Distinct roles of VEGFR-1 and VEGFR-2 in the aberrant hematopoiesis associated with elevated levels of VEGF

Abstract

Vascular endothelial growth factor (VEGF), a major factor in tumor-host interactions, plays a critical role in the aberrant hematopoiesis observed in cancer-bearing hosts. To dissect the roles of VEGF receptor (VEGFR)-1 and VEGFR-2 in cancer-associated hematopoiesis in vivo, we selectively stimulated VEGFR-1 and VEGFR-2 by continuous infusion of receptor-specific ligands or selective blockade with VEGF receptor-specific antibodies in mice infused with recombinant VEGF at levels observed in tumor-bearing animals. We found that the effect of VEGF on the accumulation of Gr1+CD11b+ cells is mediated by VEGFR-2, but that the 2 receptors have opposite effects on lymphocyte development. Pathophysiologic levels of VEGF strongly inhibit T-cell development via VEGFR-2, whereas VEGFR-1 signaling decreases this inhibition. VEGFR-1, and not VEGFR-2, signaling is responsible for the observed increase of splenic B cells. Both receptors are capable of inhibiting dendritic cell function. These data suggest that most of observed aberrant hematopoiesis caused by excess tumor-derived VEGF is mediated by VEGFR-2, and VEGFR-1 alone has very limited independent effects but clearly both positively and negatively modulates the effects of VEGFR-2. Our findings suggest that selective blockade of VEGFR-2 rather than of both receptors may optimally overcome the adverse hematologic consequences of elevated VEGF levels found in malignancy.

CD4+VEGFR1HIGH T cell as a novel Treg subset regulates inflammatory bowel disease in lymphopenic mice

“…24 In mouse model of chronic infusion of VEGF, VEGFR2 signaling significantly inhibited thymic T-cell development and decreased total number of splenic T cells, whereas VEGFR1 signaling contributed to the mobilization of T cells such as T precursors from the bone marrow and T cells from thymus to spleen. 38 Furthermore, the treatment of neutralizing anti-VEGFR1 Ab and exogenous VEGF did not affect the suppressive function of CD4 1 VEGFR1 high T cell. However, VEGFR1 would be involved in the migration of these cells and cause cleavage of IL-2 receptor a (CD25) from the surface of activated T cells through the induction of matrix metalloproteinases (MMPs) under a certain environment such as VEGF or a ligand-enriched environment.…”

“…VEGF and VEGFR have profound effects on both developmental hematopoiesis and pathologic conditions. [32][33][34][35][36][37][38] We first investigated the expression level of VEGFR1 in the murine thymocytes and T cells. We observed DN, DP, and SP (CD4 and CD8) thymocytes expressed VEGFR1.…”

Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy

“…5B). To validate this finding further, we treated F1 isografts of spontaneous MMTV-PyVT breast cancer with IgG or DC101 at different doses (10,20, and 40 mg/kg). Only quarter-dose DC101 treatment significantly increased tumorinfiltrating CD4 + and CD8 + T cells (Fig.…”

“…Proangiogenic factors not only suppress the function of various immune cells (10) but also diminish leukocyte-endothelial interactions and hinder the infiltration of immune effector cells into the tumor parenchyma (11). Clinical studies consistently support the view that malignant tumors are nonpermissive to T effector cell accumulation (3,7,12).…”

Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell–suppressive activity

“…3,8,12 It has been suggested that different tumor-derived factors, such as granulocyte macrophage-colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), IL-1␤, and prostaglandins, can mobilize MDSC recruitment from bone marrow hematopoietic precursors and induce the immunosuppressive phenotype. [13][14][15][16][17][18] While this immunosuppressive phenotype is a trademark of MDSCs, there is no clear consensus on their suppressive mechanism. Nevertheless, the L-arginine metabolism often seems to play a central role in the immune-suppressive activity of MDSCs.…”