MOLECULAR STUDIES OF VPF/VEGF

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The long-term objectives for this proposal are to identify the molecular mechanisms of tumor-related angiogenesis with the purpose of developing therapeutic approaches to reducing the morbidity and mortality associated with human cancers. Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) has been identified as an endothelial growth factor which is widely expressed in important human cancers including glioblastoma multiforme, gastrointestinal adenocarcinoma, Kaposi's sarcoma, breast carcinoma and renal cell carcinoma. Expression of VPF/VEGF also occurs in other human diseases which demonstrate vascular proliferation and hyperpermeability; namely, rheumatoid arthritis, psoriasis and diabetic retinopathy. This proposal will address two basic questions: 1. What is the role of VPF/VEGF in tumor-associated angiogenesis and tumor growth? 2. What role does VPF/VEGF play in the primary angiogenesis of normal development? The role of VPF/VEGF in tumor- related angiogenesis will be tested directly in vivo with rodent tumor models. Tumor cells will be developed that overexpress VPF/VEGF or whose expression of VPF/VEGF has been inhibited. Several tumor cell lines express variable levels of VPF/VEGF under hypoxic conditions, an important phenomenon occurring during tumor progression. Surprisingly, the ability of different tumor cell types to respond to hypoxia by induction of VPF/VEGF production directly correlates to their tumorigenicity in nude mice. Stable transfected tumor cells expressing increased or reduced levels of VPF/VEGF will be implanted in vivo and tumor growth rate, histology, vascularization and expression of VPF/VEGF and VPF/VEGF receptors will be evaluated. These tumor models will define the role of VPF/VEGF in tumor development, particularly addressing whether the expression of VPF/VEGF is a key cytokine which positively affects tumor growth and angiogenesis. The role of VPF/VEGF in normal primary angiogenesis occurring in mammalian development will be evaluated in vivo by developing transgenic animal models which either repress or overexpress VPF/VEGF. These transgenic lines will help to delineate the function of VPF/VEGF in relation to both temporal and spatial events required for proper adipose tissue and organ development. Collectively, these experiments will define the function of VPF/VEGF in tumor growth and normal angiogenesis and will determine whether VPF/VEGF is an appropriate target for therapeutic intervention in human pathologies such as cancer.