Basal Cell Carcinoma and the Carcinogenic Role of Aberrant Hedgehog Signaling

Anna Saran

Disclosures

Future Oncol. 2010;6(6):1003-1014. 

In This Article

Wnt Pathway in Skin Development & Tumorigenesis

Alongside Hh, the Wnt pathway plays an important role in the development of the hair follicles and in controlling hair follicle differentiation and growth in adult epidermis.[62–66] In the canonical pathway, Wnt signals are transduced through the seven-pass transmembrane receptor Frizzled (FZD) and LRP5/LRP6 coreceptor to the β-catenin signaling cascade.[67,68] In the absence of Wnt ligand, cytoplasmic β-catenin is degraded by a destruction complex that includes Axin, adenomatosis polyposis coli, glycogen synthase kinase 3 (GSK3) and casein kinase 1α (CK1α). Within this complex, β-catenin is phosphorylated by CK1α and GSK3, resulting in ubiquitination mediated by β-TrCP. Binding of Wnt to its receptor complex composed of FZD and the LRP5/6 coreceptor triggers a series of events that disrupts the adenomatosis polyposis coli/Axin/CK1α/GSK3 complex required for destruction of β-catenin.[69] Through phosphorylation of Dishevelled (DVL) by CK1α and interaction of DVL with FZD, β-catenin is released from phosphorylation by CK1α and GSK3. The stabilized β-catenin interacts with the T-cell factor and lymphoid enhancer factor (LEF) transcription factors in the nucleus leading to transcription of downstream targets (Figure 2).[70–73]

Figure 2.

Canonical Wnt pathway.
APC: Adenomatosis polyposis coli; CK1α: Casein kinase 1α; Dvl: Dishevelled; GSK3: Glycogen synthase kinase 3; LEF: Lymphoid enhancer factor; TCF: T-cell factor.

Several Wnt genes are expressed in the skin.[74,75] Early work has demonstrated that alteration of the levels and timing of expression of LEF-1 by transgenic technology during skin embryogenesis in mice disrupts the positioning and orientation of hair follicles, confirming a central role for LEF-1 in hair patterning and morphogenesis.[76] In accordance, mice carrying a homozygous germline mutation in the LEF-1 gene, which causes postnatal lethality, lack whiskers, hair and other skin appendages.[77] Wnt3 or Dvl2 overexpression in transgenic mouse skin causes a short-hair phenotype owing to altered differentiation of hair shaft precursor cells and hair shaft structural defects.[78] The first study pointing to the key role of Wnt signaling in hair follicle specification and in hair-follicle derived tumors was carried out using a keratin-14 promoter to drive expression of an N-terminally truncated human β-catenin mutant in the basal layer of the epidermis and in the follicle outer root sheath (ORS). β-catenin activation in mouse adult epidermis caused different effects, including formation of ectopic follicles and development of epidermal tumors also found in humans (i.e., trichofolliculomas).[64] Huelsken and collaborators, by conditional mutation of β-catenin in the skin using Cre recombinase driven by the keratin 14 promoter demonstrated that canonical Wnt signals are crucial for the generation of hair follicles, demonstrated by the fact that cyst-like structures appeared in the skin of the mutant mice instead of hair. Notably, the multilayered, stem-cell-containing epithelium surrounding the cysts was positive for epidermal markers but negative for hair follicle markers, demonstrating that Wnt/β-catenin signals control the cell fate of the bulge stem cells, and are required for follicular but not epidermal differentiation.[79] There is a large body of work published on the role of the Wnt/β-catenin pathway in development of the hair follicles and a complete synopsis of the literature in this field is beyond the scope of this article.

Although it is clear that appropriate Wnt signaling guides healthy development of the skin and its appendages, its role in skin tumor development has not been clearly defined. Indeed, previous studies have identified correlations in the alteration of Hh and Wnt pathways in BCCs, but the functional significance of Wnt signaling in Hh pathway-driven BCC tumorigenesis has remained uncertain.[80–86] Two recent papers have reported convincing evidence about the involvement of Wnt signaling in nonmelanoma skin cancer. Malanchi and colleagues have recently described a population of cancer stem cells in mouse early squamous cell carcinomas (SCCs) demonstrating dependence on β-catenin as well as phenotypical and functional similarity to normal bulge skin stem cells.[87] However, SCC derivation and pathogenesis are distinct from BCC and follicular hamartomas, and SCC is not driven by deregulation of the Hh pathway. Yang and colleagues have reported that a tight correlation exists between inhibition of canonical Wnt/β-catenin signaling and suppression of Hh pathway-induced epithelial bud and follicular hamartoma development. This study was the first to establish a stringent requirement for canonical Wnt/β-catenin signaling in Hh-driven BCC-like tumor development, although evidence for full-blown BCC is yet to be reported.[88]

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