Wnt/β‐Catenin‐Responsive Cells in Prostatic Development and Regeneration

The precise role of Wnt/β‐catenin signaling during prostatic development and tumorigenesis is unclear. Axin2 is a direct transcriptional target of β‐catenin. Recent studies have shown that Axin2‐expressing cells have stem/progenitor cell properties in a variety of mouse tissues. Here, we genetically labeled Axin2‐expressing cells at various time points and tracked their cellular behavior at different developmental and mature stages. We found that prostatic Axin2‐expressing cells mainly express luminal epithelial cell markers and are able to expand luminal cell lineages during prostatic development and maturation. They can also survive androgen withdrawal and regenerate prostatic luminal epithelial cells following androgen replacement. Deletion of β‐catenin or expression of stabilized β‐catenin in these Axin2‐expressing cells results in abnormal development or oncogenic transformation, respectively. Our study uncovers a critical role of Wnt/β‐catenin‐responsive cells in prostatic development and regeneration, and that dysregulation of Wnt/β‐catenin signaling in these cells contributes to prostatic developmental defects and tumorigenesis. Stem Cells 2015;33:3356–3367

[1]  R. Nusse,et al.  Lineage tracing with Axin2 reveals distinct developmental and adult populations of Wnt/β-catenin–responsive neural stem cells , 2013, Proceedings of the National Academy of Sciences.

[2]  T. Blauwkamp,et al.  Prospective isolation of human embryonic stem cell-derived cardiovascular progenitors that integrate into human fetal heart tissue , 2013, Proceedings of the National Academy of Sciences.

[3]  M. Taketo,et al.  β-Catenin Is Required for Prostate Development and Cooperates with Pten Loss to Drive Invasive Carcinoma , 2013, PLoS genetics.

[4]  Luigi Marchionni,et al.  Wnt signaling though beta-catenin is required for prostate lineage specification. , 2012, Developmental biology.

[5]  C. Blanpain,et al.  Multipotent and unipotent progenitors contribute to prostate postnatal development , 2012, Nature Cell Biology.

[6]  R. Nusse,et al.  Developmental stage and time dictate the fate of Wnt/β-catenin-responsive stem cells in the mammary gland. , 2012, Cell stem cell.

[7]  Jiaoti Huang,et al.  The PSA(-/lo) prostate cancer cell population harbors self-renewing long-term tumor-propagating cells that resist castration. , 2012, Cell stem cell.

[8]  J. Rosen,et al.  Targeting CreERT2 expression to keratin 8-expressing murine simple epithelia using bacterial artificial chromosome transgenesis , 2012, Transgenic Research.

[9]  M. Ittmann,et al.  Adult murine prostate basal and luminal cells are self-sustained lineages that can both serve as targets for prostate cancer initiation. , 2012, Cancer cell.

[10]  T. Blauwkamp,et al.  Endogenous Wnt signalling in human embryonic stem cells generates an equilibrium of distinct lineage-specified progenitors , 2012, Nature Communications.

[11]  R. Matusik,et al.  Wnt/β-Catenin activation promotes prostate tumor progression in a mouse model , 2010, Oncogene.

[12]  J. Zavadil,et al.  Molecular Signatures of the Primitive Prostate Stem Cell Niche Reveal Novel Mesenchymal-Epithelial Signaling Pathways , 2010, PloS one.

[13]  M. Shen,et al.  A luminal epithelial stem cell that is a cell of origin for prostate cancer , 2009, Nature.

[14]  S. Salm,et al.  Axin2 expression identifies progenitor cells in the murine prostate , 2008, The Prostate.

[15]  G. Prins,et al.  Molecular signaling pathways that regulate prostate gland development. , 2008, Differentiation; research in biological diversity.

[16]  M. Mimeault,et al.  Functions of normal and malignant prostatic stem/progenitor cells in tissue regeneration and cancer progression and novel targeting therapies. , 2008, Endocrine reviews.

[17]  L. Luo,et al.  A global double‐fluorescent Cre reporter mouse , 2007, Genesis.

