title: Loss of integrin α3 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 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 is dramatically decreased because of increased epidermal turnover, leading to a loss of DMBA-initiated label-retaining keratinocytes. Lineage tracing revealed emigration of α3-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 α3β1-null squamous cell carcinomas to undifferentiated, invasive carcinomas was increased. Therefore, α3β1 critically affects skin carcinogenesis with opposing effects early and late in tumorigenesis.
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands.
authors.forename: Norman
authors.initials: N
authors.lastname: Sachs
authors.forename: Pablo
authors.initials: P
authors.lastname: Secades
authors.forename: Laura
authors.initials: L
authors.lastname: van Hulst
authors.forename: Maaike
authors.initials: M
authors.lastname: Kreft
authors.forename: Ji-Ying
authors.initials: JY
authors.lastname: Song
authors.forename: Arnoud
authors.initials: A
authors.lastname: Sonnenberg
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D002448:Cell Adhesion; D002453:Cell Cycle; D002454:Cell Differentiation; D019070:Cell Lineage; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D004817:Epidermis / Q000378:metabolism* / Q000473:pathology*; D018859:Hair Follicle / Q000378:metabolism / Q000473:pathology; D039422:Integrin alpha3 / Q000378:metabolism*; D053569:Keratin-15 / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D013194:Staining and Labeling
chemical_list: D039422:Integrin alpha3; D053569:Keratin-15; D015127:9,10-Dimethyl-1,2-benzanthracene