Role of vascular endothelial growth factor (VEGF) and placenta-derived growth factor (PIGF) in regulating human haemopoietic cell growth

Vascular endothelial growth factor (VEGF) and placental derived growth fact or (PlGF) stimulate cell proliferation and differentiation by binding to th eir specific receptors, Flk-1/KDR and Flt-1 respectively. Flk-1/KDR-deficie nt murine embryos manifest failure of blood-island formation and vasculogen esis. The aim of this study was to directly evaluate the importance of VEGF , PlGF/FIt-1 and Flk-1/KDR receptor ligand interactions in regulating norma l and malignant human haemopoiesis. Addition of VEGF and PlGF failed to enh ance survival or cloning efficiency of human haemopoietic progenitors isola ted from adult bone marrows, fetal livers or cord blood samples. This findi ng may be explained by the apparent absence of mRNA encoding Flt-1 and Flk- 1/KDR receptors on stem cell rich CD34(+) c-kit-R+ Rh123(low) cells. Furthe r studies revealed that Flt-1 R mRNA, but not Flk-1/KDR mRNA was first dete ctable in the more mature cells isolated from haemopoietic colonies. Accord ingly VEGF receptors are either absent, or expressed at very low level, on human haemopoietic stem/progenitor cells. Of interest, normal and malignant human haemopoietic cells appeared to secrete VEGF protein. However, in con trast to normal haemopoietic progenitors, VEGF costimulated HEL cell prolif eration as well as CFU-GM colony formation from similar to 15% of the chron ic myeloid leukaemia (CML) and acute myeloid leukaemia (AML) patients studi ed. Therefore, although VEGF appeared to have minimal effects on normal hae mopoietic cell growth it would appear to drive malignant haemopoietic cell proliferation to some degree. Of more importance, however, we speculate tha t VEGF may play an very important role in leukaemogenesis by stimulating gr owth of vascular endothelium, thereby providing a sufficient blood supply t o feed the growing haematological tumour.