The Hedgehog gene was identified in genetic screens aimed to provide an understanding of body segmentation in the fruit fly. Loss of the secreted Hedgehog signaling protein was found to cause Drosophila embryos to develop as spiny balls reminiscent of hedgehogs. Hedgehog signaling plays a role in many processes during embryonic development and remains active in the adult where it is involved in the maintenance of stem cell populations.
Two key receptors that appear to be involved in the Hedgehog pathway in normal adult cells are Smoothened, which initiates a signaling cascade, and Patched, which inhibits this signaling mechanism potentially by preventing Smoothened from reaching the cell surface, and thus may function as a tumour suppressor. Binding of the Hedgehog ligand to Patched initiates its internalization, allowing Smoothened to move to the surface of the cell and initiates signaling following translocation to the cilium.
When Patched is mutated, constitutive signaling via Smoothened may lead to uncontrolled cell proliferation. Some cancer cells may also activate the pathway by mutations in Smoothened or overcome the inhibitory effects of Patched by overexpressing the Hedgehog ligand. Emerging preclinical evidence suggests that cell proliferation occurring as a result of Hedgehog signaling can be inhibited by blocking key components of the pathway, such as Smoothened.
Aberrant activation of this pathway has been implicated in the genesis and progression of some cancers, including basal cell carcinoma and medulloblastoma, making it a potential target for therapeutic intervention. For this reason, there are several small molecule antagonists of Hedgehog signaling in development. These include GDC-0449, from Genentech, which was recently presented at ASCO and objective responses in basal cell carcinoma were reported.
Other cancers it may be implicated in include breast cancer,
endometrial cancer, acute lymphoblastic leukemia, gastric and
pancreatic cancer. It is not yet known whether the pathway is critical
to the tumour growth, but represents a useful target for research.