Activation of β-catenin in prostate epithelium induces hyperplasias and squamous transdifferentiation

Abstract

The Wnt/b-catenin signaling pathway is critical for normal mammalian development, the specification of epidermal cells and neoplastic transformation of intestinal epithelium. However, precise molecular information regarding cell-specific responses to b-catenin signaling has been limited. This question was addressed using a mouse model in which exon 3 of the b-catenin gene was deleted in several cell types with loxP-mediated recombination utilizing a Cre transgene under control of the mouse mammary tumor virus-long terminal repeat (MMTV-LTR). The stabilization of b-catenin in prostate epithelium resulted in hyperplasias and extensive transdifferentiation into epidermal-like structures, which expressed keratins 1 and 6, filaggrin, loricrin and involucrin. The cell-specific loss of NKCC1 protein and reduced nuclear Stat5a is further suggestive of a loss of prostate epithelial characteristics. In addition to the prostate, hyperplasias and squamous metaplasias were detected in epithelia of the epididymis, vas deferens, coagulating gland, preputial gland and salivary gland. However, and in contrast to a recent study, no lesions reminiscent of highgrade prostate intraepithelial neoplasia were detected. Since b-catenin was activated in several cell types and impinged upon the viability of these mice, it was not possible to evaluate the cumulative effect over more than 3 months. To assess long-term consequences of b-catenin activation, mutant and control prostate tissues were transplanted into the mammary fat pads of wild-type males. Notably, squamous metaplasias, intra-acinous hyperplasia and possible neoplastic transformation were observed after a total of 18 weeks of b-catenin stimulation. This suggests that the transdifferentiation into squamous metaplasias is an early response of endodermderived cells to b-catenin, and that the development of intra-acinous hyperplasias or neoplastic foci is a later event.

Helicobacter pylori CagA interacts with E-cadherin and deregulates the β-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells

“…Recent studies have revealed that deregulated b-catenin signal induces transdifferentiation of cells from one lineage to another. For example, forced activation of b-catenin in mammary epithelial or prostate epithelial cells results in development of squamous metaplasia (Miyoshi et al, 2002;Bierie et al, 2003). Furthermore, expression of a constitutively active b-catenin-Lef1 fusion protein in the mouse lung induces transdifferentiation of lung epithelial cells to intestinal-type cells (Okubo and Hogan, 2004).…”

“…Intestinal-type carcinoma arises from gastric mucosa with intestinal metaplasia, a pathological change characterized by the transdifferentiation of gastric progenitor cells into those committed to intestinal cell lineage, which is highly associated with infection with H. pylori cagA-positive strains (Kuipers et al, 1995;Sozzi et al, 1998). Recent studies have shown that deregulation of b-catenin signal is involved in the pathological transdifferentiation of various cell lineages, including intestinal metaplasia (Bailey et al, 1998;Miyoshi et al, 2002;Bierie et al, 2003;Okubo and Hogan, 2004). b-Catenin is localized to cell-cell junctions by interaction with the cytoplasmic tail of a transmembrane protein E-cadherin.…”

Identification of a stem cell candidate in the normal human prostate gland

“…In further studies we need to determine whether this increase in cytokeratin 6a expression is due to an expansion of pre-existing cytokeratin 6a-positive cells or due to induction in initially cytokeratin 6-negative basal cells. Since cytokeratin 6 is also a marker for squamous metaplasia, which can be caused by injury, we also should consider a limited squamous differentiation as partial cause (Bierie et al, 2003) for the dramatic increase of cytokeratin 6 expression in our in vitro model. The stem cell nature again is supported by three facts: (1) The new surface epithelium expresses PSA, which is not expressed by matured squamous cells in prostatic epithelium (Lager et al, 1988).…”

Transdetermination: Drosophila imaginal disc cells exhibit stem cell-like potency

“…Mouse lung progenitor cells, for example, TD to intestinal cell types by elevated and/or prolonged Wnt signaling (Okubo & Hogan, 2004). Lineage switches were also observed when Wnt signaling is altered in hair follicle and epidermal cells (Merrill, Gat, DasGupta, & Fuchs, 2001;Niemann, 2006) and in the mammary gland and prostate (Bierie et al, 2003;Miyoshi et al, 2002).…”