title: Regulation of angiogenesis in the bone marrow of myelodysplastic syndromes transforming to overt leukaemia.
abstract: To investigate the regulatory mechanisms of angiogenesis in the development of myelodysplastic syndromes (MDS) and its progression to overt leukaemia (OL), bone marrow samples from control, paired samples from MDS patients before and after transformation to OL (MDS --> OL) and de novo acute myeloid leukaemia (AML) were analysed. Immunohistochemical staining showed a significant increase of bone marrow microvascular density (MVD) in MDS and de novo AML compared with controls. Surprisingly, in MDS, MVD significantly decreased upon transformation to OL, which was also significantly lower than the MVD of de novo AML. This evidence was strengthened by the pattern of angiogenic mediator gene expression, confirming the importance of various angiogenic mediators including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), tumour necrosis factor alpha (TNFalpha), hepatocyte growth factor (HGF) and the angiopoietin family of mediators (Ang-1 and Ang-2) as well as the receptors for angiogenic mediators, such as VEGF receptor 2 (VEGFR2) and the tyrosine kinase receptor, TIE2. By contrast, the anti-angiogenic mediator, transforming growth factor-beta (TGFbeta) exhibited significantly higher expression in the bone marrow of MDS --> OL, indicating the importance of this cytokine as the suppressive factor of angiogenesis in MDS. These findings indicate that the bone marrow microenvironment in MDS --> OL and de novo AML differs remarkably, suggesting the different efficacy of anti-angiogenic therapy between de novo AML and leukaemia secondary to MDS.
authors.affiliation: Department of Comprehensive Pathology, Aging and Developmental Sciences, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Tamara
authors.initials: T
authors.lastname: Keith
authors.forename: Yuko
authors.initials: Y
authors.lastname: Araki
authors.forename: Masaki
authors.initials: M
authors.lastname: Ohyagi
authors.forename: Maki
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Kouhei
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Morito
authors.initials: M
authors.lastname: Kurata
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Kenshi
authors.initials: K
authors.lastname: Suzuki
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kitagawa
mesh_terms: D000368:Aged; D042683:Angiopoietin-1 / Q000032:analysis; D042702:Angiopoietin-2 / Q000032:analysis; D001853:Bone Marrow / Q000737:chemistry / Q000503:physiopathology*; D018450:Disease Progression; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000032:analysis; D017228:Hepatocyte Growth Factor / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007938:Leukemia / Q000503:physiopathology*; D015470:Leukemia, Myeloid, Acute / Q000503:physiopathology; D008297:Male; D008833:Microcirculation / Q000503:physiopathology; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000503:physiopathology*; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D012333:RNA, Messenger / Q000032:analysis; D042787:Receptor, TIE-2 / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000032:analysis
chemical_list: D042683:Angiopoietin-1; D042702:Angiopoietin-2; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D017228:Hepatocyte Growth Factor; D042787:Receptor, TIE-2; D040301:Vascular Endothelial Growth Factor Receptor-2