The growth of solid malignant tumors is critically dependent upon the angiogenic switch, a hallmark of tumor pathophysiology. Despite the continuous formation of new blood vessels, vascular supply often remains qualitatively and quantitatively insufficient relative to the oxygen demand of the tumor cells and with regard to the unique microarchitecture found in solid malignancies, leading to areas of tissue hypoxia. Hypoxia-inducible factor (HIF)-1a controls an evolutionary highly conserved response to low oxygen levels, and this transcription factor is often overexpressed in hypoxic tumor microregions. Among many proteins, HIF-1a strongly induces the expression of the pro-angiogenic cytokine vascular endothelial growth factor (VEGF). Owing to this fact, angiogenesis in solid malignancies is widely regarded to be a primarily hypoxia-driven process. HIF-1a also activates mechanisms which lead to hypoxic adaptation, e.g., by inducing high-capacity membrane-bound glucose transporter (GLUT)-1 molecules. Angiogenesis and activation of a hypoxia-tolerant, glycolytic metabolism are often assumed to be mutually supportive processes, aimed at maximizing cell survival. However, this study presents evidence supporting a concept in which the intensity of angiogenesis is primarily determined by the state of metabolic adaptation of tumor-initiating cells, rather than being a function of HIF-activation during growth. Using invasive oxygen electrode measurements and image-analysis of intercapillary distances, we demonstrate that cells "conditioned" in extremely hypoxic / anoxic ascites in vivo form poorly vascularized, hypoxic tumors in rats. Allografted DS-sarcomas show a strong activation of HIF-1a and GLUT-1, as assessed by immunohistochemical expression analyses in tissue sections. Conversely, tumor-initiating cells derived from normoxic cell culture in vitro form highly angiogenic, normoxic tumors with significantly lower expression of HIF-1a and GLUT-1. These data emphasize the need for a more detailed analysis of the relative importance of the multitude of stimuli (redundancy in biological mechanisms) that can induce and support VEGF expression and angiogenesis beyond the HIF-system. Our investigation regarding the relationship between adaptive and angiogenic processes in solid tumors is of special interest for the conceptualization of treatment regimens which include inhibitors of angiogenesis.