Metabolic advantages and vulnerabilities in brain metastases

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.

Adenosine A2A receptor activation reduces brain metastasis via SDF‐1/CXCR4 axis and protecting blood‐brain barrier

“…Besides, the presence of BBB that isolates brain tissues from surrounding circulation also complicates the mechanism of brain metastasis and management strategies of brain tumor 22 . Tight junction proteins including claudin, occluding and Zo‐1 connect brain endothelial cells to form a physical obstruction, which not only blocks the circulating tumor cells from entering the brain parenchyma but also resists the seeded brain tumor cells 23 . Demonstrating the mechanism of primary tumor cells migration to the brain is urgent, and obstructing the process is undoubtedly more efficient and effective compared to treating secondary tumor in the brain afterward.…”

Inhibition of GLO1 in Glioblastoma Multiforme Increases DNA-AGEs, Stimulates RAGE Expression, and Inhibits Brain Tumor Growth in Orthotopic Mouse Models

“…GBMs may display the Warburg effect as a metabolic adaptation for survival advantage and therapeutic resistance. This metabolic remodeling from predominantly mitochondrial oxidative phosphorylation (OXPHOS) towards cytoplasmic glycolysis may promote tumor proliferation within the hypoxic tumor microenvironment while taking advantage of elevated glucose flux within the neural niche [ 3 , 4 ].…”

Onco-metabolism: defining the prognostic significance of obesity and diabetes in women with brain metastases from breast cancer

“…The availability of glucose within the CNS, however, bestows a metabolic advantage upon breast cancer, as it is conducive to the War-burg-like metabolic reprogramming from oxidative phosphorylation toward a glycolytic metabolic preference [15, 28]. IGF-1 availability is also increased in states of obesity and insulin resistance [29], and activation of the IGF-1R axis has been implicated as a key mediator of breast cancer radioresistance [30].…”