Widespread Requirement for Ligand-stimulated Hedgehog Pathway Activity in Growth of Digestive Tract Tumors
This work demonstrates that hedgehog (Hh) pathway activity plays a critical role in the growth of cancers derived from the gastrointestinal tract, including esophageal, pancreatic, biliary, and gastric cancers, and which in aggregate account for more than 10% of human cancer deaths in the USA. This study shows that cells from a majority of these deadly tumors display Hh pathway activity, as indicated by expression of endogenous markers such as patched (pct) and gli. This activity depends upon endogenous expression of Hh signaling proteins, and can be blocked by treatment either with a Hh protein-binding antibody or with cyclopamine. The ability of a Hh-neutralizing antibody to block pathway activity indicates that Hedgehog protein ligand is critical to pathway activation. This work further shows that cancer cells stop growing and die when pathway activity is blockaded by treatment with cyclopamine or a Hedgehog protein-binding antibody. Cyclopamine treatment can also cause regression of tumors grown as grafts in immunocompromised animals. These results together indicate that Hh pathway activity in these deadly cancers can be assayed by monitoring expression of endogenous gene targets of the Hh pathway, and that cancers displaying Hh pathway activity might be treated with Hh-neutralizing antibodies or with cyclopamine or other small molecule antagonists of the pathway. Description (Set) Proposed Use (Set) Hh-blocking antibodies and Hh pathway antagonists such as cyclopamine and other synthetic small molecules could be used to treat these cancers. In addition, expression of pct or of gli (protein or mRNA) might be used to diagnose tumors likely to be responsive to therapy with Hh antagonists.
Beachy, Philip A.
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