Low CD38 Identifies Progenitor-like Inflammation-Associated Luminal Cells that Can Initiate Human Prostate Cancer and Predict Poor Outcome

Abstract

SUMMARY Inflammation is a risk factor for prostate cancer, but the mechanisms by which inflammation increases that risk are poorly understood. Here, we demonstrate that low expression of CD38 identifies a progenitor-like subset of luminal cells in the human prostate. CD38lo luminal cells are enriched in glands adjacent to inflammatory cells and exhibit epithelial nuclear factor κB (NF-κB) signaling. In response to oncogenic transformation, CD38lo luminal cells can initiate human prostate cancer in an in vivo tissue-regeneration assay. Finally, the CD38lo luminal phenotype and gene signature are associated with disease progression and poor outcome in prostate cancer. Our results suggest that prostate inflammation expands the pool of progenitor-like target cells susceptible to tumorigenesis.

Functional evidence that progenitor cells near sites of inflammation are precursors for aggressive prostate cancer

“…4 Gene expression analysis of CD38lo cells revealed enrichment of many inflammatory-related genes, and immunohistochemical staining of human prostate tissue confirmed that CD38lo luminal cells are predominantly localized in glands adjacent to inflammation.…”

“…Serial biopsies of benign human prostate tissue containing chronic inflammation may help uncover the precise order of events involved in PIA. Interestingly, our gene expression analysis revealed that PIA-like cells upregulate several pro-inflammatory cytokines and chemokines, 4 suggesting that PIA-like cells may actively recruit inflammation. The assays used to measure progenitor activity require that epithelial cells be removed from their native environment, dissociated into single cells, and grown in a culture system lacking several of the key cell types found in the prostate microenvironment including inflammatory cells.…”

“…Furthermore, our ability to isolate PIA-like luminal cells allowed us to profile and characterize them in a deeper way than in previous studies. We can now show that PIA-like cells exhibit elevated nuclear factor kappa B (NF-kB) signaling, 4 , which has been associated with aggressive prostate cancer. 7 Moreover, since CD38lo cells display decreased androgen signaling and elevated BCL2 expression, they would be predicted to respond poorly to hormonal therapy.…”

“…Transplanted oncogene-expressing CD38lo luminal cells developed features of highly proliferative prostate adenocarcinoma, suggesting that they can initiate aggressive human prostate cancer in vivo. 4 Our development of an approach to isolate PIA-like luminal cells based on low expression of CD38 allowed us to functionally test their capacity. Our demonstration that PIA-like luminal cells isolated from human prostate tissue can initiate prostate cancer 3 provides functional evidence to support the model that PIA may represent a precursor to prostate cancer (Fig.…”

The potential of organoids in urological cancer research

“…Results from a 2015 study using a Pten – Tp53 -null mouse model of prostate cancer also demonstrate that luminal cells can be prostate cancer progenitors: culturing organoids derived from luminal cells initiated adenocarcinoma or tumours with multilineage histological phenotypes 91 . Liu and colleagues 92 discovered that low expression of CD38 could be used as a biomarker to identify progenitor-like, inflammation-associated luminal cells that can initiate human prostate cancer. They demonstrated that CD38-low luminal cells expressing both basal (K5 and p63) and luminal (K8) markers were enriched by fourfold to fivefold in organoid formation compared with CD38-high luminal cells.…”