Glioblastoma multiforme (GBM) is the most malignant of the primary brain cancers with only about 12 % of patients surviving beyond 36 months (longterm survivors).1–4 Most GBMs are heterogeneous in cellular composition consisting of tumor stem cells, malignantly transformed mesenchymal cells, and host stromal cells; hence, the name ‘glioblastoma multiforme.’5–11 Primary GBM appears to arise de novo, while secondary GBM is thought to arise from low-grade gliomas.7,12,13 The incidence and timing of malignant progression from low-grade glioma to GBM is variable and unpredictable.14 In addition to the neoplastic cell populations, tumor-associated macrophages/monocytes (TAM) also comprise a significant cell population in GBM sometimes equaling the number of tumor cells.15–20 TAM can indirectly contribute to tumor progression through release of pro-inflammatory and pro-angiogenic factors.16,18,20,21 Neoplastic cells with myeloid/macrophage characteristics (CD68 expression) can also contribute to the sarcomatoid characteristics of GBM.5,11,12,22 We suggested that many cells appearing as TAM within GBM could be neoplastic with properties of macrophages/ microglia.22 Using the secondary structures of Scherer, the neoplastic cells in GBM invade through the neural parenchyma well beyond the main tumor mass, making complete surgical resections exceedingly rare.2,23–26 Although systemic metastasis is rare for GBM, GBM cells can be metastatic if given access to extraneural sites.27–31 Despite extensive analysis from the cancer genome projects, no mutation is known that is unique to the GBM and no genetic alterations are seen in major signaling pathways in about 15 % of GBM.32,33 Moreover, few of the personalized molecular markers available are considered important for GBM analysis or therapy.34 Recent evidence also suggests that the genomic abnormalities seen in cancer cells arise as downstream secondary effects of disturbed energy metabolism and are unlikely to provide useful information for therapeutic treatment strategies for the majority of GBM patients.13,35,36
The Current Standard of Care for Glioblastoma
The current standard of care (SOC) for GBM and many malignant brain cancers includes maximum surgical resection, radiation therapy, and chemotherapy.2,3,37,38 The toxic alkylating agent temozolomide (TMZ) is the most common chemotherapy used for treating GBM. Most GBM patients also receive perioperative corticosteroids (dexamethasone), which are often extended throughout the course of the disease.39,40 There have been no major advances in GBM management for over 50 years, though use of TMZ has produced marginal improvement in patient survival over radiation therapy alone.3,41 Marginal benefits from the use of TMZ are also observed in those GBM patients who express promoter methylation of their DNArepair enzyme O6-methylguanine DNA methyltransferase (MGMT) gene.42,43
Despite conventional treatments, prognosis remains poor for most patients with high-grade brain tumors (see Figure 1).2–4,37,41,44,45 The optimal therapeutic strategy for recurrent high-grade gliomas is unknown, and an effective SOC does not exist. Re-irradiation together with the antiangiogenic drug, bevacizumab (Avastin®), is also often offered to some GBM patients with recurrent disease despite the removal of bevacizumab for breast cancer due to toxicity and lack of efficacy by the US Food and Drug Administration (FDA).46–48 Bevacizumab treatment increases progression-free survival in GBM patients, but does not increase overall patient survival.49 It seems that bevacizumab treatment delays the time-to-progression by technically changing the magnetic resonance imaging (MRI) findings. Bevacizumab substantially decreases contrast enhancement on T1-weighted MRI in recurrent GBM compared with highdose dexamethasone suggesting that the major benefit of bevacizumab is in its anti-edema action. Consequently, bevacizumab appears to act like steroids in reducing edema, but not in killing the most invasive tumor cells.
Do the Current Standard Treatments for Glioblastoma Multiforme Enhance Recurrenceand Progression through Effects on Energy Metabolism?
