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Blood, 15 June 2001, Vol. 97, No. 12, pp. 3919-3924
NEOPLASIA
Angiogenesis in acute promyelocytic leukemia: induction by
vascular endothelial growth factor and inhibition by
all-trans retinoic acid
Ameet R. Kini,
LoAnn C. Peterson,
Martin S. Tallman, and
Mark W. Lingen
From the Departments of Pathology and Medicine,
Northwestern University Medical School, Chicago, IL; and the Department
of Pathology, Cardinal Bernardin Cancer Center, Loyola University
Medical Center, Maywood, IL.
Recent studies indicate that angiogenesis is important in the
pathogenesis of leukemias, apart from its well-established role in
solid tumors. In this study, the possible role of angiogenesis in acute
promyelocytic leukemia (APL) was explored. Bone marrow trephine
biopsies from patients with APL showed significantly increased
microvessel density and hot spot density compared with normal control
bone marrow biopsies. To identify the mediators of angiogenesis in APL,
quantitative and functional assays were performed using the NB4 APL
cell line as a model system. Conditioned media (CM) from the NB4 cells
strongly stimulated endothelial cell migration. CM from the NB4 cells
contained high levels of vascular endothelial growth factor (VEGF) but
not basic fibroblast growth factor (bFGF). Most important, the addition
of neutralizing VEGF antibodies completely inhibited the ability of NB4
CM to stimulate endothelial cell migration, suggesting that APL
angiogenesis is mediated by VEGF. The effect of all-trans
retinoic acid (ATRA) on APL angiogenesis was then studied. ATRA therapy
resulted in a decrease in bone marrow microvessel density and hot spot
density. CM from ATRA-treated APL cells did not stimulate endothelial
cell migration. Finally, quantitative assays showed that ATRA treatment resulted in the abrogation of VEGF production by the NB4 cells. These
results show that there is increased angiogenesis and VEGF production
in APL and that ATRA therapy inhibits VEGF production and suppresses
angiogenesis. The addition of specific antiangiogenic agents to
differentiation therapy or chemotherapy should be explored.
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