Basal cell carcinomas (BCCs) are hedgehog-driven tumors that resemble follicular and interfollicular epidermal basal keratinocytes and hence long have been thought to arise from these cells. by the Lgr5 promoter specifically in colonic crypt stem cells to adduce evidence that these are the cells of origin of murine colon cancer (Barker et al., 2007) as well as the use of other cell-specific promoters to drive limited Cre expression (Barker et al., 2009; Le et al., 2009; Schuller et al., 2008; Wang et al., 2009; Yang et al., 2008). These recent molecular approaches complement older studies in which temporal separation of initiation and promotion of two stage skin chemical carcinogenesis argues that the cell of origin must be a stem cell since those are the only cells expected to persist for such a long duration (Morris, 2000; Perez-Losada and Balmain, 2003). We have used the second, Cre-Lox approach to investigate the identity of the cell of origin of basal cell carcinomas (BCCs) in Ptch1+/? mice. BCCs, the most common human cancer, buy 952021-60-2 are so named because of their histologic resemblance to basal cells of the interfollicular epidermis (IFE), the hair follicle, and the sebaceous gland, i.e. the keratinocytes adjacent to the stroma. Several lines of evidence suggest that BCCs not only histologically resemble but also may arise from basal cells specifically of the hair follicles. First, BCCs express cytokeratins that more closely resemble those of follicular outer root sheath cells than those of the basal layer of the IFE, the inner root sheath, or the hair shaft (Donovan, 2009). Second, BCCs arise as the result of mutation-driven Rabbit Polyclonal to ARRB1 aberrant activation of Hedgehog (HH) signaling, a pathway whose activity in normal adult skin is limited essentially to follicles (Dahmane et al., 1997; Oro et al., 1997). Third, after exposure of the scalp to ionizing radiation, BCCs have occurred concomitantly with trichoblastoma (Fazaa et al., 2007), a tumor type more closely resembling the follicle. BCCs would appear to be uniquely suited for studies of the cell of cancer buy 952021-60-2 buy 952021-60-2 origin because (i) activation of hedgehog signaling may be all, or at least nearly all, that is required to transform a normal keratinocyte into a BCC cell and (ii) keratinocyte stem cell populations have been studied extensively and insightfully over some decades (Blanpain and Fuchs, 2009). However, despite the indirect evidence favoring a follicular origin of BCCs, one recently published study found the murine cell of origin of cutaneous HH-driven tumors to be the IFE and not the follicle (Youssef et al., 2010). This study used cell-specific Cre to activate expression of a ROSA26-driven transgenic mutant (whose signaling is not inhibited by (acts as a tumor suppressor gene C PTCH1+/? humans (with the basal cell nevus [Gorlin] syndrome, OMIM 109400) (Hahn et al., 1996; Johnson et al., 1996) and Ptch1+/? mice are highly susceptible to developing BCCs after mutagenic insults such as ionizing or ultraviolet radiation (Aszterbaum et al., buy 952021-60-2 1999; Mancuso et al., 2004). Of sporadic human BCCs, approximately 90% have mutations in at least one copy of while approximately 10% of sporadic BCCs carry activating mutations in (Epstein, 2008). The most studied skin stem cell is located in the outer root sheath of the follicle C in the bulge region below the site of insertion of the arrector pili muscle (Blanpain and Fuchs, 2009; Watt and Jensen, 2009). Bulge cells are characterized by long-term self-renewal, slow cycling, and high proliferative capacity. These cells are activated periodically to enable cyclic regrowth of the hair follicle, and after wounding they buy 952021-60-2 can at least temporarily.