Prostate Luminal Progenitor Cells in Development and Cancer

Abstract

Prostate cancer (PCa) has a predominantly luminal phenotype. Basal cells were previously identified as a cell of origin for PCa, but increasing evidence implicates luminal cells as a preferred cell of origin for PCa, as well as key drivers of tumor development and progression. Prostate luminal cells are understudied compared with basal cells. In this review, we describe the contribution of prostate luminal progenitor (LP) cells to luminal cell development and their role in prostate development, androgen-mediated regeneration of castrated prostate, and tumorigenesis. We also discuss the potential value of LP transcriptomics to identify new targets and therapies to treat aggressive PCa. Finally, we propose future research directions focusing on molecular mechanisms underlying LP cell biology and heterogeneity in normal and diseased prostate.

Keywords: cancer stem cells; castration resistance; luminal progenitors; prostate cancer; prostate stem cells.

Figure 1.. Role of luminal progenitors (LPs) in PCa initiation and development

(A) In the human cell transformation assays using freshly purified bulk prostatic basal and luminal cells and LP-enriched populations (i.e., culture-enriched or FACS-sorted), only basal cells and LPs can be oncogenically transformed to form tumors. (B) Transformation of basal cells by loss of Pten initiates PCa by a first basal-to-luminal differentiation step followed by expansion of stem-like pAKT⁺ and proliferative luminal cells to establish luminal-like tumor (top panel). PCa initiated from luminal-cell-specific loss of Pten uniformly manifest a luminal phenotype. One study has characterized the primary PSA-CreER;Pten^fl/fltumor cells and suggested that LPs are the cells initiating and subsequently maintaining the PCa (bottom panel).

Figure I in Box 1.. Hierarchy of prostate epithelial cell lineages

(A) A simplified cartoon illustrating the epithelial cell composition and glandular structure of the adult prostate. (B, C) Hierarchy of epithelial cell lineages during early prostate development (B) and during homeostasis and regeneration (C), revealed by genetic lineage-tracing studies. Blue curved arrows denote self-renewal and dashed arrows indicate inconsistent results reported by different groups.

Figure I in Box 4.. Transcriptomics of prostate LPs

Three mouse datasets (A [48], B [52], C [22]) and three human datasets (D [58], E [11], F [29]) are used to unravel the molecular features of LPs. DAVID bioinformatics tool is employed to systematically analyze the biological categories of GO terms enriched in genes and signatures overrepresented by reported LP populations. Predominant functional categories are highlighted in color, whereas relatively less enriched categories are uncolored. Technically, the original GO terms from DAVID output were selected with a cutoff of p<0.05. For each gene signature, we then pooled the GO terms and re-categorized them by grouping similar GO terms into broad functional categories. For example, GO terms associated with organ process, development, differentiation, and SC-related pathways (e.g., IGF, growth factors) are categorized as “development & SCs”.Similarly, GO terms linked to CNS development and neural/neuronal cell biology will be categorized as “neurogenesis”. Inflammation and immunity encompass GO terms related to inflammatory cell biology and response and immune cell biology and response.