Hr. Fan et al., INDUCTION OF BASAL-CELL CARCINOMA FEATURES IN TRANSGENIC HUMAN SKIN EXPRESSING SONIC HEDGEHOG, Nature medicine, 3(7), 1997, pp. 788-792
Citations number
45
Categorie Soggetti
Medicine, Research & Experimental",Biology,"Cell Biology
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.