Role of Activated Endothelial Cells in Recurrent Ovarian Cancer
Posted: Tuesday, June 25, 2019
According to a study by Jennifer Pasquier, PhD, and Arash Rafii, MD, PhD, of Weill Cornell Medicine, Qatar, and colleagues, activated endothelial cells may promote ovarian cancer growth and chemoresistance through Notch signaling. In light of the high rates of ovarian cancer recurrence, the researchers investigated the angiocrine properties of endothelial cells in the context of an ovarian metastatic niche. The research results were published in the Journal of Translational Medicine.
In this study, Akt-activated endothelial cells, used to model tumor endothelial cells, were co-cultured, or cultured using Transwell permeable supports, with two ovarian cancer cells lines: OVCAR3 and APOCC cells. A series of xenograft, knockdown, and transfection experiments were carried out; their effects were confirmed by confocal imaging, Western blot, and gene-expression analyses.
As shown by proliferation and xenograft assays, activated endothelial cells promoted proliferation and survival of OVCAR3 cells in vitro as well as in vivo. During co-culture, upregulation of the Notch3 receptor and Jagged1 ligand were seen on APOCC and activated endothelial cells, respectively. Application of gamma secretase inhibitors eliminated the survival advantages in APOCC cells, and siRNA against Jagged1 also reduced proliferative advantages in both cell lines. Moreover, the chemoresistance (toward cisplatin and paclitaxel) demonstrated by co-culture with both cell lines was recapitulated by OVCAR3 cells treated with human recombinant Jagged1 alone and seemed to be reversed by treatment with gamma secretase inhibitors.
“In our study, we demonstrated using gene expression the up-regulation of Notch downstream effectors following co-culture as well as the many pro-survival effectors of chemoresistance,” the authors concluded. “The targeting of aberrant NOTCH signaling could constitute a strategy to disrupt the pro-tumoral endothelial niche.”
Disclosure: The study authors reported no conflicts of interest.