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Loss of integrin ?3 prevents skin tumor formation by promoting epidermal turnover and depletion of slow-cycling cells.

ABSTRACT: Progression through the various stages of skin tumorigenesis is correlated with an altered expression of the integrin ?3?1, suggesting that it plays an important role in the tumorigenic process. Using epidermis-specific Itga3 KO mice subjected to the 7,12-dimethylbenzanthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate two-stage skin carcinogenesis protocol, we demonstrate that efficient tumor development is critically dependent on the presence of ?3?1. In the absence of ?3?1, tumor initiation is dramatically decreased because of increased epidermal turnover, leading to a loss of DMBA-initiated label-retaining keratinocytes. Lineage tracing revealed emigration of ?3-deficient keratinocytes residing in the bulge of the hair follicle toward the interfollicular epidermis. Furthermore, tumor growth and cell proliferation were strongly reduced in mice with an epidermis-specific deletion of Itga3. However, the rate of progression of ?3?1-null squamous cell carcinomas to undifferentiated, invasive carcinomas was increased. Therefore, ?3?1 critically affects skin carcinogenesis with opposing effects early and late in tumorigenesis.

SUBMITTER: Sachs N

PROVIDER: S-EPMC3535625 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Loss of integrin α3 prevents skin tumor formation by promoting epidermal turnover and depletion of slow-cycling cells.

Sachs Norman N Secades Pablo P van Hulst Laura L Kreft Maaike M Song Ji-Ying JY Sonnenberg Arnoud A

Proceedings of the National Academy of Sciences of the United States of America 20121210 52

Progression through the various stages of skin tumorigenesis is correlated with an altered expression of the integrin α3β1, suggesting that it plays an important role in the tumorigenic process. Using epidermis-specific Itga3 KO mice subjected to the 7,12-dimethylbenzanthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate two-stage skin carcinogenesis protocol, we demonstrate that efficient tumor development is critically dependent on the presence of α3β1. In the absence of α3β1, tumor initiation ...[more]

PMID: 23236172

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Project description:Induction of ?6?4 integrin in the differentiated epidermal cell layers in skin is a hallmark of human cutaneous squamous cell carcinoma (SCC) pathogenesis and stimulates chemically induced SCC formation in Inv?6?4 transgenic mice, which exhibit persistent expression of ?6?4 in the suprabasal epidermal layers. However, the molecular basis for the support of SCC development by suprabasal ?6?4 is not fully understood.We examined the relevance for suprabasal ?6?4 expression in the epidermis for the recruitment of immunosuppressive leukocytes during the early stages of tumor promotion.In this study, we made use of the Inv?6?4 transgenic mouse model, which exhibits expression of ?6?4 integrin in the suprabasal layers of the epidermis driven by the involucrin promoter. First, we examined protein lysates from Inv?6?4 transgenic skin using a pro-inflammatory cytokine array panel. Next, we immunofluorescence labeling of murine skin sections was employed to immunophenotype tumor promoter-treated Inv?6?4 transgenic skin. Finally, a macrophage colony stimulating factor (M-CSF) neutralizing antibody strategy was administered to resolve Inv?6?4 transgenic skin inflammation.Employing the Inv?6?4 transgenic mouse model, we show that suprabasal ?6?4 integrin expression selectively alters the profile of secreted pro-inflammatory molecules by epidermal cells, in particular CXCL5 and M-CSF, in response to acute tumor promoter treatment. The induction of CXCL5 and M-CSF in Inv?6?4 transgenic epidermis was shortly followed by an exacerbated influx of CD200R(+) myeloid-derived suppressor cells (MDSCs), which co-expressed the M-CSF receptor, and FoxP3(+) Treg cells compared to wild-type mice. As a result, the levels of activated CD4(+) T lymphocytes were dramatically diminished in Inv?6?4 transgenic compared to wild-type skin, whereas similar levels of lymphocyte activation were observed in the peripheral blood. Finally, 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced CD200R(+) infiltrative cells and epidermal proliferation were suppressed in Inv?6?4 mice treated with M-CSF neutralizing antibodies.We conclude that aberrant expression of ?6?4 integrin in post-mitotic epidermal keratinocytes stimulates a pro-tumorigenic skin microenvironment by augmenting the influx of immunosuppressive granular cells during tumor promotion.

Dataset Information

Loss of integrin ?3 prevents skin tumor formation by promoting epidermal turnover and depletion of slow-cycling cells.

Publications

Loss of integrin α3 prevents skin tumor formation by promoting epidermal turnover and depletion of slow-cycling cells.

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