Interplay between HGF/SF‒Met-Ras signaling, tumor metabolism and blood flow as a potential target for breast cancer therapy
Sari Natan1,4,*, Galia Tsarfaty2,*, Judith Horev1, Roni Haklai3, Yoel Kloog3 and Ilan Tsarfaty1,*
1 Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University,
2 Department of Diagnostic Imaging, Chaim Sheba Medical Center, Ramat Gan, Israel,
3 Department of Neurobiology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
4 This work was done in partial fulfillment of the requirements for the Ph.D. degree of S.N.
* Equal contribution
Ilan Tsarfaty, email:
Keywords: HGF/Met/Ras as targets for therapy, Tumor metabolism, Functional molecular imaging
Received: December 1, 2013 Accepted: December 9, 2013 Published: December 11, 2013
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.