Basal Cell Carcinoma and the Carcinogenic Role of Aberrant Hedgehog Signaling

Anna Saran


Future Oncol. 2010;6(6):1003-1014. 

In This Article

Sonic Hedgehog Signaling in BCC Tumorigenesis

The hedgehog (Hh) pathway has a fundamental role in embryonic development, being responsible for patterning many developing organs and tissues.[9,10] Deregulation of Hh signaling causes development of BCC, medulloblastoma and other tumor types.[11] Of the three Hh proteins known in mammals (Sonic Hh [Shh], Indian Hh, and Desert Hh),[12] Shh is the best characterized homolog, and the only vertebrate Hh expressed in skin. During embryogenesis, Shh signaling orchestrates morphogenesis of the epidermis and its appendages by exchange of finely tuned signals between epithelial cells and adjacent dermal cells, leading to the formation of suitably spaced portions of hair and nonhair epithelium, and ultimately to maturation of the dermal papilla and growth of the follicular epithelium.[13] Shh has a similar role in controlling the growth of postnatal hair follicles from multipotent progenitors localized in the bulge,[14,15] thus representing a key signal in the periodic self-renewal of the skin and its appendages in adult organisms.

Although the majority of BCCs arise sporadically, many cases are attributable to basal cell nevus syndrome (BCNS), an autosomal dominantly inherited disorder characterized by the occurrence of multiple BCCs and by extracutaneous tumors.[16] Genetic studies on patients with BCNS have led to the identification of inactivating mutations in the human homolog of the Drosophila gene patched (Ptc), a negative regulator of the Hh pathway, as the genetic defect underlying this syndrome.[17,18] The Ptch1 gene is also inactivated in sporadic BCCs.[19] Such results reinforced the role of Ptch1 as a tumor suppressor gene whose normal function is required for suppression of BCC. Key proof, however, came from the development and characterization of Ptch1 knockout mice. Of note, the mouse is generally resistant to BCC induction by chemical carcinogens or radiation. Background genes may confer the relative resistance of the mouse species to BCCs, but it was found that heterozygous Ptch1 inactivation may overcome these protective mechanisms.[20–22] Moreover, experiments conducted with a mouse model system allowing the conditional ablation of Ptch1 have demonstrated that loss of Ptch1 function in the epidermal basal cell population of mouse skin confers a neoplastic phenotype with 100% penetrance by the age of 16 weeks. This confirmed the role of Ptch1 as a 'gatekeeper' in BCC development.[23] Ptch1 is a transmembrane protein expressed in the cell membrane of Hh target tissues, where it represses signaling by a second transmembrane protein, Smoothened (Smo) to downstream transcription factors. In Drosophila, Ptc encodes a transmembrane glycoprotein involved in segment polarity that acts by preventing Smo from reaching the cell surface. Cubitus interruptus (Ci) forms a complex with a number of interacting proteins (i.e., Cos2, Fu and Sufu), which promotes Ci processing into an inactive form (Figure 1A). Upon Hh binding, internalization of Ptc allows Smo to move to the surface of the cell, accumulate at the plasma membrane and initiate signaling after formation of a complex with Cos2 and Fu, which leads to Ci activation (Figure 1B). The effectors of Hh signaling in vertebrates are the Gli proteins (i.e., Gli1, Gli2 and Gli3), whose action is inhibited by Sufu and Iguana or DZIP1 (in zebrafish or humans, respectively), and the Drosophila Cos2 primary human homolog Kif7.[24–26] Upon binding of the Hh ligand, Smo initiates signaling following translocation to specialized membrane structures – the nonmotile primary cilia[27–30] – culminating in the nuclear translocation and activation of Gli transcription factors and enhancement of the expression of several target genes, including Gli1 and Ptch1 itself (Figure 1C & D).[31,32] Pathological activation of the Hh pathway can occur through mutational inactivation of Ptch1, which suspends the inhibition of Smo, and Ptch1 mutations have been identified in most exons of the gene in patients with BCNS and in sporadic BCCs.[19,33–35] Mutations in other genes of the pathway are also involved in deregulation of Hh signaling and in the genesis of BCC and other human tumors. Smo-activating mutations have been found in 6–21%[36–38] of sporadic BCCs, and mutations in Sufu have also been identified, though in a low percentage of cases.[39] Thus, the entire pathway may be regarded as the BCC gatekeeper (Table 1).

Figure 1.

Hedgehog pathway. (A & B)Drosophila and (C & D) vertebrates.
Ci: Cubitus interruptus; Cos2: Costal 2; Fu: Fused; Hh: Hedgehog; Ptc: Patched; Smo: Smoothened; Sufu: Suppressor of fused.

In support of this, studies with genetically engineered mice have demonstrated that inappropriate activation of Shh signaling by alterations not involving Ptch1 contributes to BCC. Oro et al. demonstrated that transgenic mice overexpressing Shh in the skin develop many features of BCNS, including abnormalities of the skeleton and skin, with multiple BCC-like epidermal proliferations after the first few days of skin development.[40] Thus, overexpression of Shh can mimic the loss of Ptch1 function in mouse skin. The skin of transgenic mice overexpressing mutant Smo using a truncated keratin 5 promoter (keratin 5-M2Smo) displays numerous epithelial downgrowths invading the underlying dermis that appear very similar to slow-growing benign human basaloid follicular hamartomas, although these mice do not develop full-blown BCCs even in advanced age.[41] Genetic ablation of one Sufu allele in mice causes a skin phenotype with basaloid changes and jaw keratocysts,[42] characteristic features of BCNS. Finally, studies of overexpression of Gli transcription factors establish Gli proteins as potent oncogenes in skin. Nilsson and collaborators demonstrated that mice ectopically expressing Gli1 in the skin develop tumors closely resembling human BCC, as well as other hair follicle-derived neoplasias, such as trichoepitheliomas, cylindromas and trichoblastomas.[43] By contrast, transgenic mice overexpressing the transcription factor Gli2 in cutaneous keratinocytes develop multiple BCCs.[44,45] Thus, several components of the Hh pathway are crucial to BCC tumorigenesis.

Recently, Yauch and colleagues have reported a paracrine requirement for Hh ligand signaling in the tumorigenesis of Hh-expressing cancers.[46] These and other findings support a model in which, in the absence of mutations in the Hh pathway, Hh ligands expressed by a subset of epithelial cancers (i.e., colon, pancreatic and ovarian cancer) promote tumor growth indirectly by activating Hh signaling in the surrounding stroma, which may in turn provide a more favorable environment for tumor growth.[46–48] While this paracrine mechanism was not directly investigated in BCC, the Hh pathway mutation-driven nature of BCC is firmly defined, and there is little doubt that the pathway is activated in a cell-intrinsic manner. Nevertheless, it cannot be excluded that both autocrine and paracrine Hh signaling cooperate in BCC, and future studies will be required to establish a role for noncanonical Hh signaling in the pathogenesis of this common tumor.


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