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Metabolic advantages and vulnerabilities in brain metastases

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Abstract

Metabolic adaptations permit tumor cells to metastasize to and thrive in the brain. Brain metastases continue to present clinical challenges due to rising incidence and resistance to current treatments. Therefore, elucidating altered metabolic pathways in brain metastases may provide new therapeutic targets for the treatment of aggressive disease. Due to the high demand for glucose in the brain, increased glycolytic activity is favored for energy production. Primary tumors that undergo Warburg-like metabolic reprogramming become suited to growth in the brain microenvironment. Indeed, elevated metabolism is a predictor of metastasis in many cancer subtypes. Specifically, metabolic alterations are seen in primary tumors that are associated with the formation of brain metastases, namely breast cancer, lung cancer, and melanoma. Because of this selective pressure, inhibitors of key metabolic factors may reduce tumor cell viability, thus exploiting metabolic pathways for cancer therapeutics. This review summarizes the metabolic advantages and vulnerabilities of brain metastases.

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Fig. 1

Reprinted by permission from Elsevier: Cell Press, copyright 2014 [26]

Fig. 2

Reprinted by permission from Macmillan Publishers Ltd: Nature, copyright 2015 [32]

Fig. 3
Fig. 4

Reprinted by permission from Elsevier: Advanced Drug Delivery Reviews, copyright 2011 [75]

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Abbreviations

AGPS:

Alkylglyceronephosphate synthase

BMs:

Brain metastases

BBB:

Blood–brain barrier

CCL2:

Chemokine C–C motif ligand 2

EGFR:

Epidermal growth factor receptor

EPR:

Enhanced permeability and retention

ER:

Estrogen receptor

FDG:

Fluorodeoxyglucose

FOXO3a:

Forkhead box O 3a

GABA:

Gamma-aminobutyric acid

GSTP1:

Glutathione S-transferase Pi 1

HER2:

Human epidermal growth factor receptor 2

MAGL:

Monoacylglycerol lipase

MCT1:

Monocarboxylic acid transporter 1

NMRl:

Nuclear magnetic resonance

NSCLC:

Non-small cell lung carcinoma

PET:

Positron emission tomography

PI3K:

Phosphoinositide 3-kinase

PTEN:

Phosphatase and tensin homolog

SCLC:

Small cell lung carcinoma

TXNIP:

Thioredoxin-interacting protein

TNBC:

Triple negative breast cancer

WBRT:

Whole brain radiation therapy

VEGF:

Vascular endothelial growth factor

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Funding

Funding was provided by National Cancer Institute (Grant No. R01CA176611 to J.T.).

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Authors and Affiliations

  1. Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope, Duarte, CA, USA

    Alexandra K. Ciminera

  2. Department of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA, USA

    Alexandra K. Ciminera & John Termini

  3. Division of Neurosurgery, Beckman Research Institute, City of Hope, Duarte, CA, USA

    Rahul Jandial

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Ciminera, A.K., Jandial, R. & Termini, J. Metabolic advantages and vulnerabilities in brain metastases. Clin Exp Metastasis 34, 401–410 (2017). https://doi.org/10.1007/s10585-017-9864-8

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