Basal Cell Carcinomas Arise from Hair Follicle Stem Cells in Ptch1+/− Mice

Wang, Grace; Wang, Joy; Mancianti, Maria Laura; Epstein, Ervin

doi:10.1016/j.ccr.2010.11.007

Cited by 195 publications

(181 citation statements)

References 67 publications

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“…The first two models also show different preferences for tumor initiation in the IFE vs. the HF, although the K5tTA and K5Cre*PR1 transgenes are driven by the same bovine K5 promoter sequence (14,15,28), and the different compartments of the HFs and the IFE are uniformly targeted (14). This and two recent studies argue for differential sensitivity of epidermal cell subpopulations to the activation of Hh signaling by targeting specific pathway components (29,30). Our data show that the bulge SC compartment, marked by expression of CD34, is largely unaffected in the Lgr5-EGFP-IRES-creER T2 /Ptch1 fl/fl model, and that cells present in early lesions exhibit an Lgr5+/CD34− staining pattern suggesting the SHG as a likely source of tumor-initiating cells in the wound areas of these mice (Fig.…”

Section: Discussionmentioning

confidence: 99%

Wounding enhances epidermal tumorigenesis by recruiting hair follicle keratinocytes

Kasper

Jaks

Are

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

135

123

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Chronic wounds and acute trauma constitute well-established risk factors for development of epithelial-derived skin tumors, although the underlying mechanisms are largely unknown. Basal cell carcinomas (BCCs) are the most common skin cancers displaying a number of features reminiscent of hair follicle (HF)-derived cells and are dependent on deregulated Hedgehog (Hh)/GLI signaling. Here we show, in a mouse model conditionally expressing GLI1 and in a model with homozygous inactivation of Ptch1, mimicking the situation in human BCCs, that the wound environment accelerates the initiation frequency and growth of BCC-like lesions. Lineage tracing reveals that both oncogene activation and wounding induce emigration of keratinocytes residing in the lower bulge and the nonpermanent part of the HFs toward the interfollicular epidermis (IFE). However, only oncogene activation in combination with a wound environment enables the participation of such cells in the initiation of BCC-like lesions at the HF openings and in the IFE. We conclude that, in addition to the direct enhancement of BCC growth, the tumor-promoting effect of the wound environment is due to recruitment of tumor-initiating cells originating from the neighboring HFs, establishing a link between epidermal wounds and skin cancer risk.

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Section: Discussionmentioning

confidence: 99%

Wounding enhances epidermal tumorigenesis by recruiting hair follicle keratinocytes

Kasper

Jaks

Are

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

135

123

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“…This indicates that either the microenvironment of IFE is more permissive or that following migration to the IFE (Kasper et al 2011) bulge SCs are reprogrammed into an IFE fate, which is required to allow the oncogenic program dictated by HH signaling. Genetic lineage-tracing experiments followed by ionizing radiation suggested that bulge SCs could be the cellular origin of ionizing radiation-induced BCC (Wang et al 2011). However, the infundibulum and IFE-ectopic activity of the K15CREPR, the K15 expression in BCC , and the leakiness of K15CREPR (Lapouge et al Figure 5.…”

Section: Regulation Of Skin Stem Cellsmentioning

confidence: 99%

Development and Homeostasis of the Skin Epidermis

Sotiropoulou

Blanpain

2012

Cold Spring Harbor Perspectives in Biology

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SUMMARYThe skin epidermis is a stratified epithelium that forms a barrier that protects animals from dehydration, mechanical stress, and infections. The epidermis encompasses different appendages, such as the hair follicle (HF), the sebaceous gland (SG), the sweat gland, and the touch dome, that are essential for thermoregulation, sensing the environment, and influencing social behavior. The epidermis undergoes a constant turnover and distinct stem cells (SCs) are responsible for the homeostasis of the different epidermal compartments. Deregulation of the signaling pathways controlling the balance between renewal and differentiation often leads to cancer formation.

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“…The E6 and E7 oncoproteins may contribute to tumor initiation and play important roles in malignant progression through the induction of genomic instability and other mechanisms (24). The complete loss of p53 was shown to result in upregulated expression of the hedgehog pathway, with activated pathway being a prerequisite for the development of BCC (25). Our data may indicate that loss of p53 by E6 of HPV-18 promotes the development of advanced-stage BCC even without UVB exposure.…”

Section: Discussionmentioning

confidence: 71%

E6 and E7 of human papillomavirus type 18 and UVB irradiation corporately regulate interleukin‐6 and interleukin‐8 expressions in basal cell carcinoma

Hsiao

Yang

et al. 2013

Experimental Dermatology

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The lack of a human papillomavirus (HPV)-infected skin cancer cell line has hampered the investigation of the interaction of UV and HPV in skin carcinogenesis. We identified a human basal cell carcinoma (BCC-1/KMC) cell line integrated with E6 and E7 genes of high-risk HPV type 18 and demonstrated that repression of E6 and E7 results in proliferation inhibition. Sublethal ultraviolet-B (UVB) irradiation induced the expressions of interleukin-6 (IL-6) and interleukin-8 (IL-8), as well as viral E6 and E7 genes, in BCC-1/KMC cells. When E6 and E7 expressions were inhibited, IL-6/IL-8 expressions were repressed. Furthermore, IL-6/IL-8 remained inducible by UVB irradiation when E6 and E7 were inhibited. These results indicated that IL-6 and IL-8 can be upregulated by viral E6 and E7 proteins without UVB irradiation. Moreover, chronic exposure to UVB upregulates IL-6 and IL-8 when E6/E7 is induced by UVB.

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Basal Cell Carcinomas Arise from Hair Follicle Stem Cells in Ptch1+/− Mice

Cited by 195 publications

References 67 publications

Wounding enhances epidermal tumorigenesis by recruiting hair follicle keratinocytes

Wounding enhances epidermal tumorigenesis by recruiting hair follicle keratinocytes

Development and Homeostasis of the Skin Epidermis

E6 and E7 of human papillomavirus type 18 and UVB irradiation corporately regulate interleukin‐6 and interleukin‐8 expressions in basal cell carcinoma

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