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Blood, 15 March 2002, Vol. 99, No. 6, pp. 2179-2184
NEOPLASIA
Vascular endothelial growth factor (VEGF)-C signaling
through FLT-4 (VEGFR-3) mediates leukemic cell proliferation, survival,
and resistance to chemotherapy
Sergio Dias,
Margaret Choy,
Kari Alitalo, and
Shahin Rafii
From Weill Medical College of Cornell University,
Division of Hematology/Oncology, New York, NY; and Molecular/Cancer
Biology Laboratory, Haartman Institute, University of Helsinki,
Finland.
Similar to solid tumors, growth of leukemias may also be
angiogenesis dependent. Furthermore, tyrosine kinase receptors specific to endothelial cells are expressed on certain subsets of leukemias. We
have previously demonstrated the existence of a VEGF/VEGFR-2 autocrine
loop on leukemic cells that supports their growth and migration. Here,
we demonstrate that in response to leukemia-derived proangiogenic and
proinflammatory cytokines such as basic fibroblast growth factor and
IL-1, endothelial cells release increasing amounts of another vascular
endothelial growth factor (VEGF) family member, VEGF-C. In turn,
interaction of VEGF-C with its receptor VEGFR-3 (FLT-4) promotes
leukemia survival and proliferation. We demonstrate in 2 cell lines and
5 FLT-4+ leukemias that VEGF-C and a mutant form of the
molecule that lacks the KDR-binding motif induce receptor
phosphorylation, leukemia proliferation, and increased survival, as
determined by increased Bcl-2/Bax ratios. Moreover, VEGF-C protected
leukemic cells from the apoptotic effects of 3 chemotherapeutic agents.
Because most leukemic cells release proangiogenic as well as
proinflammatory cytokines, our data suggest that the generation of a
novel paracrine angiogenic loop involving VEGF-C and FLT-4 may promote
the survival of a subset of leukemias and protect them from
chemotherapy-induced apoptosis. These results identify the VEGF-C/FLT-4
pathway as a novel therapeutic target for the treatment of subsets of
acute leukemia.
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