INDUCTION OF BASAL-CELL CARCINOMA FEATURES IN TRANSGENIC HUMAN SKIN EXPRESSING SONIC HEDGEHOG

Hedgehog (HH) signaling proteins mediate inductive events during anima l development(1-11). Mutation of the only known HH receptor gene, Patc hed (PTC) has recently been implicated in inherited and sporadic forms of the most common human cancer, basal cell carcinoma (BCC)(12-14). I n Drosophila, HH acts by inactivating PTC function(1,3), raising the p ossibility that overexpression of Sonic Hedgehog (SHH) in human epider mis might have a tumorigenic effect equivalent to loss of PTC function . We used retroviral transduction of normal human keratinocytes to con stitutively express SHH. SHH-expressing cells demonstrated increased e xpression of both the known HH target, BMP-2B, as well as bcl-2, a pro tein prominently expressed by keratinocytes in BCCs. These keratinocyt es were then used to regenerate human skin transgenic for long termina l repeat-driven SHH (LTR-SHH) on immune-deficient mice. LTR-SHH human skin consistently displays the abnormal specific histologic features s een in BCCs, including downgrowth of epithelial buds into the dermis, basal cell palisading and separation of epidermis from the underlying dermis. In addition, LTR-SHH skin displays the gene expression abnorma lities previously described for human BCCs, including decreased BP180/ BPAG2 and laminin 5 adhesion proteins and expression of basal epiderma l keratins. These data indicate that expression of SHH in human skin r ecapitulates features of human BCC in vivo, suggest that activation of this conserved signaling pathway contributes to the development of ep ithelial neoplasia and describe a new transgenic human tissue model of neoplasia.