The role of the Hedgehog signaling pathway in cancer: A comprehensive review

Abstract

The Hedgehog (Hh) signaling pathway was first identified in the common fruit fly. It is a highly conserved evolutionary pathway of signal transmission from the cell membrane to the nucleus. The Hh signaling pathway plays an important role in the embryonic development. It exerts its biological effects through a signaling cascade that culminates in a change of balance between activator and repressor forms of glioma-associated oncogene (Gli) transcription factors. The components of the Hh signaling pathway involved in the signaling transfer to the Gli transcription factors include Hedgehog ligands (Sonic Hh [SHh], Indian Hh [IHh], and Desert Hh [DHh]), Patched receptor (Ptch1, Ptch2), Smoothened receptor (Smo), Suppressor of fused homolog (Sufu), kinesin protein Kif7, protein kinase A (PKA), and cyclic adenosine monophosphate (cAMP). The activator form of Gli travels to the nucleus and stimulates the transcription of the target genes by binding to their promoters. The main target genes of the Hh signaling pathway are PTCH1, PTCH2, and GLI1. Deregulation of the Hh signaling pathway is associated with developmental anomalies and cancer, including Gorlin syndrome, and sporadic cancers, such as basal cell carcinoma, medulloblastoma, pancreatic, breast, colon, ovarian, and small-cell lung carcinomas. The aberrant activation of the Hh signaling pathway is caused by mutations in the related genes (ligand-independent signaling) or by the excessive expression of the Hh signaling molecules (ligand-dependent signaling - autocrine or paracrine). Several Hh signaling pathway inhibitors, such as vismodegib and sonidegib, have been developed for cancer treatment. These drugs are regarded as promising cancer therapies, especially for patients with refractory/advanced cancers.

FIGURE 1

A simplified display of the Hedgehog signaling pathway. (A) In the absence of Hedgehog ligand, full-length Gli is phosphorylated by protein kinase A, glycogen synthase kinase-3, and casein kinase 1. This leads to proteolytic cleavage of the full-length Gli into Gli repressor. Gli repressor represses the expression of target genes, (B) after binding of Hedgehog ligand, Smoothened protein is phosphorylated by protein kinase A and casein kinase 1. The inhibitory effect of Sufu is removed and Gli activator is formed. Gli activator induces the transcription of target genes. Red symbols represent the inhibitory effect, and green arrows show the activating effect. Hh - Hedgehog; Ptch - Patched; Smo - Smoothened; Gli - glioma-associated oncogene; GliFL - full-length Gli; GliA - Gli activator; GliR - Gli repressor; CK1 - casein kinase 1; PKA - protein kinase A; GSK3 - glycogen synthase kinase-3.

FIGURE 2

Three basic mechanisms of aberrant activation of Hedgehog signaling. (A) Type I - Ligand-independent Hedgehog signaling. This type includes: Ptch1 inactivating mutation (green asterisk) or Smo activating mutation (red asterisk), thereby Smoothened receptor can no longer be inhibited by Patched 1. The result is a constitutive activation of Hedgehog pathway in the absence of the ligand. (B) Type II - Ligand-dependent autocrine/juxtacrine Hedgehog signaling. The Hedgehog ligand is secreted by the tumor cell and taken up into the same tumor cell (autocrine manner) or into the nearby tumor cells (juxtacrine manner), thus activating the signal cascade downstream of the Hedgehog signaling pathway. (C-1) Type IIIa - Ligand-dependent paracrine signaling. The Hedgehog ligand is secreted by tumor cells and taken up by the stromal cells. Activated stromal cells synthesize and secrete signals, such as vascular endothelial growth factor and insulin-like growth factor, which are then taken back into the tumor cells to support their survival and growth. (C-2) Type IIIb - Ligand-dependent reverse paracrine signaling. The Hedgehog ligand is directly secreted by stromal cells and taken up by the tumor cells. Thus, the ligand helps the tumor cell proliferation and growth. Hh - Hedgehog; Ptch1 - Patched 1; Smo - Smoothened; Gli1 - glioma-associated oncogene 1; VEGF - vascular endothelial growth factor; IGF - insulin-like growth factor.