Dietary Factors in Neurooncology

Anti-Cancer Diet
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Diet is a major environmental factor that can play a role in initial development, prevention, and progression of malignant brain tumours in both positive and negative ways. Although there are no components of the diet that are proven to be direct causes of brain tumours, certain components are consistently shown to be correlated with a higher incidence of brain cancer, while others are linked to a lower risk or are suggested to slow the progression of the tumour. N-nitroso compounds are elevated in diets higher in nitrites, and are suspected to have neurocarcinogenic effects. Anti-oxidative properties of vitamins and other nutrients are thought to antagonize the effect that these nitroso compounds have, thereby reducing risk of developing brain cancer[1]. Both an individuals diet and maternal diet during pregnancy are thought to play a role. Diet can also be used as a method for treatment by using certain diets to induce metabolic alterations, intending to restrict energy sources from the tumour cells. New methods to manage brain tumours are critical because of their aggressive nature and limited effective and safe treatment options. At present, the ketogenic diet is a promising option for management of brain tumours, working to slow their growth[[2]].


N-nitroso Compounds

N-nitroso Compound
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A highly carcinogenic N-nitroso compound [25]

N-nitroso compounds, also called nitrosamines, are formed upon consumption of food products high in nitrites, such as cured meats (bacon, salami, hot dogs, etc.) and beer. They are extremely potent carcinogens and as such warranted much suspicion and investigation into their role as brain cancer-causing agents. Many studies implicate high nitrosamine levels in the maternal diet during pregnancy with childhood brain cancer, primarily gliomas [3],[4]. An individuals diet and consumption of nitrosamines has also been studied. Diets higher in cured meats are associated with an increased risk of cancerous brain tumours, with the strongest association for glioma, and weaker associations for meningioma [5-7].
Many conflicting studies show no significant association between any form of brain tumour and consumption of high-nitrosamine foods, in both individual and maternal diet. It is not clear whether these carcinogenic compounds actually contribute, and how much, to formation of glioma [8].
Other studies take into account other aspects of diet, and found that those high in certain vitamins can mitigate the risk imposed by cured meats and other high-nitrosamine foods [6].

Prevention & Decreased Risk

Dietary components in glioma treatment
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Carotenoids are pigments synthesized in the chloroplasts of plant cells. They are found in abundance in fruits and vegetables, and produce the yellow, orange, and red colours in some of these. Carotenoids may have protective anticancer properties as they are antioxidants, which have been shown to inhibit glioma cell growth and proliferation as well as reducing oxidative damage. In the majority of studies done on anti-cancer diets it was concluded that diets higher in carotenoid-rich foods have been correlated to a decreased risk of glioma [9]. In rat glioma models with implanted C6 cancer cells, rats with carotenoid supplements had a prolonged latency until tumour development, demonstrating their protective effect [10]. In a pilot study, patients with high-grade gliomas who had lycopene (a carotenoid) supplement in addition to surgery and subsequent radiotherapy had better results upon follow up clinical assessment [11].

Foods High in Anti-Cancer Agents
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Flavonoids are a class of plant-based compounds found in high levels in foods such as herbs, blueberries, tea, citrus fruits, cacao, and more. Because of their strong anti-oxidant properties they are known to act as cancer-preventing agents. Their role in cancerous brain tumours are thought to be both apoptosis-inducing and anti-proliferative to cancer cells. A therapeutic role for these compounds has been suggested when a study found that the flavonoids apigenin, (-)-epigallocatechin, (-)-epigallocatechin-3-gallate, and genistein induced apoptosis in human glioblastoma cells, but not in normal human glial cells [12]. The mechanism by which the flavonoids acted was through flavonoid-activated caspases in select cells, which, once turned on, induced cell death. Naringenin, another flavonoid, was found to inhibit glial tumour cell proliferation in rats with implanted gliomas, by downregulating factors needed for growth such as protein kinase C, nuclear factor kB, cyclin D1 and cyclin dependent kinase 4 [13].

