VEGF MESSENGER-RNA IS REVERSIBLY STABILIZED BY HYPOXIA AND PERSISTENTLY STABILIZED IN VEGF-OVEREXPRESSING HUMAN TUMOR-CELL LINES

Solid tumor growth is dependent upon angiogenesis, a process by which soluble factors released from a tumor induce the sprouting and growth of new blood vessels from nearby venules into the tumor. This process of tumor vascularization provides tumor cells with nutrients, oxygen, and an enhanced ability to establish metastasis at peripheral sites by migration through the circulatory system. Vascular endothelial growth factor is a potent angiogenic factor that is expressed at low levels by most normal cells, can be upregulated in normal cells by exposure t o hypoxia or phorbol esters, and exhibits high levels of constitutive expression in some human tumors and tumor cell lines. The mechanism un derlying the-stable change that results in VEGF overexpression in tumo rs is unknown. Here, we demonstrate that both hypoxia and TPA induce s tabilization of VEGF mRNA, that stabilization by hypoxia is rapidly re versible upon reexposure to normoxia, and that tumor cell lines exhibi ting constitutive overexpression of VEGF also exhibit constitutive sta bilization of VEGF transcripts. Stabilized VEGF transcripts in tumor c ells are refractile or nearly refractile toward further stabilization by TPA or hypoxia, respectively. Furthermore, cycloheximide induces st abilization of VEGF mRNA in normal cells but has no effect on VEGF tra nscript stability in tumor cells that contain stabilized transcripts. These results suggest that normal signal transduction mechanisms media te stabilization of the VEGF mRNA, and that mutations in this regulato ry pathway in tumor cells may lead to chronic message stabilization, o verexpression of VEGF proteins, and ensuing tumor vascularization.