Hedgehog Pathway in Pediatric Cancers: They're Not Just for Brain Tumors Anymore.

The Hedgehog (HH) pathway regulates fundamental processes in embryonic development, including stem cell maintenance, cell differentiation, tissue polarity, and cell proliferation. In the vertebrate pathway, Sonic hedgehog (SHH) binds to Patched1 (PTCH1), which relieves its inhibition of Smoothened (SMO), allowing the GLI family of transcription factors to translocate to the nucleus and activate HH target genes such as GLI1, GLI2, PTCH1, CYCLIN D1, BCL-2, and MYCN. The HH pathway is also an active participant in tumorigenesis. In 1996, loss-of-function mutation in PTCH1 was discovered to be the cause of nevoid basal cell carcinoma syndrome (NBCCS, or Gorlin syndrome), an autosomal dominant disease associated with increased rates of basal cell carcinoma (BCC), medulloblastoma (MB), and rarely, rhabdomyosarcoma. It is now estimated that 100% of sporadic BCC and up to 20% to 30% of MB also harbor activating HH pathway mutations. Together, these discoveries firmly established the linkage between HH pathway activation and cancer development. Intense research has since been focused on further defining the role of the HH pathway in BCC and MB and potential therapeutic strategies to inhibit HH signaling. Early clinical trials of SMO inhibitors have shown promising results in the treatment of adult BCC and SHH-driven MB. More recently, a number of other pediatric cancers have been reported to show HH activity, making these tumors potential candidates for HH inhibitor therapy. To date however, no HH pathway mutations have been identified in other pediatric cancers. This review will describe the HH pathway signaling in development and cancer with a focus on recent evidence for HH pathway activation in central nervous system (CNS) and non-CNS pediatric cancers.