Induction of basal cell carcinoma features in transgenic human skin expressing sonic hedgehog

ABSTRACT Hedgehog (HH) signaling proteins mediate inductive events during animal development1–11. Mutation of the only known HH receptor gene, _Patched_ (_PTC_), has recently been implicated

in inherited and sporadic forms of the most common human cancer, basal cell carcinoma (BCC)12–14. In _Drosophila_, HH acts by inactivating _PTC_ function1,3, raising the possibility that

overexpression of Sonic Hedgehog (SHH) in human epidermis might have a tumorigenic effect equivalent to loss of _PTC_ function. We used retroviral transduction of normal human keratinocytes

to constitutively express SHH. SHH-expressing cells demonstrated increased expression of both the known HH target, BMP-2B, as well as bcl-2, a protein prominently expressed by keratinocytes

in BCCs. These keratinocytes were then used to regenerate human skin transgenic for long terminal repeat-driven SHH (LTR-SHH) on immune-deficient mice. LTR-SHH human skin consistently

displays the abnormal specific histologic features seen 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 abnormalities previously described for human BCCs, including decreased BP180/BPAG2 and laminin 5 adhesion proteins

and expression of basal epidermal keratins. These data indicate that expression of SHH in human skin recapitulates features of human BCC _in vivo_, suggest that activation of this conserved

signaling pathway contributes to the development of epithelial neoplasia and describe a new transgenic human tissue model of neoplasia. Access through your institution Buy or subscribe This

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97, 39–50 (1990). Google Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA, 94304,

USA Hongran Fan & Paul A. Khavari * Department of Dermatology, P204 MSLS, Stanford University School of Medicine, Stanford, CA, 94305, USA Hongran Fan, Anthony E. Oro & Paul A.

Khavari * Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, 94305, USA Anthony E. Oro & Matthew P. Scott * Department of Developmental Biology,

Stanford University School of Medicine, Stanford, CA, 94305, USA Matthew P. Scott * Department of Genetics, Stanford University School of Medicine, Stanford, CA, 94305, USA Matthew P. Scott

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carcinoma features in transgenic human skin expressing Sonic Hedgehog. _Nat Med_ 3, 788–792 (1997). https://doi.org/10.1038/nm0797-788 Download citation * Received: 24 February 1997 *

Accepted: 22 May 1997 * Issue Date: 01 July 1997 * DOI: https://doi.org/10.1038/nm0797-788 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get

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