Signalling Pathways Driving Cancer Stem Cells: Hedgehog Pathway

Abstract

The hedgehog (Hh) pathway is one of the fundamental signal transduction pathways in animal development and is also involved in stem-cell maintenance and carcinogenesis. The hedgehog (hh) gene was first discovered in Drosophila, and members of the family have since been found in most metazoan. Hh proteins are composed of two domains, an aminoterminal domain HhN, which has the biological signal activity, and a carboxy-terminal autocatalytic domain HhC, which cleaves Hh into two parts in an intramolecular reaction and adds a cholesterol moiety to HhN. HhC has a sequence similarity to the self-splicing inteins, and the shared region is termed Hint. HhN is modified by cholesterol at its carboxyl terminus and by palmitate at its amino terminus in both flies and mammals. The modified HhN is released from the cell and travels through the extracellular space. On binding its receptor Patched, it relieves the inhibition that Patched exerts on Smoothened, a G-proteincoupled receptor. The resulting signalling cascade converges on the transcription factor Cubitus interruptus (Ci), or its mammalian counterparts, the Gli proteins, which activate or repress target genes. The Hh family of morphogens plays important instructional roles in the development of numerous metazoan structures (Ingham & McMahon, 2001). The Hh ligands, Sonic, Indian and Desert Hh in vertebrates and Hh in Drosophila, signal through binding to the membrane receptor Patched (Ptc) (Chen & Struhl, 1996), to reverse the Ptcmediated inhibition of signalling by the trans-membrane protein Smoothened (Smo) (Alcedo et al., 1996). This allows Smo to activate the intracellular signalling components, resulting in stabilization of down-stream transcriptional activator(s) and activation of target genes (Hooper & Scott, 1989). Transcription activation is facilited through the Gli family of transcription factors in vertebrates (Ingham & McMahon, 2001). Hh signalling can initiate cellular growth, division, lineage specification, axon guidance and function as a survival factor (Cohen, 2009). Given this range of biological functions, it is not surprising that mutations in components of the Hh pathway are associated with both developmental defects and tumor progression (Cohen, 2009). Disruption of PTC, which functions as a negative regulator of the pathway, is implicated in cancer development in both inherited and sporadic cancers. Mutations in PTC and/or SMO trigger inappropriate activation of the Hh pathway, and have been identified in tumor types including basal cell carcinoma,