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

• Published in: Cancer letters 2010-12, Vol.298 (2), p.264-272
• Main Authors: Bertin, Samuel, Mohsen-Kanson, Tala, Baqué, Patrick, Gavelli, Adolfo, Momier, David, Anjuere, Fabienne, Carle, Georges F, Pierrefite-Carle, Valérie
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Biochemistry, Molecular Biology; Cell culture; Cell Line, Tumor; Cell Survival - drug effects; Chemokines; Chemokines - genetics; Chemokines - metabolism; Cloning; Colon; Colon carcinoma; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colorectal cancer; Culture Media, Conditioned - pharmacology; Cytokines - genetics; Cytokines - metabolism; Disease Models, Animal; Endothelial Cells - drug effects; Experiments; Gene Expression Regulation, Neoplastic; Hematology, Oncology and Palliative Medicine; Humans; Immune system; Kinases; Life Sciences; Liver metastasis; Liver Neoplasms - metabolism; Liver Neoplasms - secondary; Male; Mice; Myeloid cells; Myeloid Cells - metabolism; Myeloid Cells - pathology; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Plasmids; Rats; Rats, Inbred Strains; Rodents; Spleen; Transfection; Tumor Burden; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor Receptor-1 - genetics; Vascular Endothelial Growth Factor Receptor-1 - metabolism; VEGF
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2010.07.017

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 25 days. 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.