Vasculotide reduces endothelial permeability and tumor cell extravasation in the absence of binding to or agonistic activation of Tie2

EMBO Molecular Medicine

Florence TH Wu¹  Christina R Lee²  Elena Bogdanovic²  Aaron Prodeus¹  Jean Gariépy¹ 

[1] Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada;Biological Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada

关键词: angiopoietin;    metastasis;    Tie2;    tumor cell extravasation;    vascular permeability;   

DOI  :  10.15252/emmm.201404193

来源: Wiley

【 摘 要 】

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.

Synopsis

Vasculotide (VT) reduced trans-endothelial permeability and tumor cell migration in vitro and, in vivo, delayed metastasis to the lungs while not affecting primary breast cancer growth. The effect of VT appeared to be independent of Tie2.

• In vitro, Vasculotide significantly counteracts transendothelial hyperpermeability and shows trends of hindering tumor cell diapedesis across endothelial cells stimulated with thrombin or tumor cell-derived cytokines.

• In mice, Vasculotide delays mortality associated with lung metastasis of intravenously injected breast cancer cells, but has no effect on experimental liver metastasis of colorectal cancer cells, lung metastasis of renal cancer cells, or lymphatic metastasis by breast or renal cancer cells.

• When breast cancer cells are implanted orthotopically, Vasculotide treatment has no effect on the local growth of primary mammary tumors but inhibits distant metastatic dissemination.

• This study revealed no evidence for Tie2 agonism or Tie2 binding by Vasculotide; further investigations will be needed to elucidate an alternative mechanism of action.

【 授权许可】

CC BY   
© 2015 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.