Tumor microenvironment modifications induced by soluble VEGF receptor expression in a rat liver metastasis model

Abstract 

Vascular endothelial growth factor is a potent pro-angiogenic growth factor which is also known to alter tumor microenvironment by inhibiting dendritic cell differentiation and promoting accumulation of myeloid-derived suppressor cells. In the present study, we analyzed the modifications induced by intratumoral expression of sFLT-1, a soluble VEGF receptor, in a rat metastatic colon carcinoma model. We generated colon cancer cell lines stably expressing sFLT-1 or a mock construct. Human umbilical vein endothelial cells cultured with conditioned medium from sFLT-1-expressing tumor cells exhibit a significantly decreased survival, demonstrating the functionality of the secreted sFLT-1. In vivo, sFLT-1 expression induced a 30% decrease in microvessel density in 15-day old experimental liver metastasis from colon carcinoma. Tumor growth was inhibited by 63% and 52% in left and right liver lobes respectively within 25days. In these tumors, sFLT-1 expression was associated with a decreased myeloid cell infiltration and a modification in the expression of several cytokines/chemokines. Altogether, these results suggest that VEGF trapping by sFLT-1 intratumoral expression results in reduced vascularization, tumor growth inhibition and modification of immune tumor microenvironment.

Abbreviations: DC, dendritic cell, FCS, fetal calf serum, HRP, horseradish peroxidase, HUVEC, human umbilical vein endothelial cells, IL-1Ra, interleukin 1 receptor antagonist, Lymphotactin β, Lt-β, MDSC, myeloid-derived suppressor cells, NK, natural killer, PlGF, placenta growth factor, RPA, RNase protection assay, TGF-β, tumor growth factor β, TNF-α, tumor necrosis factor α, VEGF, Vascular endothelial growth factor

Keywords: VEGF, Myeloid cells, Liver metastasis, Colon carcinoma