title: Activin promotes skin carcinogenesis by attraction and reprogramming of macrophages.
abstract: Activin has emerged as an important player in different types of cancer, but the underlying mechanisms are largely unknown. We show here that activin overexpression is an early event in murine and human skin tumorigenesis. This is functionally important, since activin promoted skin tumorigenesis in mice induced by the human papillomavirus 8 oncogenes. This was accompanied by depletion of epidermal γδ T cells and accumulation of regulatory T cells. Most importantly, activin increased the number of skin macrophages via attraction of blood monocytes, which was prevented by depletion of CCR2-positive monocytes. Gene expression profiling of macrophages from pre-tumorigenic skin and bioinformatics analysis demonstrated that activin induces a gene expression pattern in skin macrophages that resembles the phenotype of tumor-associated macrophages in different malignancies, thereby promoting angiogenesis, cell migration and proteolysis. The functional relevance of this finding was demonstrated by antibody-mediated depletion of macrophages, which strongly suppressed activin-induced skin tumor formation. These results demonstrate that activin induces skin carcinogenesis via attraction and reprogramming of macrophages and identify novel activin targets involved in tumor formation.
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
authors.forename: Maria
authors.initials: M
authors.lastname: Antsiferova
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Piwko-Czuchra
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Cangkrama
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
authors.forename: Mateusz
authors.initials: M
authors.lastname: Wietecha
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
authors.forename: Dilara
authors.initials: D
authors.lastname: Sahin
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
authors.forename: Katharina
authors.initials: K
authors.lastname: Birkner
authors.affiliation: Department of Dermatology, University Hospital, Zurich, Switzerland.
authors.forename: Valerie C
authors.initials: VC
authors.lastname: Amann
authors.affiliation: Department of Dermatology, University Hospital, Zurich, Switzerland.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Levesque
authors.affiliation: Department of Dermatology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hohl
authors.affiliation: Department of Dermatology, University Hospital, Zurich, Switzerland.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland sabine.werner@biol.ethz.ch.
authors.forename: Sabine
authors.identifier: 0000-0001-7397-8710
authors.initials: S
authors.lastname: Werner
mesh_terms: D000818:Animals; D001706:Biopsy; D063646:Carcinogenesis; D019295:Computational Biology; D020869:Gene Expression Profiling; D006801:Humans; D028322:Inhibin-beta Subunits / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D012878:Skin Neoplasms / Q000473:pathology*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: C103008:inhibin beta A subunit; D028322:Inhibin-beta Subunits
keywords: activin; macrophage; skin cancer; tumor microenvironment