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¹ Laboratory of Biology and Therapy of Metastasis, Department of Oncology, Mario Negri Institute for Pharmacological Research, Bergamo, Italy; ² Dipartimento di Patologia Animale, Igiene e Sanità Pubblica Veterinaria, Sezione di Anatomia Patologica Veterinaria e Patologia Aviare, University of Milan; Laboratories of ³ Molecular Pharmacology and ⁴ Clinical Research in Oncology, Department of Oncology, Mario Negri Institute for Pharmacological Research, Milan, Italy; and ⁵ Department of Human Anatomy and Histology, University of Bari Medical School, Bari, Italy

Requests for reprints: Raffaella Giavazzi, Laboratory of Biology and Therapy of Metastasis, Mario Negri Institute for Pharmacological Research, via Gavazzeni 11, 24125 Bergamo, Italy. Phone: 39-035-319888; Fax: 39-035-319331. E-mail: giavazzi{at}marionegri.it

Vascular endothelial growth factor (VEGF) performs as an angiogenic and permeability factor in ovarian cancer, and its overexpression has been associated with poor prognosis. However, models to study its role as a marker of tumor progression are lacking. We generated xenograft variants derived from the A2780 human ovarian carcinoma (1A9), stably transfected with VEGF₁₂₁ in sense (1A9-VS-1) and antisense orientation (1A9-VAS-3). 1A9, 1A9-VS-1, and 1A9-VAS-3 disseminated in the peritoneal cavity of nude mice, but only 1A9-VS-1, the VEGF₁₂₁-overexpressing tumor variant, produced ascites. Tumor biopsies from 1A9-VS-1 showed alterations in the vascular pattern and caused an angiogenic response in the chorioallantoic membrane assay. A significant level of soluble VEGF was detectable in the plasma of mice bearing 1A9-VS-1 even at an early stage of tumor growth. Plasma VEGF correlated positively with tumor burden in the peritoneal cavity and ascites accumulation. Cisplatin reduced the tumor burden and ascites in mice bearing 1A9-VS-1; the response was associated with a significant decrease of VEGF in plasma.

This 1A9-VS-1 xenograft model reproduces the behavior of human ovarian cancer by growing in the peritoneal cavity, being highly malignant, and producing ascites. Plasma VEGF as a marker of tumor progression offers a valuable means of detecting early tumor response and following up treatments in an animal model.

Key Words: VEGF • ovarian cancer • angiogenesis • metastasis

Grant support: Associazione Italiana per la Ricerca sul Cancro, Fondazione Cariplo, Ministero della Salute (Italy), and European Union FP6 LSHC-CT-2003-503233 and 503297. The generous contribution of the Nerina and Mario Mattioli Foundation is gratefully acknowledged. E. Naumova is the recipient of a fellowship from the Monzino Foundation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 11/15/04; revised 2/21/05; accepted 3/15/05.

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