HIF-lα als Regulator von Tumorangiogenese, Gefäßmorphologie und Wachstum des Adenokarzinoms des Magens

Abstract

The hypoxia inducible factor-1α (HIF-lα) is an important transcription factor for mediating vascular endothelial growth factor (VEGF) expression in solid tumors. We hypothesized that inhibition of HIF-1α in human gastric cancers cells would significantly impair angiogenesis and tumor growth in vivo. Gastric cancer cells (TMK-1) were stably transfected with a dominant-negative HIF-lα construct (HIF-lαDN) or vector alone (pCEP4) as control. Transfected cells were screened for nuclear HIF-lα expression by Western blot. Differences in VEGF secretion were detected by ELISA. Growth rates of HIF-lαDN and pCEP4 cells were first investigated in a subcutaneous (SQ) xenograft model, and subsequently in an orthotopic model of gastric cancer in mice. Vessel area (measure of functional vascular volume), proliferating tumor cells, and vessel pericyte coverage were evaluated by immunohistochemistry. HIF-1α inhibition led to a 60 - 70% reduction of constitutive VEGF secretion (P < 0.05). VEGF secretion was also blunted in DN cells in response to hypoxia (P< 0.05). In the SQ model, HIF-lαDN cells exhibited significantly reduced tumor growth, vessel area, and tumor cell proliferation (P < 0.05 for all). Similar findings were observed in the orthotopic model, where tumor growth, vessel area and vessel morphology (pericyte coverage) were significantly impaired in the HIF-lαDN groups (P < 0.05 for both). In conclusion, HIF-lα may be a viable molecular target for inhibiting angiogenesis and growth of gastric cancer.