The Angiogenic Switch

Generally, blood vessel formation takes place when the stimulatory effects of proangiogenic molecules surpass the inhibitory effects of antiangiogenic molecules. More specifically, the magnitude and actual pattern of the blood vessel formation depends upon the precise timing, distribution, and absolute and relative expression levels of these angiogenic factors. In turn, expression of these factors is initiated by various genetically programmed triggers that have been designated "angiogenic switches."106,107 Within the pathophysio-logic context of tumor-associated blood vessel formation, these switches are clinically and phenotypically important insofar as their activation is one hallmark of an aggressive, metastatic phenotype.

Within the tumor microenvironment, an angiogenic switch may be activated in response to an altered physiologic milieu. For example, when a burgeoning tumor outgrows its blood supply and creates a circumstance of tissue hypoxia, there occurs a reactive increased expression of multiple genes including, among others, hypoxia-inducible factor 1 (HIF-1).108,109 HIF-1, in turn, modulates an angiogenic cascade involving expression of a multitude of proangiogenic factors including VEGF110-112 and FGF.113 Other physiologic perturbations such as hypoglycemia114 and ischemia115 may also lead to activation of an angiogenic switch.

The angiogenic switch, in addition to the increased levels of VEGF and FGF, may also comprise increased expression of proangiogenic matrix metalloproteinases,116,117 the downregu-lation of antiangiogenic factors,118 activation of oncogenes, or inactivation of tumor suppressor genes.114,115,119,120 Activation of angiogenesis may also derive from the cumulative acquisition of proangiogenic genetic elements over time, for example, through the horizontal transfer of DNA among neighboring tumor cells.121 Ultimately, elucidation of the molecular basis of the angiogenesis activation will yield additional insight into mechanisms of tumor progression and allow for effective targeting of tumor metastasis.122

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