Vitamin A

Vitamin A is believed to have a preventative role against the formation of cancerous brain tumours. Case-control studies have shown that mothers who had a diet higher in vitamin A during pregnancy reduced their child’s risk of medulloblastoma, an aggressive form of brain cancer [14]. Diets high in vitamin A have also been shown to mitigate the increased risk seen in high-nitrosamine diets, by acting as nitrosation-inhibiting antioxidants [6]. It’s metabolite, retinoic acid, is also thought to have positive effects on various forms of brain cancer by preventing development and proliferation as well inducing differentiation in glioma stem cells, and so has been implemented as a treatment for gliomas.


Retinoic Acid

Retinoic acid, a metabolite of vitamin A, has been shown to have positive effects on various forms of brain cancer by preventing development and further proliferation as well as targeting tumour-initiating glioma stem cells for differentiation to make them a more susceptible target for therapy. One proposed mechanism is that retinoic acid inhibits epidermal growth factor receptors in glioma cells, slowing tumour growth when used as a conjunctive therapy [15]. In addition, retinoic acid has been shown to increase CRABPII, which induces apoptosis, and decrease FABP5, a protein that supports proliferation, in glioma cells [16,17]. As retinoic acid has been shown to promote differentiation of glioma stem cells, it is implemented as a form of treatment in addition to other methods such as radiation and chemotherapy. It’s efficacy in supporting positive treatment outcomes is strongly supported, with findings that groups treated with retinoic acid supplements have decreased tumour growth and prolonged survival time [18]. To administer retinoic acid treatment, a nanoparticle-based system has been formulated to target macrophages in cancer cells and deliver retinoic acid directly to them [19].
Some studies implicate deregulation of retinoic acid signaling in glioma pathogenesis. The proteins CRABPII, FABP5 and more are regulated by retinoic acid levels, and they are found in an imbalance in glioma cells[16]. This dysregulation inhibits proper differentiation of stem cells and so the tumour proliferates. Supplementing with retinoic acid may directly target one of the underlying causes of cancerous brain tumours, making it an effective treatment. 

Metabolic Conditions on the Ketogenic Diet
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Reduced Tumour Formation on Ketogenic Diet
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Black line: control rat; blue line:ketogenic diet [22]

Ketogenic Diet

The ketogenic diet was formulated to treat a variety of conditions and has since then been implemented as a therapeutic approach for cancerous brain tumours. This diet induces metabolic changes by greatly restricting carbohydrate and protein intake, with the majority of energy coming from fat sources. It also limits caloric intake. This is applicable to tumours of the brain because cancerous tissue in the brain can only use glucose as an energy source due to mitochondrial abnormalities, whereas healthy brain tissue can use both glucose and ketone bodies (products of beta-oxidation). With a ketogenic diet, the intention is to starve the cancerous cells until they die, leaving only healthy tissue to be supplemented with enough energy to survive [20,21].
Cases of extremely malignant brain tumours that are unresponsive to alternative treatment have responded extremely well to the ketogenic diet, showing drastic improvement of symptoms and reduction of tumour size [20].
In vitro study has shown a lack of hypoxia-inducible factor 1α activity in glioma cells, rendering them unable to process ketone bodies as a fuel source to make up for the lack of glycolysis [21].
Mouse models using induced-glioma show a prolonged survival on the ketogenic diet compared to control, as well as a reduction in reactive oxygen species in tumour cells. Further, it has been shown that the ketogenic diet alters cellular mechanisms resulting in a reversion of cancerous glioma cells back to healthy tissue cells, genetically [22,23].
It is hypothesized that an individuals ratio of ketolytic enzymes to glycolytic enzymes in their tumour cells will determine how well they will respond to the ketogenic diet as a treatment, however all tumour cells are lacking ketolytic enzymes and predominantly only have glycolytic enzymes compared to healthy cells which is what makes them a good target for this treatment [24].

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