Cancer Letters

Cancer Letters

Volume 356, Issue 2, Part A, 28 January 2015, Pages 289-300
Cancer Letters

Mini-review
Metabolic therapy: A new paradigm for managing malignant brain cancer

https://doi.org/10.1016/j.canlet.2014.07.015Get rights and content

Highlights

  • Abnormal energy metabolism is the common malady of all brain tumor cells.

  • The heterogeneous mutations in gliomas and most cancers can arise as a consequence of destabilized energy metabolism.

  • The current standard of care might contribute to the pathology and progression of malignant brain tumors.

  • Normal mitochondrial function can suppress tumorigenesis.

  • Calorie restriction and restricted ketogenic diets are non-toxic metabolic therapies for brain cancer management.

Abstract

Little progress has been made in the long-term management of glioblastoma multiforme (GBM), considered among the most lethal of brain cancers. Cytotoxic chemotherapy, steroids, and high-dose radiation are generally used as the standard of care for GBM. These procedures can create a tumor microenvironment rich in glucose and glutamine. Glucose and glutamine are suggested to facilitate tumor progression. Recent evidence suggests that many GBMs are infected with cytomegalovirus, which could further enhance glucose and glutamine metabolism in the tumor cells. Emerging evidence also suggests that neoplastic macrophages/microglia, arising through possible fusion hybridization, can comprise an invasive cell subpopulation within GBM. Glucose and glutamine are major fuels for myeloid cells, as well as for the more rapidly proliferating cancer stem cells. Therapies that increase inflammation and energy metabolites in the GBM microenvironment can enhance tumor progression. In contrast to current GBM therapies, metabolic therapy is designed to target the metabolic malady common to all tumor cells (aerobic fermentation), while enhancing the health and vitality of normal brain cells and the entire body. The calorie restricted ketogenic diet (KD-R) is an anti-angiogenic, anti-inflammatory and pro-apoptotic metabolic therapy that also reduces fermentable fuels in the tumor microenvironment. Metabolic therapy, as an alternative to the standard of care, has the potential to improve outcome for patients with GBM and other malignant brain cancers.

Section snippets

Glioblastoma multiforme (GBM)

GBM is the most malignant of the primary brain cancers with only about 12% of patients surviving beyond 36 months (long-term survivors) [1], [2], [3]. Most glioblastomas are heterogeneous in cellular composition consisting of tumor stem cells, mesenchymal cells, and host stromal cells [4], [5], [6], [7], [8], [9]. Primary GBM can arise de novo, whereas secondary GBM is thought to arise from lower-grade gliomas [6], [10], [11]. The timing and incidence of malignant progression from low-grade

Standard of care for malignant glioma

The current standard of care for GBM and many malignant brain cancers includes maximum surgical resection, radiation therapy, and chemotherapy [2], [55], [56], [57]. The toxic alkylating agent, temozolomide (TMZ), is the most common chemotherapy used for treating GBM. The most common adverse events of TMZ exposure besides hematological toxicities are alopecia, nausea, vomiting, anorexia, headache, and constipation. These adverse effects have been described on the NCI web site (//www.cancer.gov

Mitochondrial abnormalities in malignant brain tumors

Substantial evidence collected from numerous investigators over many years indicates that abnormalities in mitochondrial structure and function are the hallmark of most cancers including brain cancer [69], [70], [71], [72], [73], [74]. These mitochondrial abnormalities will reduce energy production through oxidative phosphorylation (OxPhos) [69], [70], [71], [72], [75], [76], [77], [78], [79], [80], [81], [82], [83], [84], [85], [86]. Although pathological mitochondrial DNA (mtDNA) mutations

The Warburg effect in malignant brain tumors

Otto Warburg first proposed that all cancers arise from irreversible damage to cellular respiration. As a result, cancer cells increase their capacity to ferment lactate even in the presence of oxygen in order to compensate for their insufficient respiration [108], [109]. Although confusion has surrounded Warburg’s hypothesis on the origin of cancer cells [39], [110], [111], his hypothesis has never been formally disproved and remains a credible explanation for the origin of tumor cells [39],

Role of glucose and glutamine in brain tumor progression

Glucose is the predominant fuel of the brain, but also fuels tumor cell glycolysis as well as serving as a precursor for glutamate synthesis [107], [109], [153], [154]. Using linear regression analysis, we showed that the growth rate of the CT-2A experimental mouse astrocytoma was directly dependent on blood glucose levels [153]. The higher the blood glucose levels, the faster the tumors grew. As glucose levels fall, tumor size and growth rate falls. Hyperglycemia not only contributes to rapid

Does the current standard of care accelerate GBM recurrence and progression through effects on energy metabolism?

It is our view that the current standard of care for managing GBM and other malignant brain cancers will contribute to tumor recurrence and progression. This prediction comes from information describing how the standard of care can enhance the availability of glucose and glutamine within the tumor microenvironment [16], [130], [176]. It is well documented that neurotoxicity from mechanical trauma (surgery), radiotherapy, and chemotherapy, can increase tissue inflammation and glutamate levels

The calorie restricted ketogenic diet as a non-toxic metabolic therapy for brain cancer

Emerging evidence suggests that metabolic therapies using ketogenic diets that lower glucose levels can help retard GBM growth in younger and older patients [227], [228], [229]. Restricted diets are those that deliver fewer total calories in order to lower circulating glucose and insulin levels. We found that the KD reduced brain cancer growth and angiogenesis in mice only when administered in restricted amounts [65], [153], [210]. The importance of this point cannot be overemphasized, as

Conflict of interest

None of the authors have a conflict of interest.

Acknowledgements

This work was supported in part from NIH - United States Grants (HD-39722, NS-1080 55195, and CA-102135), a Grant from the American Institute of Cancer Research, and the Boston College Expense Fund. We thank Dr. Giulio Zuccoli and Jeremy Marsh for helpful comments, which were included in our similar review published in “Oncology & Hematology Reviews” and cited as reference 176 in the current review.

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