The Hh pathway in cancer Similar to its role in normal development, dysregulated figure 2 Hh signaling results in the expression of a number of genes responsible for cell proliferation, survival, and self-renewal. Aberrant Hh signaling is associated with the development of cancer, as demonstrated by the Gorlin syndrome, caused by an autosomal dominant germline mutation in the PTCH1 gene.4,44 This resultant mutated Ptch is unable to exert its tonic inhibition of Smo, resulting in hyperactivation of the pathway. Patients with Gorlin syndrome are predisposed to various malignancies, most commonly BCC and medulloblastoma.45 These observations led to the discovery of Hh activation in the majority of the more common sporadic form of BCC, with mutations in the PTCH1 allele occurring in up to 30% of cases3 and SMO mutations in approximately 10%.

46 In addition, mutations in Hh pathway genes have been implicated in the pathogenesis of up to 30% of sporadic medulloblastoma.47 Mechanisms of Hh signaling in cancer Although Hh pathway gene mutations lead to inappropriate Hh signaling in BCC and medulloblastoma, a greater number of cancers are driven by Hh signaling through other mechanisms, either in the bulk population of cells or specifically within the CSC population. We will briefly discuss the different mechanisms of Hh signaling, and for a complete review, the reader is referred to Reference 8.26 In both BCC and medulloblastoma, Hh pathway activation results from specific gene mutations and is independent of the presence of Hh ligand binding to Ptch.

This mechanism of Hh activation, which is ligand-independent and driven by specific Hh gene mutations within the tumor cells, is termed Type I Hh signaling (Figure 2A).26 Hh inhibitors which are antagonists to Hh ligand will not be effective in overcoming this mechanism of aberrant signaling because it occurs downstream and independent of ligand due to the mutation. The other mechanisms of Hh signaling observed in cancer rely upon Hh ligand initiation of the signaling, and vary by source and recipient cells of ligand secretion. Figure 2 Modes of Hh pathway signaling. (A) Type I Hh signaling is activated by specific mutations within pathway genes within tumor cells, resulting in ligand-independent constitutive activation. (B) Type II Hh signaling results from autocrine signaling from … In Type II signaling, activation of the pathway is ligand-dependent and autocrine, meaning it originates and is received by the tumor cells (or neighboring cells). Most data for Type II Hh signaling comes from in vitro GSK-3 studies in various cancers including lung,48,49 prostate,50 glioblastoma,51,52 gastrointestinal,11,53 breast,54 and leukemia.