What transforms a ball of undifferentiated cells into an organism with a nervous system, digestive tract, and other specialized body parts? Among the proteins that play an important role is one with the unlikely name of hedgehog (Hh). When Hh attaches to a transmembrane protein known as patched (Ptch1), it initiates a series of molecular interactions that lead to activation of the transcription factor Gli (for “glioma associated”) and the onset of key events in embryonic differentiation. We know this process involves freeing a second transmembrane protein, smoothened (Smo), from inhibition.(1)
The Hh signaling pathway regulates cell differentiation and self-renewal in the developing embryo and is typically silenced in adult tissues. Aberrant Hh signaling may result from mutations in pathway genes or overexpression of signaling through other mechanisms in either tumor cells themselves or cells in the supportive tumor microenvironment.
In mammals, one of three Hh pathway ligands (Desert, Indian, and Sonic) binds to the transmembrane receptor Patched (Ptch) to initiate pathway signaling. In the inactive state, Ptch exerts an inhibitory effect on the signal transducer Smoothened (Smo), and no downstream signaling occurs. When Hh ligand binds to Ptch, the inhibition on Smo is released and downstream signaling occurs, regulating the expression of the transcription factors Gli1–3.
Hh expression is precisely regulated through both positive and negative feedback loops which may be interrupted by mutations in Hh pathway genes themselves or epigenetic changes. Increased transcription of Hh target genes results in increased cell proliferation and survival, induction of stem cell markers, as well as promotion of bone metastases. Aberrant Hh signaling has also been associated with chemotherapy-resistance in gliomas, pancreatic cancer, leukemia, lymphoma, and multiple mieloma. Interactions with other signaling pathways, including Notch, PI3K, RAS-MEK/AKT, and NF-κB, to promote cancer growth, recurrence, and chemotherapy resistance have also been described.
Similar to its role in normal development, dysregulated 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. 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.
Targeting Hh signaling in cancer
The identification of a naturally-occurring Hh pathway antagonist, cyclopamine, led to the subsequent development of synthetic and semi-synthetic derivatives of cyclopamine with increased potency and bioavailability. In addition, a commonly used anti-fungal agent, itraconazole, has also been found to have Hh inhibitory activity. These agents are now moving from the laboratory into clinical trials. Similar to challenges encountered in translating other targeted therapies, questions remain including the optimal way to integrate them into regimens of conventional chemotherapy. In addition, our growing understanding of mechanisms of Hh signaling in different malignancies raises the issue of whether there should be different approaches to using these agents which vary by the mechanism of Hh signaling in each disease. Currently, all of the Hh inhibitors in clinical development are at the level of Smo, but other agents with distinct mechanisms of action have been identified and it is possible that these may be more or less effective depending on the mode of signaling. (2)
1. Hoff M. Inhibiting Hedgehog: New Insights into a Developmentally Important Signaling Pathway. PLoS Biol. 2006 August; 4(8): e258.
2. Tara L Lin, William Matsui. Hedgehog pathway as a drug target: Smoothened inhibitors in development.