Excessive tumor-elaborated VEGF and its neutralization define a lethal paraneoplastic syndrome

Vascular endothelial growth factor (VEGF) is a potent endothelial cell mito gen and key regulator of both physiologic and pathologic (e.g.. tumor) angi ogenesis. In the course of studies designed to assess the ability of consti tutive VEGF to block tumor regression in an inducible RAS melanoma model, m ice implanted with VEGF-expressing tumors sustained high morbidity and mort ality that were out of proportion to the tumor burden. Documented elevated serum levels of VEGF were associated with a lethal hepatic syndrome charact erized by massive sinusoidal dilation and endothelial cell proliferation an d apoptosis. systemic levels of VEGF correlated with the severity of liver pathology and overall clinical compromise. A striking reversal of VEGF-indu ced liver pathology and prolonged survival were achieved by surgical excisi on of VEGF secreting tumor or by systemic administration of a potent VEGF a ntagonist (VEGF-TRAP(R1R2)), thus defining a paraneoplastic syndrome caused by excessive VEGF activity. Moreover, this VEGF-induced syndrome resembles peliosis hepatis, a rare human condition that is encountered in the settin g of advanced malignancies, high-dose androgen therapy, and Bartonella hens elae infection. Thus, our findings in the mouse have suggested an etiologic role for VEGF in this disease and may lead to diagnostic and therapeutic o ptions for this debilitating condition in humans.