Basal cell carcinomas in mice arise from hair follicle stem cells and multiple epithelial progenitor populations
Marina Grachtchouk, … , Monique Verhaegen, Andrzej A. Dlugosz
Marina Grachtchouk, … , Monique Verhaegen, Andrzej A. Dlugosz
Published April 25, 2011
Citation Information: J Clin Invest. 2011;121(5):1768-1781. https://doi.org/10.1172/JCI46307.
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Research Article

Basal cell carcinomas in mice arise from hair follicle stem cells and multiple epithelial progenitor populations

Abstract

Uncontrolled Hedgehog (Hh) signaling leads to the development of basal cell carcinoma (BCC), the most common human cancer, but the cell of origin for BCC is unclear. While Hh pathway dysregulation is common to essentially all BCCs, there exist multiple histological subtypes, including superficial and nodular variants, raising the possibility that morphologically distinct BCCs may arise from different cellular compartments in skin. Here we have shown that induction of a major mediator of Hh signaling, GLI2 activator (GLI2ΔN), selectively in stem cells of resting hair follicles in mice, induced nodular BCC development from a small subset of cells in the lower bulge and secondary hair germ compartments. Tumorigenesis was markedly accelerated when GLI2ΔN was induced in growing hair follicles. In contrast, induction of GLI2ΔN in epidermis led to the formation of superficial BCCs. Expression of GLI2ΔN at reduced levels in mice yielded lesions resembling basaloid follicular hamartomas, which have previously been linked to low-level Hh signaling in both mice and humans. Our data show that the cell of origin, tissue context (quiescent versus growing hair follicles), and level of oncogenic signaling can determine the phenotype of Hh/Gli-driven skin tumors, with high-level signaling required for development of superficial BCC-like tumors from interfollicular epidermis and nodular BCC-like tumors from hair follicle stem cells.

Authors

Marina Grachtchouk, Joanna Pero, Steven H. Yang, Alexandre N. Ermilov, L. Evan Michael, Aiqin Wang, Dawn Wilbert, Rajiv M. Patel, Jennifer Ferris, James Diener, Mary Allen, Seokchun Lim, Li-Jyun Syu, Monique Verhaegen, Andrzej A. Dlugosz

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Figure 6

Anagen accelerates GLI2ΔN-driven tumorigenesis.

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Anagen accelerates GLI2ΔN-driven tumorigenesis. (A) Hair growth cycle in...
(A) Hair growth cycle in dorsal skin showing timing of depilation (to induce anagen) and doxycycline treatment (to activate GLI2ΔN expression in either early or mid-anagen). (B) Depilation of control mice activates hair follicle growth, with anagen follicles extending into the subcutaneous adipose layer. Tangential section (right panel) shows outer root sheath compartment of the anagen follicle (arrowheads) and pigmented hair shafts (asterisks). Original magnification, ×100 (left and middle panels); ×400 (right panel). (C) Induction of GLI2ΔN in iK15;rtTA;GLI2ΔN mice during early anagen leads to widespread tumor development from growing hair follicles in 2 weeks, at a time when spontaneous tumors in adjacent skin are rare (left panel). In some areas, tumors are contiguous with and appear to replace the outer root sheath compartment of the anagen follicle (arrowheads in right panel). Original magnification, ×40 (left panel); ×100 (middle panel); ×400 (right panel). (D) GLI2ΔN induction for 1 week in mature hair follicles (mid-anagen) shows tumor derivation directly from the outer root sheath. Immunostaining for transgene (right panel) reveals GLI2ΔN expression in all regions exhibiting BCC-like changes. Dashed lines delineate hair follicles. Typical BCC-like tumors develop after an additional week of transgene expression (lower panels). Original magnification, ×100 (upper-left panel); ×400 (upper-middle and -right panels); ×40 (lower-left panel); ×100 (lower-middle panel); ×400 (lower-right panel).