Vascular Endothelial Growth Factor Inhibits the Development of Dendritic Cells and Dramatically Affects the Differentiation of Multiple Hematopoietic Lineages In Vivo

Abstract

Defective function of dendritic cells (DC) in cancer has been recently described and may represent one of the mechanisms of tumor evasion from immune system control. We have previously shown in vitro that vascular endothelial growth factor (VEGF), produced by almost all tumors, is one of the tumor-derived factors responsible for the defective function of these cells. In this study, we investigated whether in vivo infusion of recombinant VEGF could reproduce the observed DC dysfunction. Continuous VEGF infusion, at rates as low as 50 ng/h (resulting in serum VEGF concentrations of 120 to 160 pg/mL), resulted in a dramatic inhibition of dendritic cell development, associated with an increase in the production of B cells and immature Gr-1+ myeloid cells. Infusion of VEGF was associated with inhibition of the activity of the transcription factor NF-κB in bone marrow progenitor cells. Experiments in vitro showed that VEGF itself, and not factors released by VEGF-activated endothelial cells, affected polypotent stem cells resulting in the observed abnormal hematopoiesis. These data suggest that VEGF, at pathologically relevant concentrations in vivo, may exert effects on pluripotent stem cells that result in blocked DC development as well as affect many other hematopoietic lineages.

Low recruitment of immune cells with increased expression of endothelial adhesion molecules in margins of the chronic diabetic foot ulcers

“…This is consistent with the previously observed reduction of CD1a+ Langerhans cells at the edge of venous leg ulcers 21 . The variation in CD1a+ cell numbers may reflect differences in the recruitment capacities in various microenvironments, possibly based on the expression of molecules responsible for Langerhans cell trafficking into the skin 22,23 or influencing Langerhans cell differentiation 24,25 . Langerhans cells are localized in the epidermis where surrounding keratinocytes produce a number of cytokines and growth factors influencing Langerhans cells 26 .…”

Vascular endothelial growth factor (VEGF) impairs the motility and immune function of human mature dendritic cells through the VEGF receptor 2‐RhoA‐cofilin1 pathway

“…It was reported that VEGF can enhance the phosphorylation of Erk1/2, but not those of p38MAPK or Akt in mDCs . Moreover, our results and those from other groups showed that VEGF can impair the immune function through the NF‐κB pathway . From these results, it could be inferred that the molecular targets of VEGF to mDCs were COF1, Erk1 and 2, and NF‐κB, all of which are related to the cytoskeleton, motility, and gene transcription.…”

“…As shown in Figures and , the motility of mDCs was impaired by VEGF through the VEGFR2‐RhoA‐COF1 pathway. Several groups have shown that VEGFR1 is the major mediator of VEGF effects on the NF‐κB pathway in hematopoietic stem cells and that VEGF affects the early stage of myeloid/DC differentiation . Clauss et al showed that VEGFR1 is biologically active in monocytes/macrophages and that VEGF stimulates the migration and chemotaxis of human monocytes.…”

“…Moreover, DC density is negatively associated with VEGF level in vivo . Vascular endothelial growth factor can inhibit the functional maturation of imDCs and impair the differentiation of DCs . As a mAb of VEGF, bevacizumab has achieved great successes in the clinical field of tumors, but many problems still need to be solved, such as toxic side‐effects, inaccurate curative effect, and inaccurate targeting .…”

Regulatory T Cells in Ovarian Cancer: Biology and Therapeutic Potential

“…These studies established the concept that experimentally induced TAA‐specific immunity is a rational and potentially efficacious means to treat cancer, including ovarian cancer. Nonetheless, recent work demonstrates that lack of naturally induced TAA‐specific immunity is not simply a passive process 5–12 . We discuss recent data clearly demonstrating that ‘tumors actively prevent induction of TAA‐specific immunity through induction of TAA‐specific tolerance’ 13 .…”