Generation of a syngeneic mouse model to study the effects of vascular endothelial growth factor in ovarian carcinoma.
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.
Zhang
Lin
L
Center for Research on Reproduction and Women's Health, University of Pennsylvania, 421 Curie Boulevard, Philadelphia, PA 19104, USA.
Yang
Nuo
N
Garcia
Jose-Ramon Conejo
JR
Mohamed
Alisha
A
Benencia
Fabian
F
Rubin
Stephen C
SC
Allman
David
D
Coukos
George
G
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology; D001201:Ascites / Q000378:metabolism; D019496:Cancer Vaccines / Q000276:immunology / Q000378:metabolism; D002277:Carcinoma / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002469:Cell Separation; D017690:Cell Transplantation; D002945:Cisplatin / Q000494:pharmacology; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008222:Lymphokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D010051:Ovarian Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000378:metabolism / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008164:Luminescent Proteins; D008222:Lymphokines; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D049452:Green Fluorescent Proteins; D002945:Cisplatin