title: Role of vascular endothelial growth factor (VEGF) and placenta-derived growth factor (PlGF) in regulating human haemopoietic cell growth.
abstract: Vascular endothelial growth factor (VEGF) and placental derived growth factor (PlGF) stimulate cell proliferation and differentiation by binding to their specific receptors, Flk-1/KDR and Flt-1 respectively. Flk-1/KDR-deficient murine embryos manifest failure of blood-island formation and vasculogenesis. The aim of this study was to directly evaluate the importance of VEGF, PlGF/Flt-1 and Flk-1/KDR receptor ligand interactions in regulating normal and malignant human haemopoiesis. Addition of VEGF and PlGF failed to enhance survival or cloning efficiency of human haemopoietic progenitors isolated from adult bone marrows, fetal livers or cord blood samples. This finding 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. Further studies revealed that Fit-1 R mRNA, but not Flk-1/KDR mRNA was first detectable in the more mature cells isolated from haemopoietic colonies. Accordingly, 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 contrast to normal haemopoietic progenitors, VEGF co-stimulated HEL cell proliferation as well as CFU-GM colony formation from approximately 15% of the chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML) patients studied. Therefore, although VEGF appeared to have minimal effects on normal haemopoietic cell growth it would appear to drive malignant haemopoietic cell proliferation to some degree. Of more importance, however, we speculate that VEGF may play an very important role in leukaemogenesis by stimulating growth of vascular endothelium, thereby providing a sufficient blood supply to feed the growing haematological tumour.
authors.affiliation: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
authors.forename: M Z
authors.initials: MZ
authors.lastname: Ratajczak
authors.forename: J
authors.initials: J
authors.lastname: Ratajczak
authors.forename: B
authors.initials: B
authors.lastname: Machalinski
authors.forename: M
authors.initials: M
authors.lastname: Majka
authors.forename: W
authors.initials: W
authors.lastname: Marlicz
authors.forename: A
authors.initials: A
authors.lastname: Carter
authors.forename: Z
authors.initials: Z
authors.lastname: Pietrzkowski
authors.forename: A M
authors.initials: AM
authors.lastname: Gewirtz
mesh_terms: D000208:Acute Disease; D002455:Cell Division; D002470:Cell Survival; D002478:Cells, Cultured; D002908:Chronic Disease; D016228:Endothelial Growth Factors / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D007951:Leukemia, Myeloid / Q000473:pathology; D008222:Lymphokines / Q000502:physiology*; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D008222:Lymphokines; C000608036:PGF protein, human; D011257:Pregnancy Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000072483:Placenta Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D040281:Vascular Endothelial Growth Factor Receptor-1