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.
Highlights
Metastatic disease—as opposed to primary tumors—accounts for 90% of cancer-related mortality (Steeg, 2012)
Using in vitro modified Boyden chamber assays, where insert filter membranes were lined by confluent human microvascular endothelial cells (ECs) of either lung or dermal blood vessel origin (HMVEC-LBl, Fig 1A–C; HMVEC-DBl, Fig 1D and E), we observed that VT treatment was able to counteract thrombin-stimulated increases in transendothelial permeability of FITC-dextran (P < 0.05, Fig 1A and D) and showed trends of reducing thrombin-stimulated migration of CMTPX-labeled tumor cells (TCs) (Fig 1B, C and E)
Consistent with the aforementioned findings, VT inhibits the early stages of the metastatic process in vivo and may be potentially effective as an adjuvant therapy; in contrast, it does not inhibit tumor growth per se, for example, of established primary tumors
Summary
Metastatic disease—as opposed to primary tumors—accounts for 90% of cancer-related mortality (Steeg, 2012). Most cancer drugs are selected from preclinical studies based on their potency at inhibiting primary tumor growth, and brought into clinical trials with the rationale that they will inhibit the growth of metastases (Francia et al, 2011; Guerin et al, 2013). The inadequacy of this approach has been reviewed and editorials have highlighted the need for new anti-metastatic therapies that block not just the growth (progression) and the spread or formation (incidence) of metastases (Steeg, 2012). Surgical trauma associated with primary tumor resections can sometimes paradoxically fuel metastatic spread—for example, by mechanically dislodging tumor cells into the circulation and by inducing the production/release of inflammatory and angiogenic cytokines that promote metastatic seeding and progression (Goldfarb & Ben-Eliyahu, 2006)
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