Prostate luminal progenitor cells: from mouse to human, from health to disease

Abstract

Stem and progenitor cells of the adult prostate epithelium have historically been believed to reside mainly or exclusively within the basal cell compartment and to possess basal-like phenotypic characteristics. Within the past decade, evidence of the existence of luminal epithelial cells exhibiting stem/progenitor properties has been obtained by lineage tracing and by functional characterization of sorted luminal-like cells. In 2020, the boom of single-cell transcriptomics led to increasingly exhaustive profiling of putative mouse luminal progenitor cells and, importantly, to the identification of cognate cells in the human prostate. The enrichment of luminal progenitor cells in genetically modified mouse models of prostate inflammation, benign prostate hypertrophy and prostate cancer, and the intrinsic castration tolerance of these cells, suggest their potential role in prostate pathogenesis and in resistance to androgen deprivation therapy. This Review bridges different approaches that have been used in the field to characterize luminal progenitor cells, including the unification of multiple identifiers employed to define these cells (names and markers). It also provides an overview of the intrinsic functional properties of luminal progenitor cells, and addresses their relevance in mouse and human prostate pathophysiology.

Transcriptomic Signature and Growth Factor Regulation of Castration-Tolerant Prostate Luminal Progenitor Cells

“…This is very similar to what has been observed by us and others for WT mouse LSC med cells (our unpublished data), WT SCA-1 + luminal progenitor cells [ 9 ] (that are equivalent to LSC med cells; see Ref. [ 8 ]) and PROM1+ luminal progenitors enriched from Pten-null mice [ 58 ].…”

“…The involvement of LSC med cells in prostate cancer is supported by several observations in preclinical models for a review, Ref. [ 8 ]. While they are rare in healthy prostates (~5% of epithelial cells), LSC med cells represent up to 80% of epithelial cells in prostate tumors driven by prostate-specific deficiency of the tumor suppressor gene Pten (mice are hereafter called Pten-null) [ 5 , 7 ].…”

“…We recently discovered, isolated and profiled in mouse prostate an unprecedentedly defined population of non-secretory luminal cells matching these three criteria [ 5 , 6 , 7 , 8 ]. We named these cells LSC med according to their FACS profile (Lin − /Sca-1 + /CD49f med ) using stem cell antigen-1 (SCA-1) and CD49f (integrin α6) as cell surface markers [ 6 ].…”

“…The stem/progenitor properties of LSC med cells have also been widely assessed by us and others through their enriched capacity versus mature luminal cells to form spheres and organoids in vitro, to self-renew, and to generate glandular structures when engrafted into host mice [ 5 , 6 , 9 ]. Exhaustive description of LSC med cell properties is provided in a recent review article [ 8 ].…”

High Keratin-7 Expression in Benign Peri-Tumoral Prostatic Glands Is Predictive of Bone Metastasis Onset and Prostate Cancer-Specific Mortality

“…Biomarker validation remains critical to accurately predict metastasis and PC-specific mortality and to be able to discriminate patients who need radical therapy (prostatectomy or radiation) from those who can be safely managed by active surveillance. Much research is now focused on identifying the tumor-initiating cells/castration-tolerant cells that could lead to progression on active surveillance or recurrence after aggressive treatment, and adult stem/progenitor cells are alleged to be those critical cells [ 30 ]. KRT7 has been described as a recent novel prostate progenitor cell marker in mice and has been identified in both the basal and luminal cell layers of the mouse prostate, with a preferential localization in ducts and in the proximal prostate [ 21 ].…”