The orderly process of development depends upon well-orchestrated signals. These signals transform a single cell into a complex multicellular organism. Incredibly, in spite of the complex end-result, the transformation employs relatively few types of signal, including Wnt, Notch, TGFβ, FGF, and Hedgehog (Hh). These secreted protein signals direct cell proliferation, cell fate determination, epithelium-to-mesenchyme transitions, and rearrangement of cells by motility and adhesion changes. The ability to build organs and tissues during development is highly relevant to cancer. Mounting evidence suggests that tumors hijack normal developmental pathways for their own growth. By activating a single transduction pathway, the cancer is able to turn on growth, recruit a blood supply, and invade adjacent tissues. In this review, we first focus on how Hh signaling leads to normal organ development and then describe how the reawakened Hh cascade drives the initation, growth, invasion, and maintenance of tumors associated with these organ systems.
Hh signaling was first described in the context of cell fate determination and patterning of the fruit fly, Drosophila melanogaster
]. The core components of the Hh pathway have been delineated in the Drosophila and are conserved in mammals () [2
]. The basic signaling cascade exists as a series of repressive interactions, each protein holding the next in check, until the Hh-ligand induces the transcription of a still mostly unknown array of target genes. In the absence of Hh pathway activity, genes are actively repressed. When secreted Hh binds to its receptor Ptc, the inhibition of Smoothened (Smo) by Ptc is relieved. Smo subsequently activates the transcription of target genes (including ptc
) through the Gli family of transcription factors [3
]. The resultant genetic program forms and organizes many tissues and organ systems during embryogenesis.
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 (more ...)
The role Hh plays in the growth of tumors can be classified according to how the pathway is activated (for a review, see [4
]). These mechanisms include loss-of-function mutations in inhibitory proteins such as Patched1, gain-of-function mutations in positive regulators such as Smo, over-expression of the Hh ligands leading to activation of the pathway in an autocrine or paracrine fashion, and renewal of cancer stem cells (). Hh signaling was first linked to cancer when a mutation in the PTCH
gene) was found to cause Gorlin syndrome, a rare genetic disorder characterized by tumor formation in the skin (Basal Cell Carcinoma, BCC), cerebellum (medulloblastoma, MB), and soft tissue (Rhabdomyosarcoma, RMS) [5
]. Loss of one copy of PTCH
is sufficient to cause the syndrome; germline mutation of both copies is presumably fatal as it is in mice [6
]. Thus PTCH
is a tumor suppressor gene; PTCH
mutations are inherited as autosomal dominant causes of Gorlin syndrome. In the tumors, both copies of the gene are usually inactivated. In the late 1990s, most sporadic BCCs were found to have hyper-activated Hh signaling [7
]. Subsequently, mutations in other Hh pathway components, including hyper-activating mutations of SMO
] and loss-of-function mutations in Suppressor of fused
), were discovered in BCC [10
]. Activating Hh pathway mutations can cause sporadic MB [11
]. As is typical in other developmental pathways, activating components of the pathway are potentially proto-oncogenes that promote tumor growth when over-active, while restraining components of the normal pathway are tumor suppressors that can become damaged to allow tumor growth (). Following this initial indication that the Hh pathway was playing a role in rare cancers, numerous other cancers have been discovered to have aberrant pathway activation (). It has been speculated that Hh plays a role in over one-third of deaths caused by cancers [12
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 (more ...)
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. (more ...)
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 (more ...)
Development provides a critical context for understanding tumorigenesis. Just as Hh signaling will play a different role in each tissue where it operates, the effect of damage to Hh signaling may have different implications for tumorigenesis in each type of developing cancer. In this review, we classify tumors by when Hh becomes important for the neoplastic process (). We describe Hh signaling during normal development of the tissue, followed by how Hh is thought to be important for the tumor arising from that same tissue. The first category includes cancers in which a mutation in the Hh pathway plays an initiating role in tumorigenesis. Examples of this type include MB and BCC. The second category includes cancers where Hh signaling does not initiate tumorigenesis but contributes to maintaining tumor growth. This category includes colon cancer and pancreatic cancer. The final category, the unclassified group, includes cancers where the Hh pathway has been implicated, but its exact role remains a mystery. An example is lymphoma. Finally, we will discuss future challenges in tumor biology as they relate to Hh signaling.