21 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.22�C26 Much of our knowledge of the Hh pathway comes from studies in Drosophila, and although several major components of leave a message the pathway are well described, some details remain poorly understood. 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�C3 (Figure 1).

Primary cilia present on most cells during interphase are involved in signal transduction, and Hh pathway components translocate during activation. In the inactive state, when Hh ligand is not present, Ptch is located in the primary cilia but Smo is not. When ligand binds and Ptch inhibition of Smo is released, Ptch moves out of the primary cilia and Smo moves in to facilitate interaction with Glis and associated proteins. They subsequently enter the nucleus and regulate expression of Hh target genes.27�C32 Figure 1 Hh signaling pathway. In the absence of Hh ligand, Ptch exerts an inhibitory effect on Smo, and no downstream signaling occurs. In the presence of Hh ligand binding to Ptch, the suppression of Smo is released.

Smo interacts with Suppressor of fused (SUFU), … 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.33 Aberrant Hh signaling has also been associated with chemotherapy-resistance in gliomas,34 pancreatic cancer,35 leukemia,36,37 lymphoma,17,38 and MM.39 Interactions with other signaling pathways, including Notch, PI3K, RAS-MEK/AKT, and NF-��B, to promote cancer growth, recurrence, and chemotherapy resistance have also been described.40�C43 Several Smo inhibitors are in clinical development for the treatment of human cancers.

Recently, emerging clinical data have demonstrated the potential activity of these agents in several diseases, particularly medulloblastoma, basal cell carcinoma (BCC), pancreatic cancer, and hematologic malignancies. Ongoing trials will evaluate the role for Smo inhibitors as single agents, as well as in combination with traditional chemotherapy. Dacomitinib This review will discuss the mechanisms of Hh signaling in malignancy and the evidence for Hh signaling in CSCs.