title: Microparticles mediated cross-talk between tumoral and endothelial cells promote the constitution of a pro-metastatic vascular niche through Arf6 up regulation.
abstract: The tumor stroma plays an essential role in tumor growth, resistance to therapy and occurrence of metastatic phenotype. Tumor vessels have been considered as passive conducts for nutrients but several studies have demonstrated secretion of pro-tumoral factors by endothelial cells. The failure of anti-angiogenic therapies to meet expectations raised by pre-clinical studies prompt us to better study the cross-talk between endothelial and cancer cells. Here, we hypothesized that tumor cells and the endothelium secrete bio-active microparticles (MPs) participating to a functional cross-talk. We characterized the cancer cells MPs, using breast and ovarian cancer cell lines (MCF7, MDA-MB231, SKOV3, OVCAR3 and a primary cell lines, APOCC). Our data show that MPs from mesenchymal-like cell lines (MDA-MB231, SKOV3 and APOCC) were able to promote an activation of endothelial cells through Akt phosphorylation, compared to MPs from epithelial-like cell lines (OVCAR3 and MCF7). The MPs from mesenchymal-like cells contained increased angiogenic molecules including PDGF, IL8 and angiogenin. The endothelial activation was associated to increased Arf6 expression and MPs secretion. Endothelial activation functionalized an MP dependent pro-tumoral vascular niche promoting cancer cells proliferation, invasiveness, stem cell phenotype and chemoresistance. MPs from cancer and endothelial cells displayed phenotypic heterogeneity, and participated to a functional cross-talk where endothelial activation by cancer MPs resulted in increased secretion of EC-MPs sustaining tumor cells. Such cross-talk may play a role in perfusion independent role of the endothelium.
authors.affiliation: Stem Cell and Microenvironment Laboratory, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, Doha, Qatar.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pasquier
authors.forename: Hamda Al
authors.initials: HA
authors.lastname: Thawadi
authors.forename: Pegah
authors.initials: P
authors.lastname: Ghiabi
authors.forename: Nadine
authors.initials: N
authors.lastname: Abu-Kaoud
authors.forename: Mahtab
authors.initials: M
authors.lastname: Maleki
authors.forename: Bella S
authors.initials: BS
authors.lastname: Guerrouahen
authors.forename: Fabien
authors.initials: F
authors.lastname: Vidal
authors.forename: Bettina
authors.initials: B
authors.lastname: Courderc
authors.forename: Gwenael
authors.initials: G
authors.lastname: Ferron
authors.forename: Alejandra
authors.initials: A
authors.lastname: Martinez
authors.forename: Haya
authors.initials: H
authors.lastname: Al Sulaiti
authors.forename: Renuka
authors.initials: R
authors.lastname: Gupta
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
authors.forename: Arash
authors.initials: A
authors.lastname: Rafii