title: Neuropilin-1 identifies a subset of bone marrow Gr1- monocytes that can induce tumor vessel normalization and inhibit tumor growth.
abstract: Improving tumor perfusion, thus tempering tumor-associated hypoxia, is known to impair cancer progression. Previous work from our laboratory has shown that VEGF-A165 and semaphorin 3A (Sema3A) promote vessel maturation through the recruitment of a population of circulating monocytes expressing the neuropilin-1 (Nrp1) receptor (Nrp1-expressing monocytes; NEM). Here, we define the characteristics of bone marrow NEMs and assess whether these cells might represent an exploitable tool to induce tumor vessel maturation. Gene expression signature and surface marker analysis have indicated that NEMs represent a specific subset of CD11b+ Nrp1+ Gr1- resident monocytes, distinctively recruited by Sema3A. NEMs were found to produce several factors involved in vessel maturation, including PDGFb, TGF-β, thrombospondin-1, and CXCL10; consistently, they were chemoattractive for vascular smooth muscle cells in vitro. When directly injected into growing tumors, NEMs, isolated either from the bone marrow or from Sema3A-expressing muscles, exerted antitumor activity despite having no direct effects on the proliferation of tumor cells. NEM inoculation specifically promoted mural cell coverage of tumor vessels and decreased vascular leakiness. Tumors treated with NEMs were smaller, better perfused and less hypoxic, and had a reduced level of activation of HIF-1α. We conclude that NEMs represent a novel, unique population of myeloid cells that, once inoculated into a tumor, induce tumor vessel normalization and inhibit tumor growth.
authors.affiliation: Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Carrer
authors.forename: Silvia
authors.initials: S
authors.lastname: Moimas
authors.forename: Serena
authors.initials: S
authors.lastname: Zacchigna
authors.forename: Lucia
authors.initials: L
authors.lastname: Pattarini
authors.forename: Lorena
authors.initials: L
authors.lastname: Zentilin
authors.forename: Giulia
authors.initials: G
authors.lastname: Ruozi
authors.forename: Miguel
authors.initials: M
authors.lastname: Mano
authors.forename: Milena
authors.initials: M
authors.lastname: Sinigaglia
authors.forename: Federica
authors.initials: F
authors.lastname: Maione
authors.forename: Guido
authors.initials: G
authors.lastname: Serini
authors.forename: Enrico
authors.initials: E
authors.lastname: Giraudo
authors.forename: Federico
authors.initials: F
authors.lastname: Bussolino
authors.forename: Mauro
authors.initials: M
authors.lastname: Giacca
mesh_terms: D020533:Angiogenesis Inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D001854:Bone Marrow Cells / Q000378:metabolism / Q000502:physiology; D016026:Bone Marrow Transplantation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism / Q000502:physiology*; D009369:Neoplasms / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000517:prevention & control* / Q000628:therapy; D039942:Neuropilin-1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism / Q000502:physiology
chemical_list: D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D011956:Receptors, Cell Surface; C551746:granulocyte receptor 1, mouse; D039942:Neuropilin-1