Leukemia-stimulated bone marrow endothelium promotes leukemia cell survival.
Extensive endothelial cell proliferation and marked neovascularization are the most pronounced microenvironmental changes consistently observed in the bone marrow (BM) of patients with acute lymphoblastic leukemia (ALL). It is not known whether ALL cells induce this phenotype and whether they receive critical signals from the tumor-associated BM endothelium. Here, we show that leukemia cells actively stimulate BM endothelium, promote de novo angiogenesis, and induce neovascularization in the leukemic BM. Soluble factors, present in the leukemic BM microenvironment, promote the proliferation, migration, and morphogenesis of BM endothelial cells, which are critical processes in tumor angiogenesis. We also show in vitro that leukemia cells display directional motion towards assembled BM endothelium and following adherence exhibit cell polarization, pseudopodia, and ultrastructural features that suggest the existence of leukemia-endothelium cross-talk. Finally, we show that BM endothelium promotes leukemia cell survival through a mechanism mediated through the anti-apoptotic molecule bcl-2. These studies indicate that ALL cells actively recruit BM endothelium and mediate the leukemia-associated neovascularization observed in ALL. Therefore, disruption of interactions between leukemia cells and BM endothelium may constitute a valid therapeutic strategy.
Veiga
J Pedro
JP
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Costa
Lara F
LF
Sallan
Stephen E
SE
Nadler
Lee M
LM
Cardoso
Angelo A
AA
D000818:Animals; D001853:Bone Marrow / Q000473:pathology* / Q000648:ultrastructure; D049109:Cell Proliferation; D002470:Cell Survival; D004727:Endothelium / Q000473:pathology* / Q000648:ultrastructure; D006801:Humans; D007938:Leukemia / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D009389:Neovascularization, Pathologic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology
D019253:Proto-Oncogene Proteins c-bcl-2