Stromal Gli signaling regulates the activity and differentiation of prostate stem and progenitor cells

Abstract

Interactions between cells in the stroma and epithelium facilitate prostate stem cell activity and tissue regeneration capacity. Numerous molecular signal transduction pathways, including the induction of sonic hedgehog (Shh) to activate the Gli transcription factors, are known to mediate the cross-talk of these two cellular compartments. However, the details of how these signaling pathways regulate prostate stem and progenitor cell activity remain elusive. Here we demonstrate that, although cell-autonomous epithelial Shh-Gli signaling is essential to determine the expression levels of basal cell markers and the renewal potential of epithelial stem and progenitor cells, stromal Gli signaling regulates prostate stem and progenitor cell activity by increasing the number and size of prostate spheroids Blockade of stromal Gli signaling also inhibited prostate tissue regeneration The inhibition of stromal Gli signaling suppressed the differentiation of basal and progenitor cells to luminal cells and limited prostate tubule secretory capability. Additionally, stromal cells were able to compensate for the deficiency of epithelial Shh signaling in prostate tissue regeneration. Mechanistically, suppression of Gli signaling increased the signaling factor transforming growth factor β (TGFβ) in stromal cells. Elevation of exogenous TGFβ1 levels inhibited prostate spheroid formation, suggesting that a stromal Gli-TGFβ signaling axis regulates the activity of epithelial progenitor cells. Our study illustrates that Gli signaling regulates epithelial stem cell activity and renewal potential in both epithelial and stromal compartments.

YAP is required for prostate development, regeneration, and prostate stem cell function

“…Furthermore, Shahi et al found that the Notch signaling plays critical roles in prostate progenitor cells and concluded that Notch signaling is required to modulate the cell cycle and permit normal development and differentiation of prostate spheres [ 56 ]. Consistent with our results, Li et al suggested that cell-autonomous epithelial Shh-Gli signaling and stromal Gli signaling are both essential to the renewal and differentiation potential of epithelial stem and progenitor cells [ 57 , 58 ].…”

Advances in the Current Understanding of the Mechanisms Governing the Acquisition of Castration-Resistant Prostate Cancer

“…The Hedgehog (Hh) pathway has increasingly been reported to be derepressed in PCA cells under therapeutic treatment, contributing to the progression of CRPC [ 124 , 125 ]. Within the CRPC cells, the higher levels of the Hh pathway ligands (Shh, Ihh, Dhh) promote Smoothed (Smo) derepression, leading to its activation and the consequent activation of Glid, which is a transcription factor [ 124 , 126 , 127 , 128 ]. This Hh pathway plays a central role in cancer stem-cell maintenance, promoting PCA stem cell development, which can contribute to both metastatic progression and chemoresistance [ 126 , 129 , 130 , 131 ].…”

“…Within the CRPC cells, the higher levels of the Hh pathway ligands (Shh, Ihh, Dhh) promote Smoothed (Smo) derepression, leading to its activation and the consequent activation of Glid, which is a transcription factor [ 124 , 126 , 127 , 128 ]. This Hh pathway plays a central role in cancer stem-cell maintenance, promoting PCA stem cell development, which can contribute to both metastatic progression and chemoresistance [ 126 , 129 , 130 , 131 ]. Under conditions of low androgen availability, the abnormal GLI signaling within the epithelial cells contributes to higher levels of p63 expression, resulting in an increase in cancer stem cell activity, facilitating proliferation, metastasis, and resistance to therapeutic intervention [ 129 , 132 , 133 ].…”

Hedgehog Signaling for Urogenital Organogenesis and Prostate Cancer: An Implication for the Epithelial–Mesenchyme Interaction (EMI)

“…The expression of Hh signaling components, such as Gli, is also correlated with a higher Gleason score [59][60][61]. During prostate development, Gli signaling is involved in the differentiation of prostate progenitor cells [62], and Gli mediates the oncogenic transformation of prostate basal cells [63]. Furthermore, Gli1 confers basal-like characteristics onto LNCaP cells, leading to the acquisition of PCa hormone independence [64].…”