Figure 2

Three basic mechanisms of Hedgehog constitutive activation in cancer. 1. Hedgehog (Hh) ligand-independent signalling observed in basal cell carcinoma, medulloblastoma and rhabdomyosarcoma is caused by inactivating mutations in the Ptch1 gene (red asterisk) or activating Smo mutations (yellow star). It leads to the constitutive activation and transcription of the Hh target genes even in the absence of Hh ligand. 2. Hh ligand-dependent autocrine/juxtacrine activation observed in melanoma and lung cancers is associated with an over-expression of Hh ligand by the neoplastic cells, leading to a cell-autonomous stimulation. 3. Hh ligand-dependent paracrine activation is due to the over-secretion of Hh ligand by the non-malignant stromal (A) or the neoplastic cells (B). In the basal-like subtype of breast cancer, a crucial paracrine mode of canonical Hh signalling has been described by our group: the epithelial tumour cells secrete Hh ligand, leading to Hh pathway activation by the stroma. Stromal cells produce unknown additional growth or survival signals within the microenvironment that promote tumourigenesis (B). GLI, Glioma-associated oncoprotein.