Intravital imaging reveals conversion between distinct tumor vascular morphologies and localized vascular response to Sunitinib

Abstract

Tumour vasculature is abnormal and heterogeneous. However, tumor vessel development and dynamics are not well understood. Here we use intravital imaging to study intra-tumoral heterogeneity in endothelial cell dynamics, vascular network growth and morphology and response to Sunitinib anti-angiogenic therapy. We show three main categories of vascular network organization: relatively well organized vessels within the tumor, sprouting networks at the tumor margin with dynamic filopodial and bleb-like protrusions and more tortuous vessels further from the tumor. Longitudinal imaging using windows demonstrates that sprouting margin vessels can give rise to either relatively well ordered intra-tumoral vessels or highly tortuous margin vessels. Further vascular response to Sunitinib anti-angiogenic therapy is heterogeneous. Although treatment with Sunitinib reduces overall tumor vascular density and slows tumor growth, Sunitinib has no significant effect on the sprouting behavior of endothelial cells at the tumor margin. Therefore, within tumors that are broadly responsive to Sunitinib, there are pre-existing refractory microenvironments. These microenvironments have increased protease activity and CXCL12, FGF-2, HGF expression. We propose that these micro-environments may account for the partial and heterogeneous response to anti-angiogenic therapy in the clinical setting.