Tumor microenvironment modifications induced by soluble VEGF receptor expression in a rat liver metastasis model.
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. Invivo, 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.
Bertin
Samuel
S
Université de Nice-Sophia Antipolis, Faculté de Médecine, 06107 Nice cédex 2, France.
Mohsen-Kanson
Tala
T
Baqué
Patrick
P
Gavelli
Adolfo
A
Momier
David
D
Anjuere
Fabienne
F
Carle
Georges F
GF
Pierrefite-Carle
Valérie
V
D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000556:secondary; D008297:Male; D051379:Mice; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051381:Rats; D011919:Rats, Inbred Strains; D014162:Transfection; D047368:Tumor Burden; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism*
D018925:Chemokines; D017077:Culture Media, Conditioned; D016207:Cytokines; D040281:Vascular Endothelial Growth Factor Receptor-1