Mirshahi P, Rafii A, Vincent L, Berthaut A, Varin R, Kalantar G, Marzac C, Calandini O A, Marie J-P, Soria C, Soria J, Mirshahi M
Department of Onco Haematology, UMRS 872, CNRS, E 18, INSERM, Université Paris VI, Paris, France.
Leukemia. 2009 Jun;23(6):1039-48. doi: 10.1038/leu.2009.10. Epub 2009 Apr 2.
Angiogenesis is thought to be involved in the development of acute leukemia (AL). We investigated whether bone marrow stromal cells (BMSCs) derived from stem cells might be responsible for the increase in microvascular density (MVD), and compared 13 bone marrow samples from AL patients with 23 samples from patients in complete remission (controls). We demonstrated that AL-derived BMSC secreted more insulin growth factor-1 (IGF-1) and SDF-1alpha than controls. In addition, in contrast to normal adherent BMSCs, adherent BMSCs derived from CD133+/CD34+ stem cells from AL patients were able to form capillary-like structures ('vasculogenic mimicry') on Matrigel. The increase in vasculogenic mimicry occurred through PI3 kinase and rho GTPase pathway as inhibitors of these signaling pathways (wortmannin and GGTI-298, respectively) were able to reduce or prevent capillary tube formation. In normal BMSC, addition of exogenous IGF-1 generated capillary-like tubes through the same pathway as observed spontaneously in AL-derived BMSC. The involvement of IGF-1 in the mimicry process was confirmed by the addition of a neutralizing antibody against IGF-1R or a IGF-1R pathway inhibitor (picropodophyllin). In conclusion, AL-derived BMSC present functional abnormalities that may explain the increase in MVD in the bone marrow of AL patients.
血管生成被认为与急性白血病（AL）的发展有关。我们研究了源自干细胞的骨髓基质细胞（BMSC）是否可能是微血管密度（MVD）增加的原因，并将13例AL患者的骨髓样本与23例完全缓解患者（对照组）的样本进行了比较。我们证明，源自AL的BMSC比对照组分泌更多的胰岛素生长因子-1（IGF-1）和SDF-1α。此外，与正常贴壁BMSC不同，源自AL患者CD133+/CD34+干细胞的贴壁BMSC能够在基质胶上形成毛细血管样结构（“血管生成拟态”）。血管生成拟态的增加是通过PI3激酶和rho GTPase途径发生的，因为这些信号通路的抑制剂（分别为渥曼青霉素和GGTI-298）能够减少或阻止毛细血管管的形成。在正常BMSC中，添加外源性IGF-1通过与在源自AL的BMSC中自发观察到的相同途径产生毛细血管样管。通过添加抗IGF-1R中和抗体或IGF-1R途径抑制剂（鬼臼苦毒素）证实了IGF-1参与拟态过程。总之，源自AL的BMSC存在功能异常，这可能解释了AL患者骨髓中MVD的增加。
