Learning from Jekyll to control Hyde: Hedgehog signaling in development and cancer

Abstract

The Hedgehog (Hh) cascade controls cell proliferation, differentiation and patterning of tissues during embryogenesis but is largely suppressed in the adult. The Hh pathway can become reactivated in cancer. Here, we assimilate data from recent studies to understand how and when the Hh pathway is turned on to aid the neoplastic process. Hh signaling is now known to have a role in established tumors, enabling categorization of tumors based on the role Hh signaling plays in their growth. This categorization has relevance for prognosis and targeted therapeutics. In the first category, abnormal Hh signaling initiates the tumor. In the second category, Hh signaling helps maintain the tumor. In the third category, Hh signaling is implicated but its role is not yet defined.

Figure 1

Activating components of the Hh pathway support normal development of the organs and tissues indicated, but are potential proto-oncogenes that promote tumor growth in those same tissues when overactive. Restraining components of the normal Hh pathway also support development, but function as tumor suppressors that allow tumor growth if they are damaged in adulthood. This schematic depicts the array of tissues in which Hh supports development and can promote tumorigenesis.

Figure 2

This simplified view of the Hh pathway depicts only those core components most commonly mutated in cancer. The basic signaling cascade consists of a series of repressive interactions. Normally, in the absence of Shh, Gli proteins and target genes are actively repressed. When secreted Shh binds to its receptor Patched (Ptc/PTCH), the inhibition of Smoothened (Smo/SMOH), a G protein-coupled receptor that activates downstream intracellular components of the pathway, by Ptc is relieved.

Figure 3

Mechanisms for Hh pathway involvement in cancer include the following: loss-of-function mutations in inhibitory proteins such as Ptc1, gain-of-function mutations in positive regulators such as Smo and overexpression of the Hh ligands, leading to autocrine or paracrine activation of the pathway and renewal of cancer stem cells (Adapted from Rubin and de Sauvage. Nature Reviews Drug Discovery 5, 1026-1033. 2006 )

Figure 4

In the first two categories of Hh-associated tumors, Hh pathway deregulation supports different aspects of tumorigenesis. In the final category of Hh-associated tumors, more data are needed to determine the role of Hh in tumor initiation and/or maintenance.