PMID- 25593982
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20150116
LR  - 20201001
IS  - 2331-4737 (Print)
IS  - 2331-4737 (Electronic)
IS  - 2331-4737 (Linking)
VI  - 1
IP  - 1
DP  - 2014
TI  - Interplay Between HGF/SF-Met-Ras Signaling, Tumor Metabolism and Blood Flow as a 
      Potential Target for Breast Cancer Therapy.
PG  - 30-38
AB  - 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.
FAU - Natan, Sari
AU  - Natan S
AD  - Department of Clinical Microbiology and Immunology, Sackler School of Medicine, 
      Tel Aviv University.
AD  - This work was done in partial fulfillment of the requirements for the Ph.D. 
      degree of S.N.
FAU - Tsarfaty, Galia
AU  - Tsarfaty G
AD  - Department of Diagnostic Imaging, Chaim Sheba Medical Center, Ramat Gan, Israel.
FAU - Horev, Judith
AU  - Horev J
AD  - Department of Clinical Microbiology and Immunology, Sackler School of Medicine, 
      Tel Aviv University.
FAU - Haklai, Roni
AU  - Haklai R
AD  - Department of Neurobiology, The George S. Wise Faculty of Life Sciences, Tel Aviv 
      University, Tel Aviv, Israel.
FAU - Kloog, Yoel
AU  - Kloog Y
AD  - Department of Neurobiology, The George S. Wise Faculty of Life Sciences, Tel Aviv 
      University, Tel Aviv, Israel.
FAU - Tsarfaty, Ilan
AU  - Tsarfaty I
AD  - Department of Clinical Microbiology and Immunology, Sackler School of Medicine, 
      Tel Aviv University.
LA  - eng
PT  - Journal Article
DEP - 20131211
PL  - United States
TA  - Oncoscience
JT  - Oncoscience
JID - 101636666
PMC - PMC4295761
OTO - NOTNLM
OT  - Functional molecular imaging
OT  - HGF/Met/Ras as targets for therapy
OT  - Tumor metabolism
EDAT- 2015/01/17 06:00
MHDA- 2015/01/17 06:01
PMCR- 2013/12/11
CRDT- 2015/01/17 06:00
PHST- 2013/12/01 00:00 [received]
PHST- 2013/12/09 00:00 [accepted]
PHST- 2015/01/17 06:00 [entrez]
PHST- 2015/01/17 06:00 [pubmed]
PHST- 2015/01/17 06:01 [medline]
PHST- 2013/12/11 00:00 [pmc-release]
AID - 10.18632/oncoscience.6 [doi]
PST - epublish
SO  - Oncoscience. 2013 Dec 11;1(1):30-38. doi: 10.18632/oncoscience.6. eCollection 
      2014.