KGF suppresses α2β1 integrin function and promotes differentiation of the transient amplifying population in human prostatic epithelium

Abstract

Prostate epithelial stem cells are self-renewing cells capable of differentiation into prostate epithelium, and are thought to contribute towards both benign and malignant conditions in the human prostate. We have previously demonstrated that prostate epithelial basal cells express high levels of integrin α2β1 and this population can be subdivided into stem (α2β1hi CD133+) and transient-amplifying population (TAP) cells (α2β1hi CD133-). However, the molecular mechanism(s) controlling the commitment and regulation of these cells towards differentiated epithelium remains unclear. Here, we demonstrate that β1 integrin function is required for the maintenance of basal prostatic epithelial cells and suppression of its function by either methylcellulose or, more specifically, β1-blocking antibody (80 μg/ml) induces differentiation, with associated expression of the differentiation-specific markers prostate acid phosphatase (PAP) and cytokeratin 18 (CK18). Keratinocyte growth factor (KGF), a stromal-derived growth factor, has previously been implicated in prostate organogenesis using in vitro tissue recombination experiments. We show that treatment with KGF (10 ng/ml) potently induces epithelial differentiation with concomitant suppression of α2β1 integrin expression as well as the induction of androgen receptor expression. Specifically, p38-MAPK appears to be involved and the presence of SB202190, a p38 inhibitor, significantly blocks KGF-induced differentiation. Furthermore, the expression of the high-affinity receptor tyrosine kinase to KGF (FGFR2) is predominantly detectable in α2β1hi CD133- TAP cells when compared with stem cells (α2β1hi CD133+), which would therefore be relatively unresponsive to the differentiating effect of KGF. Taken together, using a human primary culture model, we have demonstrated key roles for interactions between KGF and integrin-mediated function in the regulation of prostate epithelial differentiation.

Modeling the Prostate Stem Cell Niche: An Evaluation of Stem Cell Survival and Expansion In Vitro

“…Experiments with cultured prostate epithelium, keratinocytes, and colonic crypt cells show that differentiation and cell survival is matrixintegrin-dependent [4,[26][27][28]. The inhibition of β 1 -integrin signaling causes terminal differentiation of PSCs and amplifying cells [18]. This published data, and the results reported here, emphasize the importance of cell-to-cell contact and the presence of matrix when establishing a niche model for stem cell study.…”

“…Scale bars = 50 μm. undergo differentiation [18]. To determine whether cells within spheres can maintain CD133 expression, spheres were stained for CD133 after 24 h or 7 days in culture ( Fig.…”

Fibroblast growth factor receptor 2 tyrosine kinase is required for prostatic morphogenesis and the acquisition of strict androgen dependency for adult tissue homeostasis

“…Disruption of the FGFR2 signaling axis in prostates significantly reduced the basal cell population, especially in mature prostates. FGF7 has been suggested to have a negative effect on the maintenance of basal cell properties in cell culture by promoting differentiation (Heer et al, 2006).…”

Characterisation of human prostate epithelial progenitor differentiation in response to androgens

“…5,19 However, AR transcript expression had been confirmed and observations of direct androgen responsiveness allowed speculation that AR protein expression may exist albeit at low levels, beneath the threshold of detection by conventional protein-based assays such as Western blotting and flow cytometry. AR protein is rapidly degraded in the absence of ligand 23 and, on androgen binding, leads to stabilisation of AR.…”