title: Bone marrow-derived cells are implicated as a source of lymphatic endothelial progenitors in human breast cancer.
abstract: Bone marrow-derived endothelial progenitor cells (EPCs) infiltrate into sites of neovascularization in adult tissues and mature into functional blood endothelial cells (BECs) during a process called vasculogenesis. Human marrow-derived EPCs have recently been reported to display a mixed myeloid and lymphatic endothelial cell (LEC) phenotype during inflammation-induced angiogenesis; however, their role in cancer remains poorly understood. We report the in vitro differentiation of human cord blood CD133+CD34+progenitors into podoplanin+cells expressing both myeloid markers (CD11b, CD14) and the canonical LEC markers vascular endothelium growth factor receptor 3 (VEGFR-3), lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), and prospero homeobox 1 (PROX-1). These podoplanin+cells displayed sprouting behavior comparable to that of LECs in vitro and a dual hemangiogenic and lymphangiogenic activity in vivo in an endothelial cell sprouting assay and corneal vascularization assay, respectively. Furthermore, these cells expressed vascular endothelium growth factor (VEGF) family members A, -C, and -D. Thus, bone-marrow derived EPCs stimulate hemangiogenesis and lymphangiogenesis through their ability to differentiate into LECs and to produce angiogenic factors. Importantly, plasma from patients with breast cancer induced differentiation of CD34+cord blood progenitors into hemangiogenic and lymphangiogenic CD11b+myeloid cells, whereas plasma from healthy women did not have this effect. Consistent with these findings, circulating CD11b+cells from breast cancer patients, but not from healthy women, displayed a similar dual angiogenic activity. Taken together, our results show that marrow-derived EPCs become hemangiogenic and lymphangiogenic upon exposure to cancer plasma. These newly identified functions of bone-marrow derived EPCs are expected to influence the diagnosis and treatment of breast cancer.
authors.affiliation: Ludwig Center for Cancer Research; University of Lausanne; Lausanne, Switzerland.
authors.forename: Eveline Faes
authors.initials: EF
authors.lastname: Van't Hull
authors.affiliation: Ludwig Center for Cancer Research; University of Lausanne; Lausanne, Switzerland.
authors.forename: Sylvian
authors.initials: S
authors.lastname: Bron
authors.affiliation: Ludwig Center for Cancer Research; University of Lausanne; Lausanne, Switzerland.
authors.forename: Luc
authors.initials: L
authors.lastname: Henry
authors.affiliation: Centre du Sein CHUV; University of Lausanne; Lausanne, Switzerland.
authors.forename: Assia
authors.initials: A
authors.lastname: Ifticene-Treboux
authors.affiliation: Ludwig Center for Cancer Research; University of Lausanne; Lausanne, Switzerland.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Turrini
authors.affiliation: Ludwig Center for Cancer Research; University of Lausanne; Lausanne, Switzerland.
authors.forename: George
authors.initials: G
authors.lastname: Coukos
authors.affiliation: Centre du Sein CHUV; University of Lausanne; Lausanne, Switzerland.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Delaloye
authors.affiliation: Ludwig Center for Cancer Research; University of Lausanne; Lausanne, Switzerland.
authors.forename: Marie-Agnès
authors.initials: MA
authors.lastname: Doucey
keywords: angiogenesis; bone-marrow derived cells; breast cancer; lymphangiogenesis; lymphatic endothelial cells; podoplanin; vasculogenesis
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