Hedgehog–Gli signaling in brain tumors: stem cells and paradevelopmental programs in cancer

The Hedgehog–Gli signaling pathway is involved in the regulation of the proliferation of precursors in different organs of the normal vertebrate embryo. These cells express Gli1 and may be the target of cancer-causing agents. Many tumor types derived from organs that contain Gli1+ precursors appear to consistently express Gli1, indicating their origin and/or the presence of an active pathway. Inappropriate pathway activation in a variety of precursor cells in model organisms leads to tumor formation while inhibition of the pathway in human tumor cells leads to a decrease in their proliferation. In the brain we have documented the expression of Gli1 in germinative zones, and a variety of brain tumors express GLI1, including medulloblastomas of the cerebellum and a number of gliomas of the cerebral cortex. The requirement for SHH–Gli signaling in the growth of the mouse brain, together with the ability of inappropriate pathway activation in the cerebellum to cause medulloblastomas, and the inhibition of the growth of a number of brain tumors with cyclopamine, a SHH signaling inhibitor, underscores the critical role of the SHH–GLI pathway in brain growth and tumor formation. Moreover, they highlight the components of this pathway as prime targets for drug development, with special emphasis on the GLI proteins. Such reagents would allow a rational therapeutic approach to highly intractable diseases.