title: Proangiogenic factor PlGF programs CD11b(+) myelomonocytes in breast cancer during differentiation of their hematopoietic progenitors.
abstract: Tumor-mobilized bone marrow-derived CD11b(+) myeloid cells promote tumor angiogenesis, but how and when these cells acquire proangiogenic properties is not fully elucidated. Here, we show that CD11b(+) myelomonocytic cells develop proangiogenic properties during their differentiation from CD34(+) hematopoietic progenitors and that placenta growth factor (PlGF) is critical in promoting this education. Cultures of human CD34(+) progenitors supplemented with conditioned medium from breast cancer cell lines or PlGF, but not from nontumorigenic breast epithelial lines, generate CD11b(+) cells capable of inducing endothelial cell sprouting in vitro and angiogenesis in vivo. An anti-Flt-1 mAb or soluble Flt-1 abolished the generation of proangiogenic activity during differentiation from progenitor cells. Moreover, inhibition of metalloproteinase activity, but not VEGF, during the endothelial sprouting assay blocked sprouting induced by these proangiogenic CD11b(+) myelomonocytes. In a mouse model of breast cancer, circulating CD11b(+) cells were proangiogenic in the sprouting assays. Silencing of PlGF in tumor cells prevented the generation of proangiogenic activity in circulating CD11b(+) cells, inhibited tumor blood flow, and slowed tumor growth. Peripheral blood of breast cancer patients at diagnosis, but not of healthy individuals, contained elevated levels of PlGF and circulating proangiogenic CD11b(+) myelomonocytes. Taken together, our results show that cancer cells can program proangiogenic activity in CD11b(+) myelomonocytes during differentiation of their progenitor cells in a PlGF-dependent manner. These findings impact breast cancer biology, detection, and treatment.
authors.affiliation: Division of Experimental Oncology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Faculty of Biology and Medicine, Lausanne, Switzerland. julien.laurent@chuv.ch
authors.forename: Julien
authors.initials: J
authors.lastname: Laurent
authors.forename: Eveline Faes-van't
authors.initials: EF
authors.lastname: Hull
authors.forename: Cedric
authors.initials: C
authors.lastname: Touvrey
authors.forename: François
authors.initials: F
authors.lastname: Kuonen
authors.forename: Qiang
authors.initials: Q
authors.lastname: Lan
authors.forename: Girieca
authors.initials: G
authors.lastname: Lorusso
authors.forename: Marie-Agnès
authors.initials: MA
authors.lastname: Doucey
authors.forename: Laura
authors.initials: L
authors.lastname: Ciarloni
authors.forename: Natsuko
authors.initials: N
authors.lastname: Imaizumi
authors.forename: Gian Carlo
authors.initials: GC
authors.lastname: Alghisi
authors.forename: Ernesta
authors.initials: E
authors.lastname: Fagiani
authors.forename: Khalil
authors.initials: K
authors.lastname: Zaman
authors.forename: Roger
authors.initials: R
authors.lastname: Stupp
authors.forename: Masabumi
authors.initials: M
authors.lastname: Shibuya
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Delaloye
authors.forename: Gerhard
authors.initials: G
authors.lastname: Christofori
authors.forename: Curzio
authors.initials: C
authors.lastname: Ruegg
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D018952:Antigens, CD34 / Q000096:biosynthesis; D001943:Breast Neoplasms / Q000098:blood supply* / Q000276:immunology / Q000473:pathology; D039481:CD11b Antigen / Q000096:biosynthesis*; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D005260:Female; D005312:Fetal Blood / Q000166:cytology; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000473:pathology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology / Q000473:pathology*; D000072483:Placenta Growth Factor; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000276:immunology* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D018952:Antigens, CD34; D039481:CD11b Antigen; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D011994:Recombinant Proteins; D000072483:Placenta Growth Factor