[18]  J. Resau,et al.  Inactivation of Apc in the mouse prostate causes prostate carcinoma. , 2007, Cancer research.

[19]  R. Nusse,et al.  The Wnt signaling pathway in development and disease. , 2004, Annual review of cell and developmental biology.

[20]  R. Nusse,et al.  Convergence of Wnt, ß-Catenin, and Cadherin Pathways , 2004, Science.

[21]  R. Nusse.  Wnts and Hedgehogs: lipid-modified proteins and similarities in signaling mechanisms at the cell surface , 2003, Development.

[22]  G. Cunha,et al.  Mouse urogenital development: a practical approach. , 2003, Differentiation; research in biological diversity.

[23]  R. Cardiff,et al.  Activation of β-catenin in prostate epithelium induces hyperplasias and squamous transdifferentiation , 2003, Oncogene.

[24]  M. Kühl,et al.  Increasingly complex: new players enter the Wnt signaling network. , 2002, BioEssays : news and reviews in molecular, cellular and developmental biology.

[25]  O. Grace,et al.  The role of smooth muscle in regulating prostatic induction. , 2002, Development.

[26]  Hans Clevers,et al.  Negative Feedback Loop of Wnt Signaling through Upregulation of Conductin/Axin2 in Colorectal and Liver Tumors , 2002, Molecular and Cellular Biology.

[27]  Choun-Ki Joo,et al.  Wnt/β-Catenin/Tcf Signaling Induces the Transcription of Axin2, a Negative Regulator of the Signaling Pathway , 2002, Molecular and Cellular Biology.

[28]  M. Wiesmann,et al.  Elevated expression of axin2 and hnkd mRNA provides evidence that Wnt/β-catenin signaling is activated in human colon tumors , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[29]  A. McMahon,et al.  Inactivation of the beta-catenin gene by Wnt1-Cre-mediated deletion results in dramatic brain malformation and failure of craniofacial development. , 2001, Development.

[30]  D. Laurents,et al.  The cadherin cytoplasmic domain is unstructured in the absence of beta-catenin. A possible mechanism for regulating cadherin turnover. , 2001, The Journal of biological chemistry.

[31]  P. Polakis.  Wnt signaling and cancer. , 2000, Genes & development.

[32]  G. Stamp,et al.  Phenotypic and genotypic characterization of commonly used human prostatic cell lines , 2000, BJU international.

[33]  J. Herman,et al.  E-cadherin expression is silenced by DNA hypermethylation in human breast and prostate carcinomas. , 1995, Cancer research.

[34]  J. Kawamura,et al.  Morphological and functional heterogeneity in the rat prostatic gland. , 1991, Biology of reproduction.

[35]  S. J. Higgins,et al.  The endocrinology and developmental biology of the prostate. , 1987, Endocrine reviews.

[36]  G. Cunha,et al.  Morphogenesis of ductal networks in the mouse prostate. , 1986, Biology of reproduction.

[37]  G. Cunha,et al.  Stromal-epithelial interactions and heterogeneity of proliferative activity within the prostate. , 1986, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[38]  Angela N. Bowmana,et al.  Lineage tracing with Axin 2 reveals distinct developmental and adult populations of Wnt / β-catenin – responsive neural stem cells , 2013 .

[39]  R. Nusse,et al.  Wnt signaling in disease and in development , 2005, Cell Research.

[40]  R. Nusse,et al.  Convergence of Wnt, beta-catenin, and cadherin pathways. , 2004, Science.

[41]  W. Birchmeier,et al.  Adherens junction proteins in tumour progression. , 1995, Cancer surveys.

[42]  R. Santen,et al.  Response of glandular versus basal rat ventral prostatic epithelial cells to androgen withdrawal and replacement , 1987, The Prostate.

[43]  L. Chung,et al.  Stromal‐epithelial interactions: II. Regulation of prostatic growth by embryonic urogenital sinus mesenchyme , 1983, The Prostate.