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Review
. 2009 Dec;22(6):724-39.
doi: 10.1111/j.1755-148X.2009.00627.x. Epub 2009 Aug 25.

Hear the Wnt Ror: how melanoma cells adjust to changes in Wnt

Michael P O'Connell  1 , Ashani T Weeraratna
Affiliations
Review

Hear the Wnt Ror: how melanoma cells adjust to changes in Wnt

Michael P O'Connell et al. Pigment Cell Melanoma Res. 2009 Dec.

Abstract

The interplay between canonical and non-canonical Wnt pathways in development and tumorigenesis is tightly regulated. In this review we will describe the yin and the yang of canonical and non-canonical Wnt signaling pathways during melanocyte development, and melanoma genesis. Canonical Wnt signaling, represented by Wnts such as Wnt1 and Wnt3A, signals via beta-catenin to promote melanocyte differentiation and tumor development. Non-canonical Wnt signaling, specifically Wnt5A, regulates canonical pathways, and signals to induce melanoma metastasis. This review will focus on the role of Wnt5A during melanoma progression, and its relationship to canonical Wnt signaling.

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Figures

Figure 1
Figure 1. The Yin and Yang of Wnt Signaling in Melanoma Devlopment and Progression
Both Wnt signaling pathways are critical to melanoma, existing in an opposite and complimentary role. Canonical Wnt signaling is important in the early stages of tumor development during a conversion of melanocytes to radial growth phase melanoma (RGP), but its continued expression in later stages such as vertical growth phase melanoma (VGP), and metastases, due to its promotion of differentiation, may inhibit metastasis. β-catenin is also important for the regeneration of melanocytes, and promotes the entry of quiescent stem cells (SC) from the hair follicle (HF) into the cell cycle. Wnt5A signaling, on the other hand, is absent in the early stages of the tumor, However, once melanocytes have transformed, Wnt5A activation downregulates β-catenin, and promotes metastasis, and may contribute to the maintenance of the stem cell.
Figure 2
Figure 2. Wnt5A Signaling in Melanoma Metastasis
Wnt5A binds to ROR2, perhaps via Frizzled, and is internalized via clathrin (CLTC), activating Ca2+ and PKC signaling which increases mRNA stabilization of Wnt5A and its increased secretion. Secreted Wnt5A is sequestered to the surface of the cell by HSPGs, and re-presented to its receptor, resulting in a positive feedback loop, with multiple downstream effects that promote a metastatic phenotype, including an EMT, upregulation of CD44, loss of Kiss-1, downregulation of melanogenic antigens, and cytoskeletal changes. See text for details.
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