The role of the hedgehog signaling pathway in the regulation of gastrointestinal cancer cell death.

The Hh signaling pathway critically drives tumorigenesis and progression in multiple cancers, including gastrointestinal cancers such as gastric, hepatic, pancreatic, esophageal, and colorectal cancer. Aberrant Hh signaling pathway activation, often driven by ligands such as Sonic Hedgehog (Shh) and transcription factors such as Gli1/2, promotes tumor cell proliferation, survival, metastasis, cancer stem cells, and chemoresistance while inhibiting programmed cell death pathways. High levels of Hh signaling pathway activity are a characteristic feature of gastrointestinal cancers. Therapeutic targeting of the Hh signaling pathway has shown promise, with Smoothened (Smo) inhibitors approved for basal cell carcinoma but yielding mixed results in gastrointestinal cancer trials. Emerging strategies, including Hh inhibitors; natural compounds from traditional Chinese medicine; and combinations of chemotherapy, immunotherapy or radiation to induce cell death and remodel the tumor microenvironment, could lead to a new therapeutic avenue for gastrointestinal cancers. In this review, we summarize advances in our understanding of Hh-mediated cell death in gastrointestinal cancers and the role and mechanisms, and highlight the underlying therapeutic opportunities. These new findings advance the rapidly expanding field of translational cancer research focused on the Hh signaling pathway.