Abstract
The angiogenic switch is an important oncogenic step that determines whether microtumors remain dormant or progresses further. It has been generally perceived that the primary function of this tumorgenic event is to supply oxygen and nutrients through blood circulation. Using in vivo imaging of zebrafish and mouse tumor models, we showed that endothelial cords aggressively penetrated into microtumors and remained non-circulatory for several days before undergoing vascular blood perfusion. Unexpectedly, we found that initial tumor growth in both models was significantly reduced if endothelial cords were removed by blocking VEGF-VEGFR2 signaling or using a vascular deficient zebrafish mutant. It was further shown that soluble factors including IL-8, secreted by endothelial cells (ECs) were responsible for stimulating tumor cells proliferation. These findings establish that tumor angiogenesis play a much earlier and broader role in promoting tumor growth, which is independent of vascular circulation. Understanding this novel mechanism of angiogenic tumor progression offers new entry points for cancer therapeutics.
Highlights
Vascular endothelium has been shown producing active substrates affecting normal development and function of several organs and tissues[12,13,14]
Our studies indicate that the angiogenesis acts to promote microtumor growth by a two-phase model: endothelial cords in microtumors drive tumor growth through a paracrine mechanism by releasing endothelium-derived proliferative factors, they support tumor progression by supplying oxygen and nutrients through the blood circulation
To further confirm that the elimination of solid endothelial cords by either siVEGF or SU5416 treatment was the basis for the interruption of initial microtumor growth, B16 tumor cells were transplanted into the Tg(flk1:eGFP) transgenic zebrafish embryos carrying the Cloche mutation, which lacks endothelial cells (ECs) and blood cells[26]
Summary
Vascular endothelium has been shown producing active substrates affecting normal development and function of several organs and tissues[12,13,14]. These results suggested that solid endothelial cords within microtumors prior to the blood-perfusion are a general phenomenon both for xenograft and endogenous tumors in zebrafish.
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