title: Clever-1/stabilin-1 controls cancer growth and metastasis.
abstract: OBJECTIVE
  Immunosuppressive leukocytes and vasculature are important host cell components regulating tumor progression. Clever-1/Stabilin-1, a multifunctional scavenger and adhesion receptor, is constitutively present on a subset of type II macrophages and lymphatic endothelium, but its functional role in cancer is unknown.
  
  
  METHODS
  Here, we generated full Clever-1 knockout mice and cell-specific ones lacking Clever-1 either on macrophages or endothelium. We also used anti-Clever-1 antibody therapy to treat B16 melanoma and EL-4 lymphoma.
  
  
  RESULTS
  Clever-1-deficient mice had smaller primary and metastatic tumors than wild-type (WT) controls. Growth of primary tumors, but not of metastases, was attenuated also in mice lacking Clever-1 selectively in macrophages or in vascular endothelium. Anti-Clever-1 antibody treatment inhibited tumor progression in WT mice. Both genetically and therapeutically induced absence of functional Clever-1 led to diminished numbers of immunosuppressive leukocyte types in tumors. Functionally Clever-1 mediated binding of immunosuppressive leukocytes to the intratumoral blood vessels aberrantly expressing Clever-1, and tumor cell traffic via the lymphatics. The antibody therapy did not aggravate autoimmunity.
  
  
  CONCLUSIONS
  This work identifies Clever-1 in type II macrophages and in tumor vasculature as a new immunosuppressive molecule in cancer. Our finding that Clever-1 supports binding of tumor-infiltrating lymphocytes to tumor vasculature increases our understanding of leukocyte immigration to tumors. The ability of anti-Clever-1 antibody treatment to attenuate tumor progression in WT mice in vivo is therapeutically relevant. Thus, Clever-1 may be an emerging new target for modulating immune evasion and lymphatic spread in cancer.
authors.affiliation: MediCity Research Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland.
authors.forename: Marika
authors.initials: M
authors.lastname: Karikoski
authors.affiliation: MediCity Research Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Marttila-Ichihara
authors.affiliation: MediCity Research Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland. Department of Medical Biochemistry and Genetics, Institute of Biomedicine, University of Turku, Turku, Finland.
authors.forename: Kati
authors.initials: K
authors.lastname: Elima
authors.affiliation: MediCity Research Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland. Department of Physiology and Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland.
authors.forename: Pia
authors.initials: P
authors.lastname: Rantakari
authors.affiliation: MediCity Research Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland.
authors.forename: Maija
authors.initials: M
authors.lastname: Hollmén
authors.affiliation: MediCity Research Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland.
authors.forename: Tiina
authors.initials: T
authors.lastname: Kelkka
authors.affiliation: MediCity Research Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland.
authors.forename: Heidi
authors.initials: H
authors.lastname: Gerke
authors.affiliation: MediCity Research Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland.
authors.forename: Ville
authors.initials: V
authors.lastname: Huovinen
authors.affiliation: MediCity Research Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland. Department of Otorhinolaryngology, Turku University Hospital, Turku, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Irjala
authors.affiliation: MediCity Research Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland.
authors.forename: Rikard
authors.initials: R
authors.lastname: Holmdahl
authors.affiliation: MediCity Research Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland. National Institute for Health and Welfare, Turku, Finland. Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland.
authors.forename: Marko
authors.initials: M
authors.lastname: Salmi
authors.affiliation: MediCity Research Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland. National Institute for Health and Welfare, Turku, Finland. Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland. sirpa.jalkanen@utu.fi.
authors.forename: Sirpa
authors.initials: S
authors.lastname: Jalkanen
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D015816:Cell Adhesion Molecules, Neuronal / Q000037:antagonists & inhibitors / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007109:Immunity / Q000187:drug effects / Q000235:genetics; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008546:Melanoma, Experimental; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000235:genetics; D015676:Osteonectin / Q000378:metabolism; D011817:Rabbits; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D059016:Tumor Microenvironment / Q000187:drug effects / Q000235:genetics / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D015816:Cell Adhesion Molecules, Neuronal; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D015676:Osteonectin; C578250:SPARC protein, mouse; C486732:Stab1 protein, mouse