Proangiogenic factor PIGF programs CD11b+ myelomonocytes in breast cancer during differentiation of their hematopoietic progenitors

Julien Laurent*, Eveline Faes-van't Hull, Cedric Touvrey, François Kuonen, Qiang Lan, Girieca Lorusso, Marie Agnès Doucey, Laura Ciarloni, Natsuko Imaizumi, Gian Carlo Alghisi, Ernesta Fagiani, Khalil Zaman, Roger Stupp, Masabumi Shibuya, Jean François Delaloye, Gerhard Christofori, Curzio Ruegg

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3781-3791
Number of pages11
JournalCancer Research
Volume71
Issue number11
DOIs
StatePublished - Jun 1 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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