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(American Journal of Pathology. 2002;161:2295-2309.)
© 2002 American Society for Investigative Pathology

Animal Models

Generation of a Syngeneic Mouse Model to Study the Effects of Vascular Endothelial Growth Factor in Ovarian Carcinoma

Lin Zhang^*, Nuo Yang, Jose-Ramon Conejo Garcia^*, Alisha Mohamed^*, Fabian Benencia^*, Stephen C. Rubin, David Allman and George Coukos^*

From the Center for Research on Reproduction and Women’s Health;^* the Cellular and Molecular Biology Program and Department of Genetics; the Department of Obstetrics and Gynecology, Division of Gynecologic Oncology; and the Abramson Family Cancer Research Institute; University of Pennsylvania, Philadelphia, Pennsylvania

Abstract

Vascular endothelial growth factor (VEGF) performs multifaceted functions in the tumor microenvironment promoting angiogenesis, suppressing anti-tumor immune response, and possibly exerting autocrine functions on tumor cells. However, appropriate syngeneic animal models for in vivo studies are lacking. Using retroviral transfection and fluorescence-activated cell sorting, we generated a C57BL6 murine ovarian carcinoma cell line that stably overexpresses the murine VEGF164 isoform and the enhanced green fluorescent protein. VEGF164 overexpression dramatically accelerated tumor growth and ascites formation, significantly enhanced tumor angiogenesis, and substantially promoted the survival of tumor cells in vivo. In vitro, VEGF164 overexpression significantly enhanced cell survival after growth factor withdrawal and conferred resistance to apoptosis induced by cis-platin through an autocrine mechanism. VEGF/green fluorescent protein-expressing tumors were not recognized by the adaptive immune system. After vaccination, a specific anti-tumor T-cell response was detected, but tumor growth was not inhibited. This engineered murine carcinoma model should prove useful in the investigation of the role of VEGF in modulating the tumor microenvironment and affecting the complex interactions among angiogenesis mechanisms, anti-tumor immune mechanisms, and tumor cell behavior at the natural state or during therapy in ovarian carcinoma.

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