Editors' ChoiceCancer

Healed into Cancer

Science Signaling  15 Mar 2011:
Vol. 4, Issue 164, pp. ec74
DOI: 10.1126/scisignal.4164ec74

Basal cell carcinoma (BCC) is a common form of human skin cancer and frequently involves dysregulated Hedgehog (Hh) signaling. The Hh pathway is involved in the normal hair follicle cycle, during which stem cells from various regions of the hair follicle, such as the bulge, coordinate hair growth and the formation of cells of the interfollicular epidermis and hair follicle. Wong and Reiter and Kasper et al. found that when cells of the bulge were genetically engineered to have increased Hh signaling, then these cells produced skin tumors in response to deep skin wounding (excision or incision). Wong and Reiter used two different genetic models to direct inducible expression of an oncogenic allele of the Hh pathway component Smoothened (SmoM2) in either bulge cells (K15:SmoM2) or interfollicular epidermis (K14:SmoM2). Skin from the K15:SmoM2 mice did not develop tumors in the absence of injury, but excisional wounding triggered the formation of tumors with BCC-like characteristics. In contrast, the K14:SmoM2 mice exhibited tumorigenesis even in the absence of wounding, and these cells were also detected in the tumors that formed in the healed epithelium after wounding. Analysis of marker genes indicative of Hh signaling suggested that, within the hair follicle, the oncogenic Smo was suppressed but that, in response to migration induced by wounding to participate in re-epithelialization, Hh signaling became activated in SmoM2-expressing cells derived from the bulge. Kasper et al. performed a similar analysis using different genetically engineered inducible systems, K5Cre*PR1/Ptch1fl/fl and K5tTA/TREGLI1, to either inactivate Patched1 (Ptch1), a negative regulator of the Hh pathway, or stimulate the expression of Gli1, a mediator of Hh signaling, respectively, in cells of the bulge. In both of these models, skin tumors formed in the absence of wounding, but wounding enhanced the size of the tumors and, in the Ptch1 model, the frequency of tumor formation was also increased. Both groups used lineage tracing to verify that the cells in the tumors were derived from the follicular bulge and that superficial wounding or hair plucking was insufficient to trigger tumorigenesis.

S. Y. Wong, J. F. Reiter, Wounding mobilizes hair follicle stem cells to form tumors. Proc. Natl. Acad. Sci. U.S.A. 108, 4093–4098 (2011). [Abstract] [Full Text]

M. Kasper, V. Jaks, A. Are, Å. Bergström. A. Schwäger, N. Barker, R. Toftgård, Wounding enhances epidermal tumorigenesis by recruiting hair follicle keratinocytes. Proc. Natl. Acad. Sci. U.S.A. 108, 4099–4104 (2011). [Abstract] [Full Text]