title: Vasculotide reduces endothelial permeability and tumor cell extravasation in the absence of binding to or agonistic activation of Tie2.
abstract: Angiopoietin-1 (Ang1) activation of Tie2 receptors on endothelial cells (ECs) reduces adhesion by tumor cells (TCs) and limits junctional permeability to TC diapedesis. We hypothesized that systemic therapy with Vasculotide (VT)-a purported Ang1 mimetic, Tie2 agonist-can reduce the extravasation of potentially metastatic circulating TCs by similarly stabilizing the host vasculature. In vitro, VT and Ang1 treatments impeded endothelial hypermeability and the transendothelial migration of MDA-MB-231∙LM2-4 (breast), HT29 (colon), or SN12 (renal) cancer cells to varying degrees. In mice, VT treatment inhibited the transit of TCs through the pulmonary endothelium, but not the hepatic or lymphatic endothelium. In the in vivo LM2-4 model, VT monotherapy had no effect on primary tumors, but significantly delayed distant metastatic dissemination to the lungs. In the post-surgical adjuvant treatment setting, VT therapeutically complemented sunitinib therapy, an anti-angiogenic tyrosine kinase inhibitor which limited the local growth of residual disease. Unexpectedly, detailed investigations into the putative mechanism of action of VT revealed no evidence of Tie2 agonism or Tie2 binding; alternative mechanisms have yet to be determined.
authors: Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada Biological Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada.
authors: Florence T H
authors: FT
authors: Wu
authors: Biological Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada.
authors: Christina R
authors: CR
authors: Lee
authors: Biological Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada.
authors: Elena
authors: E
authors: Bogdanovic
authors: Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada Physical Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada.
authors: Aaron
authors: A
authors: Prodeus
authors: Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada Physical Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada.
authors: Jean
authors: J
authors: Gariépy
authors: Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada Biological Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada robert.kerbel@sri.utoronto.ca.
authors: Robert S
authors: RS
authors: Kerbel
mesh_terms: D042683:Angiopoietin-1 / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D010539:Permeability / Q000187:drug effects; D042787:Receptor, TIE-2 / Q000819:agonists*; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects*
chemical_list: D042683:Angiopoietin-1; C467628:Angpt1 protein, mouse; D042787:Receptor, TIE-2; C079086:Tek protein, mouse
keywords: Tie2; angiopoietin; metastasis; tumor cell extravasation; vascular permeability