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Interplay Between HGF/SF-Met-Ras Signaling, Tumor Metabolism and Blood Flow as a Potential Target for Breast Cancer Therapy.

Natan S, Tsarfaty G, Horev J, Haklai R, Kloog Y, Tsarfaty I - Oncoscience (2013)

Bottom Line: 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.FTS did not affect basal blood-flow but abolished the HGF/SF effect.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University ; This work was done in partial fulfillment of the requirements for the Ph.D. degree of S.N.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Effect of RAS inhibition on tumor growthMice bearing DA3-xenograft mammary tumors were fed and treated as described in Materials and Methods. Tumors were measured by ultrasound, and their average growth at the end of the 3-week period of the experiment is presented as a bar chart. Compared to baseline, vehicle-treated tumors grew 17.8-fold (n = 7) on average, while tumors treated at the indicated periods with low-dose or high dose FTS grew 15.8-fold (n = 7) and 7.7-fold (n = 5), respectively. Compared to the average tumor size in the control group, tumor size after 3 weeks in the low-dose and high-dose FTS-treated groups were 88.6% (not significant) and 50.7% (P = 0.019), respectively.
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Figure 3: Effect of RAS inhibition on tumor growthMice bearing DA3-xenograft mammary tumors were fed and treated as described in Materials and Methods. Tumors were measured by ultrasound, and their average growth at the end of the 3-week period of the experiment is presented as a bar chart. Compared to baseline, vehicle-treated tumors grew 17.8-fold (n = 7) on average, while tumors treated at the indicated periods with low-dose or high dose FTS grew 15.8-fold (n = 7) and 7.7-fold (n = 5), respectively. Compared to the average tumor size in the control group, tumor size after 3 weeks in the low-dose and high-dose FTS-treated groups were 88.6% (not significant) and 50.7% (P = 0.019), respectively.

Mentions: FTS inhibits mammary tumor growth. Next, we examined the effect of Ras inhibition on mammary tumor growth. The effect of FTS treatment on tumor growth is depicted in Figure 3. Over the 3 weeks of the experiment, tumors in the control mice (treated with the vehicle alone 0.5% CMC) grew 17.8 fold, while tumors treated with 10 mg/kg FTS grew 15.8 fold (to 88.6% of tumor volume in the control group), and tumors treated with 40 mg/kg FTS grew 7.7 fold (to 50.7% of tumor volume in the control group; n = 12; P < 0.02) (Fig. 3). These results demonstrated that FTS treatment inhibits the growth of mammary tumors.


Interplay Between HGF/SF-Met-Ras Signaling, Tumor Metabolism and Blood Flow as a Potential Target for Breast Cancer Therapy.

Natan S, Tsarfaty G, Horev J, Haklai R, Kloog Y, Tsarfaty I - Oncoscience (2013)

Effect of RAS inhibition on tumor growthMice bearing DA3-xenograft mammary tumors were fed and treated as described in Materials and Methods. Tumors were measured by ultrasound, and their average growth at the end of the 3-week period of the experiment is presented as a bar chart. Compared to baseline, vehicle-treated tumors grew 17.8-fold (n = 7) on average, while tumors treated at the indicated periods with low-dose or high dose FTS grew 15.8-fold (n = 7) and 7.7-fold (n = 5), respectively. Compared to the average tumor size in the control group, tumor size after 3 weeks in the low-dose and high-dose FTS-treated groups were 88.6% (not significant) and 50.7% (P = 0.019), respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4295761&req=5

Figure 3: Effect of RAS inhibition on tumor growthMice bearing DA3-xenograft mammary tumors were fed and treated as described in Materials and Methods. Tumors were measured by ultrasound, and their average growth at the end of the 3-week period of the experiment is presented as a bar chart. Compared to baseline, vehicle-treated tumors grew 17.8-fold (n = 7) on average, while tumors treated at the indicated periods with low-dose or high dose FTS grew 15.8-fold (n = 7) and 7.7-fold (n = 5), respectively. Compared to the average tumor size in the control group, tumor size after 3 weeks in the low-dose and high-dose FTS-treated groups were 88.6% (not significant) and 50.7% (P = 0.019), respectively.
Mentions: FTS inhibits mammary tumor growth. Next, we examined the effect of Ras inhibition on mammary tumor growth. The effect of FTS treatment on tumor growth is depicted in Figure 3. Over the 3 weeks of the experiment, tumors in the control mice (treated with the vehicle alone 0.5% CMC) grew 17.8 fold, while tumors treated with 10 mg/kg FTS grew 15.8 fold (to 88.6% of tumor volume in the control group), and tumors treated with 40 mg/kg FTS grew 7.7 fold (to 50.7% of tumor volume in the control group; n = 12; P < 0.02) (Fig. 3). These results demonstrated that FTS treatment inhibits the growth of mammary tumors.

Bottom Line: 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.FTS did not affect basal blood-flow but abolished the HGF/SF effect.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University ; This work was done in partial fulfillment of the requirements for the Ph.D. degree of S.N.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus