular characterization has not been performed on this phenotype. Methods Using freshly digested tissue from surgical specimens, we performed RNA-seq analysis of flow cytometry-purified basal epithelia from 3 patients with and 4 patients without a majority BCH phenotype. qPCR was performed on 28 genes identified as significant from 13 non-BCH and 7 BCH specimens to confirm transcriptomic analysis. IHC was performed on several non-BCH and BCH specimens for 3 proteins identified as significant by transcriptomic analysis. Results A total of 141 human BPH specimens were analyzed for the presence of BCH. Clinical characteristics of non-BCH and BCH cohorts revealed no significant differences in age, PSA, prostate volume, medical treatment, or comorbidities. Quantitation of cellular subsets by flow cytometry in 11 BCH patients vs. 11 non-BCH patients demonstrated a significant increase in the ratio of basal to luminal epithelia in patients with BCH (P <0.05), but no significant differences in the total number of leukocytes. RNA-seq data from flow cytometry isolated basal epithelia from patients with and without BCH were subjected to gene set enrichment analysis of differentially expressed genes, which revealed increased expression of members of the epidermal differentiation complex. Transcriptomic data were complemented by immunohistochemistry for members of the epidermal differentiation complex, revealing a morphological similarity to other stratified squamous epithelial layers. Conclusions Increased expression of epidermal differentiation complex members and altered epithelial stratification resembles the progression of other metaplastic diseases. These data provide insight into the plasticity of the human prostate epithelium and suggest a classification of basal cell hyperplasia as a metaplasia.

Mutational and transcriptomic landscapes of a rare human prostate basal cell carcinoma

“…The molecular features of normal human prostate basal cells, 19 prostate basal cell hyperplasia, 20 and human prostate cancer derived basal populations 18 prostate cancer are generated using bulk samples, 10,11,13 and the single-cell transcriptional profiles of prostate BCC provide an opportunity for deeper utilization of these data. For example, analysis using genes highly expressed in prostate BCC reveals the existence of basal cell features in some bulk samples of prostate cancer, which is consistent with recent classification of prostate cancer samples into basal-like and luminal-like subtypes using the PAM50 classifier.…”

“…4 Despite being largely regarded as pursuing an indolent clinical course, aggressive behaviors like recurrence or metastasis have been observed and deaths are also reported, highlighting the complex and yet poorly understood mechanism. [5][6][7][8][9] There have been extensive reports on the genomic features of common prostate cancer, [10][11][12][13][14][15][16][17] and the molecular features of normal human prostate basal cells, prostate basal cell hyperplasia, and basal populations from human prostate cancer have also been reported, [18][19][20] but the molecular profile of prostate BCC is still lacking. The mutational and transcriptomic features of this tumor subtype will thus be valuable for understanding of its tumorigenesis mechanism and development of future clinical treatments.…”

Distinct expression patterns of SULT2B1b in human prostate epithelium

“…11 Benign prostate hyperplasia (BPH) is predominantly due to the expansion of the luminal epithelial cells (glandular hyperplasia) with 8% to 10% of BPH cases due to the hyperplasia of the basal layer (basal hyperplasia). [12][13][14] Luminal and basal epithelial cells have both been identified as the cell of origin for prostate cancer, 15 with basal cells being linked with more aggressive prostate cancer. 16 Prostate cancer with luminal or basal subtypes also exhibits different responses to therapies such as androgen deprivation therapy.…”

“…For identification in situ, luminal epithelial cells have historically been identified by cytokeratin 8/18 and PSA (prostate‐specific antigen) expression, whereas basal cells express cytokeratin 5/14 and p63 . Benign prostate hyperplasia (BPH) is predominantly due to the expansion of the luminal epithelial cells (glandular hyperplasia) with 8% to 10% of BPH cases due to the hyperplasia of the basal layer (basal hyperplasia) . Luminal and basal epithelial cells have both been identified as the cell of origin for prostate cancer, with basal cells being linked with more aggressive prostate cancer .…”

Basal Cell Hyperplasia Observed at Biopsy Specimens after HIFU Therapy: Implication of Stemness for Organ Regeneration

“…Each organ has somatic type stem cells preparing for repair of tissue injury, usually residing in specialized microenvironment or niches. Basal cell hyperplasia (BCH) is observed in association with a repairing process of tissue damage such as inflammation or injury [4]. Basal cell hyperplasia also has a relation to prostate carcinogenesis [5].…”