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Metabolic targeting of HIF-dependent glycolysis reduces lactate, increases oxygen consumption and enhances response to high-dose single-fraction radiotherapy in hypoxic solid tumors

Overview of attention for article published in BMC Cancer, June 2017
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Title
Metabolic targeting of HIF-dependent glycolysis reduces lactate, increases oxygen consumption and enhances response to high-dose single-fraction radiotherapy in hypoxic solid tumors
Published in
BMC Cancer, June 2017
DOI 10.1186/s12885-017-3402-6
Pubmed ID
Authors

Eric Leung, Rob A. Cairns, Naz Chaudary, Ravi N. Vellanki, Tuula Kalliomaki, Eduardo H. Moriyama, Hilda Mujcic, Brian C. Wilson, Bradly G. Wouters, Richard Hill, Michael Milosevic

Abstract

A high rate of glycolysis leading to elevated lactate content has been linked to poor clinical outcomes in patients with head and neck and cervical cancer treated with radiotherapy. Although the biological explanation for this relationship between lactate and treatment response remains unclear, there is a continued interest in evaluating strategies of targeting metabolism to enhance the effectiveness of radiotherapy. The goal of this study was to investigate the effect of metabolic-targeting through HIF-1α inhibition and the associated changes in glycolysis, oxygen consumption and response on the efficacy of high-dose single-fraction radiotherapy (HD-SFRT). HIF-1α wild-type and HIF-1α knockdown FaDu and ME180 xenograft tumors were grown in the hind leg of mice that were placed in an environmental chamber and exposed to different oxygen conditions (air-breathing and hypoxia). Ex vivo bioluminescence microscopy was used to measure lactate and ATP levels and the hypoxic fraction was measured using EF5 immunohistochemical staining. The oxygen consumption rate (OCR) in each cell line in response to in vitro hypoxia was measured using an extracellular flux analyzer. Tumor growth delay in vivo was measured following HD-SFRT irradiation of 20 Gy. Targeting HIF-1α reduced lactate content, and increased both oxygen consumption and hypoxic fraction in these tumors after exposure to short-term continuous hypoxia. Tumors with intact HIF-1α subjected to HD-SFRT immediately following hypoxia exposure were less responsive to treatment than tumors without functional HIF-1α, and tumors irradiated under air breathing conditions regardless of HIF-1α status. Blocking the HIF1 response during transient hypoxic stress increased hypoxia, reduced lactate levels and enhanced response to HD-SFRT. This strategy of combining hypofractionated radiotherapy with metabolic reprogramming to inhibit anaerobic metabolism may increase the efficacy of HD-SFRT through increased oxygen consumption and complementary killing of radiosensitive and hypoxic, radioresistant cells.

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Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 46 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 46 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 7 15%
Student > Master 7 15%
Student > Bachelor 7 15%
Researcher 5 11%
Student > Doctoral Student 2 4%
Other 7 15%
Unknown 11 24%
Readers by discipline Count As %
Medicine and Dentistry 13 28%
Biochemistry, Genetics and Molecular Biology 11 24%
Neuroscience 2 4%
Nursing and Health Professions 1 2%
Agricultural and Biological Sciences 1 2%
Other 5 11%
Unknown 13 28%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 31 August 2017.
All research outputs
#15,474,679
of 22,996,001 outputs
Outputs from BMC Cancer
#4,154
of 8,356 outputs
Outputs of similar age
#199,127
of 317,041 outputs
Outputs of similar age from BMC Cancer
#64
of 130 outputs
Altmetric has tracked 22,996,001 research outputs across all sources so far. This one is in the 22nd percentile – i.e., 22% of other outputs scored the same or lower than it.
So far Altmetric has tracked 8,356 research outputs from this source. They receive a mean Attention Score of 4.3. This one is in the 40th percentile – i.e., 40% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 317,041 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 28th percentile – i.e., 28% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 130 others from the same source and published within six weeks on either side of this one. This one is in the 43rd percentile – i.e., 43% of its contemporaries scored the same or lower than it.