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Vascular Endothelial Growth Factor and Cellular Chemotaxis

A Possible Autocrine Pathway in Adult T-Cell Leukemia Cell Invasion

Department of Haematology, Molecular Medicine Unit, Atomic Disease Institute [T. H., H. M., T. J., T. Mae., M. T.]; and Departments of Biochemistry [T. H., T. Mi., T. Mai.] and Laboratory Medicine [Y. Y., S. K.], Nagasaki University School of Medicine; and Faculty of Environmental Studies [T. Mi.], and Department of Preventive Medicine and AIDS Research, Institute of Tropical Medicine [N. M.], Nagasaki University, Nagasaki 852-8523, Japan

Our previous report (T. Hayashibara et al., Leukemia, 13: 1634–1635, 1999) revealed a possible link between high plasma vascular endothelial growth factor (VEGF) concentration and leukemic cell invasion in adult T-cell leukemia (ATL). However, the biological mechanism of this link has not been elucidated. The purpose of this study was to address that mechanism. Our present observations showed that VEGF mRNA was expressed in ATL cell lines. The corresponding protein was secreted into the extracellular environment, which suggested that the major source of plasma VEGF is ATL cells themselves. More interestingly, all of the cell lines examined were found to express the mRNA and protein for fms-like tyrosine kinase-1 (Flt-1), which is one of the receptors for VEGF. Cytofluorometric analysis demonstrated the VEGF binding potency of these cells. In clinical specimens, expression of VEGF and Flt-1 mRNAs was detected in all (100%) of 11 and 8 (73%) of 11 ATL patients, respectively. Cytofluorometric analysis revealed that VEGF effectively bound only to Flt-1-expressing cells. These findings are highly suggestive of an autocrine pathway involving VEGF operating in ATL. The proliferation of ATL cell lines was not affected by treatment with an anti-VEGF antibody or exogenous VEGF, which indicated that VEGF has no mitogenic effect on ATL cells. In contrast, we made the interesting finding that treatment with exogenous VEGF enhanced the chemotactic activities of some ATL cell lines, which may play a key role in ATL cell invasion. Collectively, these data lead us to propose a possible autocrine mechanism involving VEGF operating by way of Flt-1, in which ATL cells up-regulate their own chemotaxis to facilitate their invasion into various organs.

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