Vascular endothelial growth factor and cellular chemotaxis: A possible autocrine pathway in adult T-cell leukemia cell invasion

Our previous report (T. Hayashibara et al., Leukemia, 13: 1634-1635, 1999) revealed a possible link between high plasma vascular endothelial growth fa ctor (VEGF) concentration and leukemic cell invasion in adult T-cell leukem ia (ATL). However, the biological mechanism of this link has not been eluci dated. The purpose of this study was to address that mechanism. Our present observations showed that VEGF mRNA was expressed in ATL cell lines. The co rresponding protein was secreted into the extracellular environment, which suggested that the major source of plasma VEGF is ATL cells themselves. Mor e interestingly, all of the cell lines examined were found to express the m RNA and protein for fms-like tyrosine kinase-1 (Flt-1), which is one of the receptors for VEGF. Cytofluorometric analysis demonstrated the VEGF bindin g 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, r espectively. 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 AT L cell lines was not affected by treatment with an anti-VEGF antibody or ex ogenous VEGF, which indicated that VEGF has no mitogenic effect on ATL cell s. In contrast, we made the interesting finding that treatment with exogeno us VEGF enhanced the chemotactic activities of some ATL cell lines, which m ay play a key role in ATL cell invasion. Collectively, these data lead us t o propose a possible autocrine mechanism involving VEGF operating by way of Flt-1, in which ATL cells up-regulate their own chemotaxis to facilitate t heir invasion into various organs.