Thesis or Dissertation Pigment epithelium-derived factor inhibits the growth of human esophageal squamous cell carcinoma by suppressing neovascularization.

角谷, 昌俊

Introduction: Neovascularization consists of angiogenesis and vasculogenesis during which bone marrow-derived endothelial progenitor cells (EPCs) are mobilized for blood vessel formation. Pigment epithelium-derived factor (PEDF) is known to be a potent inhibitor of angiogenesis in some solid carcinomas. However, the effects of PEDF on human esophageal squamous cell carcinoma (ESCC) and vasculogenesis are still unknown. The purpose of this research was to investigate the effect of PEDF on angiogenesis, tumor growth, and vasculogenesis in ESCC.Materials and Methods: The PEDF gene was transduced to the TE8 ESCC cell line not secreting endogenous PEDF and the HEC46 cell line originally secreting endogenous PEDF by lentivirus-based vectors expressing PEDF. In vitro endothelial cell proliferation and migration assays were performed using the supernatant derived from PEDFoverexpressing cells. In in vivo experiments, the effects of PEDF on chronological tumor growth, intratumoral microvessel density (MVD), tumor cell apoptosis, and the frequency of EPCs in peripheral blood and tumor tissues were examined in murine subcutaneous tumor models.Results: PEDF inhibited endothelial cell proliferation and migration in vitro and showed potent in vivo antitumor properties by inhibiting MVD in the human ESCC cell line that did not secrete endogenous PEDF. However, in the cell line secreting endogenous PEDF, additional PEDF gene transfer showed no inhibition of angiogenesis and no subsequent antitumor properties. With respect to vasculogenesis, PEDF was found to have potential to suppress vasculogenesis; the frequency of EPCs both in peripheral blood and tumor tissue was decreased in mice implanted with PEDFoverexpressing TE8 and HEC46 cells.Conclusion: PEDF may have potent antiangiogenic and antitumor effects in ESCC cells naturally not secretingendogenous PEDF and can be expected to be applied as gene therapy in the future.
Hokkaido University(北海道大学). 博士(医学)

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