Published online before print June 12, 2001
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.121192298
Medical Sciences
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, and Lynda Chin*,§,¶
* Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA 02115; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115; Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591; and § Department of Dermatology, Harvard Medical School, Boston, MA 02115
Communicated by David M. Livingston, Dana-Farber Cancer Institute, Boston, MA, April 18, 2001 (received for review December 22, 2000)
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. |
