Figure 2.
Regulation of angiogenesis by tumor microenvironment. (A) Relationship between VEGF promoter activity and local pO2 or pH in U87 glioma xenografts. Tumor cell VEGF promoter activity was determined by the intensity of GFP (which is driven by the VEGF promoter). Tissue pO2 and pH were determined by phosphorescence quenching microscopy with a porphyrin probe and fluorescence ratio-imaging microscopy with BCECF, respectively. Tissue pO2 level inversely correlated with VEGF promoter activity especially in the region with neutral pH (left) and hypoxic region (not shown). On the other hand, tissue pH level inversely correlated with VEGF promoter activity in the oxygenated area (right). (B) Imaging of VEGF promoter activity in host stromal cells: MCaIV murine breast cancer grown in the dorsal skin chamber of a transgenic mouse expressing GFP under the control of VEGF promoter. Left: high density of activated fibroblasts exhibiting strong VEGF promoter activity (in green) at the host-tumor interface. Blood vessels are contrast enhanced by tetramethylrhodamine-dextran. Right: in contrast, deeper (200 µm) inside the tumor the VEGF expressing host stromal cells (in green) closely associate with blood vessels (in red). The bar indicates 100 µm. (C) Angiogenesis and tissue NO level in B16F1 and F10 tumors grown in the dorsal skin chamber and the cranial window. Vessel density was determined by intravital microscopy and tissue NO level was measured by an NO sensitive recessed microelectrode. (D) Microangiography of B16F1 and F10 murine melanomas grown in the cranial window. A: adapted from ref. [44]; B, adapted from ref. [9]; C, D: adapted from ref. [84].