Defining the origins of Ras/p53-mediated squamous cell carcinoma - PubMed (original) (raw)

Defining the origins of Ras/p53-mediated squamous cell carcinoma

Andrew C White et al. Proc Natl Acad Sci U S A. 2011.

Abstract

The precise identity of cancer cells of origin and the molecular events of tumor initiation in epidermal squamous cell carcinoma (SCC) are unknown. Here we show that malignancy potential is related to the developmental capacity of the initiating cancer cell in a genetically defined, intact, and inducible in vivo model. Specifically, these data demonstrate that SCCs can originate from inside the hair follicle stem cell (SC) niche or from immediate progenitors, whereas more developmentally restricted progeny, the transit amplifying (TA) cells, are unable to generate even benign tumors in the same genetic context. Using a temporal model of tumorigenesis in situ, we highlight the phenotypes of cancer progression from the hair follicle SC niche, including hyperplasia, epithelial to mesenchymal transition, and SCC formation. Furthermore, we provide insights into the inability of hair follicle TA cells to respond to tumorigenic stimuli.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

Phenotypes resulting from KrasG12D expression in SC and TA cell populations of the hair follicle. (A) Model depicting the location and promoter specificity of SCs (K15+) and TA cells (Shh+) of the hair follicle during the growing phase of the hair cycle (anagen). In addition, a number of relevant cell types are shown (cp, companion layer; cx, hair cortex; ors, outer root sheath; dp, dermal papillae; mx, matrix; ge, hair germ). (B) Model of the targeting strategy to express oncogenic KrasG12D in either bulge SCs or matrix TA cells. (C) Histopathology of phenotypes induced by KrasG12D expression in the follicular bulge, including hyperplastic sebaceous glands (i), hyperplastic hair follicles (ii), and follicular cysts (iii). No apparent abnormal hair follicle phenotypes were detected in ShhCreER; KrasG12D skin. (Magnification, 10×.) (D) Quantification of phenotypes in treated and untreated mice. The indicated phenotypes were quantified on a per-follicle basis on the indicated genotypes with or without mifepristone treatment. The timecourse indicates the number of weeks after anagen, as measured by regrowth after shaving. The number of phenotypes found in treated animals was significantly increased over those found in untreated animals, even at timepoints far later than those used for phenotypic analysis in treated animals. *P ≤ 0.049).

Fig. 2.

Fig. 2.

Bulge expansion resulting from KrasG12D expression. (A and D) During telogen, control and _KrasG12D_-induced follicles appear similar. (B and E) At the onset of anagen, before full hair follicle formation but after SC exit from quiescence, bulge expansion is evident in _KrasG12D_-induced animals. (C and F) After formation of a full hair follicle, notable ORS hyperplasia can be detected in most follicles.

Fig. 3.

Fig. 3.

Expression of oncogenic KrasG12D and p53 ablation in the SC niche generates SCC, whereas the same stimulus in TA cells does not. (A) Model depicting the strategy for KrasG12D expression combined with deletion of the tumor suppressor p53. (B) Macroscopic phenotype of an SCC derived from the hair follicle bulge in K15CrePR; KrasG12D; p53ff mice. Tumors can be detected on the animal within 10 wk after mifepristone treatment. (C) K15-CrePR; KrasG12D; p53ff skin demonstrates hyperplastic sebaceous glands, hyperplastic hair follicles, epidermal cysts, transformed spindle cells invading and populating the dermis, and large exophytic SCCs. No skin abnormalities were detected in ShhCreER; KrasG12D; p53ff animals. (D) Cancer cells invading the dermis were derived from YFP-labeled bulge K15CrePR; KrasG12D; p53ff; LSL-YFP cells. Asterisks indicate Krt5+ remnant hair follicles.

Fig. 4.

Fig. 4.

Activation of signaling pathways downstream of Ras signaling during tumorigenesis arising from the bulge. (A) Erk activity (p-Erk) appeared in hyperplastic follicles but not in follicular cysts or in SCCs. (B) Akt activity (p-Akt) was detected in bulges, in non-ORS cells of hyperplastic follicles, cysts, and in remnant potions of hair follicles within SCCs (Inset). (C) Phosphorylated S6 (p-S6) was found in hyperplastic follicles, cysts and, at a lower level, throughout SCCs. (Magnification, 20×.)

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