Analyses of tumor angiogenesis and development of antiangiogenic gene therxpy

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1. Analyses of tumor angiogenesis from the viewpoint of microstructureVascular endothelial growth factor (VEGF) plays a central role in tumor angiogenesis. In a mouse tumor model using VEGF-transfected HT1080 human fibrosarcoma cell, we investigated morphological features and remodeling patterns of tumor angiogenesis by transmission electron microscope. VEGF-transfected tumors showed vigorous angiogenesis. Among three types of angiogenesis, I.e., sprouting, luminal division and intussusceptive microvascular growth, the number of abluminal processes leading to sprouting was significantly higher than control tumors. Mural cell coverage of endothelial cells was singificantly smaller in VEGF-transfectant. We evaluated microvessel density (MVD) and microvessel pericyte coverage index (MPI) using clinical specimen of colon cancer by immunohistochemical double staining with CD34 and α-SMA against endothelial cell and pericyte, respectively. The prognosis was poor in high-MVD group, especially … More , in high-MVD and low-MPI group. These results suggested that the interaction of endothelial cell and pericyte was a key role in tumor angiogenesis2. Development of antiangiogenic gene therapy for cancerWe reported that repeated in vivo transduction of mouse macrophage metalloelastase (MME) gene directly into the tumor of CT-26 mouse colon cancer using HVJ-cationic liposomes suppressed the tumor growth by an antiangiogenic mechanismWe reported that administration of autologous fibroblasts transfected with soluble form of Flt-1, a VEGF receptor, suppressed the tumor growth and prolonged the survival in the wound recurrence model of RCN-9 rat colon cancerWe investigated MVD representing aerobic metabolism and expression of hexiokinase II mRNA (HK II) representing anaerobic metabolism using clinical specimens of hepatocellular carcinoma and metastatic liver cancer from colon. MVD was significantly higher in hepatocellular carcinoma and HK II was significantly higher in metastatic liver cancer. We are developing a hypoxia-induced suicide gene system for treatment of angiogenesis-independent tumor Less