The Hedgehog Signaling Pathway and Epithelial Skin Cancer

Abstract

The hedgehog signaling pathway plays an important role in the embryonic development of various organ systems including the skin. Aberrant activation of hedgehog signaling by mutations in genes encoding important members of this pathway, such the hedgehog receptor genes PTCH and SMOH, plays a crucial role in the pathogenesis of cutaneous basal cell carcinomas, the most common human cancers. Germline mutations in the PTCH gene underly the early and multifocal development of basal cell carcinomas in patients suffering from nevoid basal cell carcinoma syndrome. Somatic mutations in PTCH or SMOH, as well as upregulation of different hedgehog target genes are found in the vast majority of sporadic basal cell carcinomas. In contrast, squamous cell carcinomas of the skin rarely show genetic alterations and aberrant expression of hedgehog pathway genes. Recently, specific inhibitors of the hedgehog signaling cascade have been identified and showed promising therapeutic efficacy in preclinical studies using experimental basal cell carcinomas generated in heterozygous PTCH knock-out mice. Furthermore, immunization against the hedgehog interacting protein (Hip), a hedgehog-regulated protein specifically upregulated in basal cell carcinomas, has been suggested as a promising new approach to skin tumor prevention. However, the clinical significance of these novel, pathogenesis-based molecular therapeutic strategies remains to be evaluated.