Reduced Susceptibility to Two-Stage Skin Carcinogenesis in Mice with Epidermis- Specific Deletion of Cd151 Norman Sachs, Pablo Secades, Laura van Hulst,

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Reduced Susceptibility to Two-Stage Skin Carcinogenesis in Mice with Epidermis- Specific Deletion of Cd151 Norman Sachs, Pablo Secades, Laura van Hulst, Ji-Ying Song, Arnoud Sonnenberg Journal of Investigative Dermatology Volume 134, Issue 1, Pages 221-228 (January 2014) DOI: 10.1038/jid.2013.280 Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Impaired tumor formation in Cd151 eKO mice after 7,12-dimethylbenzanthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) carcinogenesis. (a) Tumor burden of wild-type and Cd151 eKO littermates 20 weeks into the DMBA/TPA protocol. (b) Tumor volume and number are diminished in Cd151 eKO mice compared with those in wild-type littermates after DMBA/TPA-induced skin carcinogenesis. Both parameters are further reduced in the absence of one Itga3 allele (* on top of the wild-type group represents P<0.05 compared with Cd151 eKO; Itga3 eHET group; * below the wild-type group represents P<0.05 compared with Cd151 eKO group as determined by one-way analysis of variance (ANOVA) and Bonferroni). (c) The incidence of tumors with a diameter of at least 1 mm is equal in the two groups. However, tumors >4 mm occur less often and considerably later in Cd151 eKO mice than in wild-type littermates. (d) Papillomas and keratoacanthomas of wild-type and Cd151 eKO mice differ in size but not in structure. Moderately differentiated squamous cell carcinomas (SCCs) are regularly found in both groups (scale bars=100 μm). Journal of Investigative Dermatology 2014 134, 221-228DOI: (10.1038/jid.2013.280) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Decreased proliferation of (transformed) keratinocytes lacking Cd151. (a) Single and multiple doses of 12-O-tetradecanoylphorbol-13-acetate (TPA) applied to Cd151 eKO back skin result in significantly decreased hyperproliferation compared with that of skin of wild-type littermates. (b) The number of apoptotic cells in the interfollicular epidermis (IFE) of wild-type and Cd151 eKO mice does not differ significantly after a single dose of 7,12-dimethylbenzanthracene (DMBA) as assessed by cleaved caspase-3 stainings. (c) Cd151 eKO papillomas of the DMBA/TPA protocol contain significantly less proliferating cells than wild-type papillomas, as indicated by Ki67 immunohistochemistry. Cd151 eKO; Itga3 eHET papillomas display an even further reduction in proliferation (scale bars=100 μm, 5 × insets). (d) In vitro, untransformed Cd151−/− mouse keratinocytes proliferate significantly less strongly than cells from the parental Cd151fl/fl mouse keratinocyte (MK) line. The proliferation defect is rescued by the expression of not only wild-type, but also the integrin-binding mutant CD151 (see Supplementary Figure S2 online for characterization of these cells). Journal of Investigative Dermatology 2014 134, 221-228DOI: (10.1038/jid.2013.280) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Loss of label-retaining cells (LRCs) lacking Cd151. (a) The number of BrdU LRCs is significantly reduced in the back skin hair follicles (HFs) of 8-week-old Cd151 eKO mice compared with HFs of wild-type littermates. (b) Krt15+ keratinocytes are confined to the HFs of wild-type mouse tails, but present in HFs and interfollicular epidermis (IFE) of Cd151 eKO mouse tails (dotted lines outline HF; scale bars=100 μm). DP, dermal papilla; Inf., infundibulum; Isth., isthmus; SG, sebaceous gland (stained aspecifically). (c) The 12-O-tetradecanoylphorbol-13-acetate (TPA)–dependent increased epidermal turnover in Cd151 eKO back skin is shown by accelerated loss of dansyl chloride from the epidermis after 4 days of daily TPA treatments. (d) Krt15+ keratinocytes are restricted to the basal IFE of Cd151 eKO mouse tails (bottom row), but regularly found suprabasally after 2 days of daily TPA applications (top row). Displayed are XY projections (large image) as well as XZ and YZ projections along the indicated white lines (narrow images below and to the right of XY images). Scale bars=50 μm. Journal of Investigative Dermatology 2014 134, 221-228DOI: (10.1038/jid.2013.280) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Complete carcinogenesis in wild-type and Cd151 eKO mice. (a) Macroscopic image of two littermates following a 25-week regimen of 7,12-dimethylbenzanthracene (DMBA)-only carcinogenesis with (b) corresponding quantification of the entire cohort. Cd151 eKO and wild-type mice develop the same number of tumors. (c) Representative histological examples of squamous cell carcinomas (SCCs) found in wild-type and Cd151 eKO mice after complete carcinogenesis (scale bars=1 mm (overview) and 100 μm (detail)). (d) Pie chart of SCC differentiation showing mild increase of poorly differentiated SCCs in the wild-type group (P<0.0005; χ2 test; see Supplementary Figure S4 online for total tumor numbers). Journal of Investigative Dermatology 2014 134, 221-228DOI: (10.1038/jid.2013.280) Copyright © 2014 The Society for Investigative Dermatology, Inc Terms and Conditions