National Cancer Research Institute South of England
Prostate Cancer Collaborative
Research

The effects of purified Wnt proteins on prostate cell growth and differentiation

Author

Imperial College

Work in my laboratory focuses on the involvement of the Wnt signalling pathway in prostate cancer. The NCRI Pilot Award will provide us with funding for consumables to purify Wnt proteins and assess their effects on cultured primary prostate cells.

Wnts are secreted growth/differentiation factors that play significant roles during development (for recent reviews see the Wnt homepage http://www.stanford.edu/~rnusse/wntwindow.html). They can be grouped into two classes: canonical and noncanonical. Canonical Wnts stabilise beta-catenin and activate gene expression; noncanonical Wnts affect other pathways, for example, involving PKC and JNK activation, thereby regulating cell survival, cell motility and cell polarity. Importantly, there are instances when noncanonical Wnts inhibit the actions

of canonical Wnts (Saneyoshi et al., 2002; Topol et al., 2003), suggesting that the balance of Wnt family members expressed in a tissue will be an important determinant of beta-catenin activation. We have identified Wnts

from both classes that are expressed to different degrees in primary prostate cells and in prostate cancer cell lines. These are therefore candidates for factors that regulate prostate stem cell growth and differentiation.

Research in the Wnt field has been hampered by the inability to purify active Wnt proteins, and, until recently, all studies used conditioned medium from cells transfected with Wnt expression plasmids. This problem, which resulted from the high hydrophobicity of Wnts, has now been solved for at least three Wnts. It has been shown that purified Wnt3A

maintains hematopoietic stem cells in an undifferentiated state to a greater extent than Wnt3A-conditioned medium (Willert et al., 2003; Reya et al., 2003). Thus cell-conditioned medium   might contain factors that induce stem and/or progenitor cell differentiation, and any meaningful studies of the effects of Wnts on   prostate cell growth and differentiation will ultimately require the use of purified proteins.

It has been suggested that prostate cancer arises from abnormal prostate stem cells. If Wnt proteins are found to regulate prostate stem cell development, then they might also play a primary role in the origins of prostate cancer. There is circumstantial evidence to support this idea. Wnt

proteins, foir example, play important roles in stem cell maintenance in several other organs (reviewed in Taipale and Beachy, 2001 and in Fuchs et al., 2001), and activation of the Wnt signalling pathway occurs during androgen-induced regrowth of the rat prostate (Chesire et al., 2002).

Moreover, even though only 5% of prostate tumours contain activating mutations in the beta-catenin gene, beta-catenin is 'activated' (that is, found in the nucleus and cytoplasm rather than solely at cell-cell junctions) in up to 38% of advanced prostate tumours (Chesire et al., 2002;

de la Taille, 2003). We hope that by exploring   the effects of Wnts on prostate cell growth and differentiation we will be able to shed light on any link between stem cells and prostate cancer.

References

  1. Chesire DR, Ewing CM, Gage WR, Isaacs WB. In vitro evidence for complex modes of nuclear beta-catenin signaling during prostate growth and tumorigenesis. Oncogene. 2002 Apr 18;21(17):2679-94.
  2. De La Taille A, Rubin MA, Chen MW, Vacherot F, De Medina SG,Burchardt M, Buttyan R, Chopin D. beta-Catenin-related Anomalies in Apoptosis-resistant and Hormone-refractory Prostate Cancer Cells. Clin Cancer Res. 2003 May;9(5):1801-7.
  3. Fuchs E, Merrill BJ, Jamora C, DasGupta R. At the roots of a never-ending cycle. Dev Cell. 2001 Jul;1(1):13-25.
  4. Hudson DL, Masters JR.   Prostate epithelial stem cell isolation and culture. Methods Mol Med. 2003;81:59-67.
  5. Saneyoshi T, Kume S, Amasaki Y, Mikoshiba K. The Wnt/calcium pathway activates NF-AT and promotes ventral cell fate in Xenopus embryos. Nature. 2002 May 16;417(6886):295-9.
  6. Taipale J, Beachy PA. The Hedgehog and Wnt signalling pathways in cancer. Nature. 2001 May 17;411(6835):349-54.
  7. Topol L, Jiang X, Choi H, Garrett-Beal L, Carolan PJ, Yang Y. Wnt-5a inhibits the canonical Wnt pathway by promoting GSK-3-independent beta-catenin degradation. J Cell Biol. 2003 Sep 1;162(5):899-908.
  8. Wodarz A, Nusse R. Mechanisms of Wnt signaling in development. Annu Rev Cell Dev Biol. 1998;14:59-88.
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