High
glucose uptake and increase blood flow is a characteristic of most metastatic
tumors. Activation of Ras signaling increases glycolytic flux into
lactate, de novo
nucleic acid synthesis and uncoupling of
ATP synthase from the
proton gradient. Met
tyrosine kinase receptor signaling upon activation by its
ligand,
hepatocyte growth factor/
scatter factor (HGF/SF), increases glycolysis, oxidative phosporylation, oxygen consumption, and
tumor blood volume. Ras is a key factor in Met signaling. Using the Ras inhibitor
S-trans,trans-farnesylthiosalicylic acid (FTS), we investigated interplay between HGF/SF-Met-Ras signaling, metabolism, and
tumor blood-flow regulation. In vitro, HGF/SF-activated Met increased Ras activity, Erk phosphorylation, cell motility and
glucose uptake, but did not affect
ATP. FTS inhibited basal and HGF/SF-induced signaling and cell motility, while further increasing
glucose uptake and inhibiting
ATP production. In vivo, HGF/SF rapidly increased
tumor blood volume. FTS did not affect basal blood-flow but abolished the HGF/SF effect. Our results further demonstrate the complex interplay between
growth-factor-receptor signaling and cellular and
tumor metabolism, as reflected in blood flow. Inhibition of Ras signaling does not affect
glucose consumption or basal
tumor blood flow but dramatically decreases
ATP synthesis and the HGF/SF induced increase in
tumor blood volume. These findings demonstrate that the HGF/SF-Met-Ras pathway critically influences
tumor-cell metabolism and
tumor blood-flow regulation. This pathway could potentially be used to individualize
tumor therapy based on functional molecular imaging, and for combined signaling/anti-metabolic targeted
therapy.