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

Alex K. Wong, Myra Alfert, Diego H. Castrillon, Qiong Shen, Jocelyn Holash, George D. Yancopoulos, Lynda Chin

Research output: Contribution to journalArticle

60 Scopus citations

Abstract

Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen and key regulator of both physiologic and pathologic (e.g., tumor) angiogenesis. In the course of studies designed to assess the ability of constitutive VEGF to block tumor regression in an inducible RAS melanoma model, mice implanted with VEGF-expressing tumors sustained high morbidity and mortality that were out of proportion to the tumor burden. Documented elevated serum levels of VEGF were associated with a lethal hepatic syndrome characterized by massive sinusoidal dilation and endothelial cell proliferation and apoptosis. Systemic levels of VEGF correlated with the severity of liver pathology and overall clinical compromise. A striking reversal of VEGF-induced liver pathology and prolonged survival were achieved by surgical excision of VEGF-secreting tumor or by systemic administration of a potent VEGF antagonist (VEGF-TRAPR1R2), 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 setting of advanced malignancies, high-dose androgen therapy, and Bartonella henselae infection. Thus, our findings in the mouse have suggested an etiologic role for VEGF in this disease and may lead to diagnostic and therapeutic options for this debilitating condition in humans.

Original languageEnglish (US)
Pages (from-to)7481-7486
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number13
DOIs
StatePublished - Jun 19 2001

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