Involvement of Flt-1 (VEGF receptor-1) in cancer and preeclampsia.

We previously isolated a novel tyrosine kinase receptor, Flt-1, now known as VEGF-receptor (VEGFR)-1. The VEGF-VEGFR system plays a pivotal role in not only physiological but also pathological angiogenesis. We examined the role of Flt-1 in carcinogenesis using Flt-1-signal-deficient (Flt-1 TK-/-) mice, and found that this receptor stimulates tumor growth and metastasis most likely via macrophages, making it an important potential target in the treatment of cancer. In addition to the full-length receptor, the Flt-1 gene produces a soluble protein, sFlt-1, an endogenous VEGF-inhibitor. sFlt-1 is expressed in trophoblasts of the placenta between fetal and maternal blood vessels, suggesting it to be a barrier against extreme VEGF-signaling. Abnormally high expression of sFlt-1 occurs in most preeclampsia patients, whose main symptoms are hypertension and proteinurea. In cancer patients, strong suppression of VEGF-VEGFR by drugs induces similar side effects including hypertension. These results indicate a close relationship between abnormal VEGF-block and hypertension/proteinurea. sFlt-1 is an attractive target for the control of preeclampsia.