Abstract
BackgroundPreclinical research indicate that vascular disrupting agent (VDA) treatment induces extensive tumor death but also a systemic mobilization of bone marrow derived cells including endothelial progenitor cells (EPC) leading to revascularization and renewed growth within the residual tumor. This study investigates if combination of VDA with the anti-angiogenic agent Sunitinib increases the treatment efficacy in a colorectal liver metastases mouse model.MethodsCBA mice with established liver metastases were given a single dose of OXi4503 at day 16 post tumor induction, a daily dose of Sunitinib starting at day 14 or day 16 post tumor induction or a combination of Sunitinib given daily from day 14 or day 16 post tumor induction in combination with a single dose of OXi4503 at day 16. Treatment was terminated at day 21 post tumor induction and its effects were assessed using stereological and immunohistochemical techniques. Long term effects were assessed in a survival study.ResultsCombination with long (7 day) Sunitinib treatment lead to liver toxicity but this was ameliorated in the shorter (5 day) treatment without significantly altering the effects on tumor reduction. Combination treatment resulted in significant reduction of viable tumor, reduction in tumor vasculature, reduction in tumor proliferation, increase in tumor apoptosis and prolonged mouse survival compared to control and single arm treatments. Complete tumor eradication was not achieved. Redistribution of E-cadherin and strong up regulation of ZEB1 and Vimentin were observed in the surviving tumor; indicative of epithelial to mesenchymal transition (EMT), a mechanism that could contribute to tumor resistance.ConclusionsCombination treatment significantly reduces viable tumor and prolongs animal survival. EMT in the surviving tumor may prevent total tumor eradication and could provide novel targets for a more lasting treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2568-7) contains supplementary material, which is available to authorized users.
Highlights
Preclinical research indicate that vascular disrupting agent (VDA) treatment induces extensive tumor death and a systemic mobilization of bone marrow derived cells including endothelial progenitor cells (EPC) leading to revascularization and renewed growth within the residual tumor
Combination therapy has an additive effect on tumor death A single OXi4503 treatment has profound effects immediately following treatment and it peaks by 24 h, there is a robust re-vascularization and regrowth by day 5 post-treatment [10] and Additional file 1
Quantitation of live tumor area demonstrate significantly less live tumor in the combination treatment compared to single arm treatments and about half the live tumor area compared to Sunitinib (P < 0.01, Fig. 1c)
Summary
Preclinical research indicate that vascular disrupting agent (VDA) treatment induces extensive tumor death and a systemic mobilization of bone marrow derived cells including endothelial progenitor cells (EPC) leading to revascularization and renewed growth within the residual tumor. Tumor vessels are immature, unstable, leaky and deficient in pericyte and smooth muscle coverage. They undergo constant remodelling in order to supply the rapidly growing tumor with oxygen and nutrients [3]. Incomplete destruction of the tumor is evident by the presence of a distinctive rim of viable tumor cells at the tumor periphery [5, 6] These surviving tumor cells undergo vigorous revascularization through angiogenesis resulting in disease recurrence
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