Emerging evidence indicates that cancer is primarily a disease of energy metabolism.35,50 In light of this information it is our view that the current SOC for GBM and other malignant brain cancers could contribute to tumor recurrence and progression through effects on tumor cell metabolism. Our suggestion comes from new information describing how the SOC can enhance the availability of glucose and glutamine within the tumor microenvironment.18,47,51 Glucose and glutamine are major drivers of tumor cell energy metabolism.48,52–54 It is well documented that neurotoxicityfrom mechanical trauma (surgery), radiation therapy, and chemotherapy, will increase tissue inflammation and glutamate levels.24,55–58 Damage to brain tissue can induce hyperglycolysis and an increased demand for glucose.59 Necrotic brain injury can arise from radiotherapy.60,61 Tumor radiation will also up-regulate the PI3K/Akt signaling pathway, which drives glioma glycolysis and chemotherapeutic drug resistance.62–66 Fatigue is not uncommon in GBM patients that receive the SOC.67,68 Radiation of tissues is known to induce systemic inflammation, which is suggested to underlie the fatigue associated with cancer therapy.69 It is not yet clear if the fatigue seen in some GBM patients might arise in part from brain irradiation or from other toxic effects of SOC. Tissue inflammation also enhances local hypoxia while providing a plethora of growth factors that facilitate angiogenesis and tumor cell rescue.18 Local astrocytes rapidly clear extracellular glutamate, metabolizing it to glutamine for release to neurons.70 In the presence of dead or dying neurons, however, surviving tumor cells and the TAM will use astrocyte-derived glutamine for their energy and growth. TAM also release pro-angiogenic growth factors, which further stimulate tumor progression.18,20,48 Most neoplastic GBM cells are infected with human cytomegalovirus (HCMV), which could further accelerate tumor cell growth through increased metabolism of glucose and glutamine.71,72 In contrast to normal glia that metabolize glutamate to glutamine, Takano and co-workers showed that neoplastic glioma cells secrete glutamate.55 Glioma glutamate secretion is thought to contribute in part to neuronal excitotoxicity and tumor expansion.55 Lawrence and co-workers suggested that survival was better for glioma patients who experienced less neurologic toxicity than for patients who experienced more neurologic toxicity.73 It appears that therapies that enhance neurotoxicity could facilitate GBM progression. This raises the question of whether the current SOC creates a metabolic environment that could promote GBM progression.
In addition to the potential tumor-enhancing effects of radiation and HCMV on GBM energy metabolism, most GBM patients are also given glucocorticoids (dexamethasone).40 Although dexamethasone is given to reduce radiation-associated brain swelling and tumor edema, dexamethasone elevates blood glucose levels.64,74–78 Glucose fuels the Warburg effect as well as serving as a precursor for glutamate synthesis and nucleotide synthesis through the pentose phosphate pathway.35,50,70,79,80 It is not likely that therapies, which elevate blood glucose, will improve patient survival. Indeed, prognosis was considered worse for glioma patients with higher blood glucose levels than in patients with lower glucose levels.81,82 These observations in GBM patients support our original work in a preclinical glioma model.78
Could Metabolic Therapy Become a Viable Alternative to the Standard of Care for Managing Glioblastoma?
Little progress has been made in the long-term management of glioblastoma multiforme (GBM) for more than 40 years. The current standard of care (SOC) for GBM involves radiotherapy with concomitant adjuvant temozolomide chemotherapy. Perioperative corticosteroids are also administered to the majority of GBM patients. The current standard treatment strategy for GBM increases availability of glucose (from steroids) and glutamine (from radio-necrosis) in the tumor microenvironment. Emerging evidence indicates that GBM, like most cancers, is a metabolic disease displaying a robust Warburg effect. It is well documented that glucose and glutamine are major metabolic fuels that drive tumor progression. Recent evidence suggests that neoplastic cells with macrophage/microglia properties can contribute to the most invasive cellsubpopulation within GBM. Glucose and glutamine are major fuels for myeloid cells as well as for the more rapidly proliferating cancer cells. Metabolic therapy exploits the biological differences between tumor cells and normal cells for the non-toxic targeting of the tumor cells. Studies in preclinical models show that calorie restricted ketogenic diets (KD-R), anti-glycolytic drugs, and hyperbaric oxygen therapy can reduce availability of glucose and glutamine in the tumor microenvironment while enhancing oxidative stress in tumor cells. The predominant ketone body (b-hydroxybutyrate) reduces oxidative stress in normal brain cells. The potential success of metabolic therapy was also seen in human glioma case studies suggesting that this therapeutic strategy could become a viable alternative to the SOC.
An erratum to this article can be found below.
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