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Nutrition in cancer: metabolites, enzymes and kinases struggle to dictate chemo and immuno outcomes

Background

Diet and nutrition play a fundamental role in human health, with the quantity, composition, and quality of the diet, as well as meal timings, being important determining factors for the availability of nutrients, which, in turn, regulate physiological processes. Recent research has also focused on understanding how diet influences disease trajectories. However, there still is a dearth of information on the impact of specific dietary components on the prevention or risk of diseases. Results from various epidemiological studies have found that specific dietary patterns modulate the risk of various diseases, including cancer. While diets rich in sugars and saturated fats have been found to increase the risk of diabetes and cardiovascular disease, those consisting largely of vegetables, fruits, and fiber are believed to lower the risk of metabolic and cardiovascular diseases. Similarly, diets high in processed meat and alcohol are thought to increase the risk of cancer, but the Mediterranean diet is believed to lower the risk of carcinogenesis.

Tumor metabolic pathways and nutrient availability

The researchers reviewed the existing knowledge on the differences in the nutrient requirements and metabolic pathways between the tumor microenvironment and the surrounding healthy tissues. The immunosuppressive environment inside tumors is a result of the cancer cells depriving the immune cells of essential metabolites such as oxygen and glucose while increasing the levels of adenosine, lactate, and other mediators that further decrease immune cell function. The metabolic reprogramming that occurs inside the tumor microenvironment impacts various immune cell subsets. The major metabolic pathways in immune cells that are believed to be reprogrammed within the tumor microenvironment include the tricarboxylic acid cycle, glycolysis, the pentose phosphate pathway, oxidative phosphorylation, the amino acid pathway and fatty acid synthesis.

Biochemical heterogeneity: the example of breast cancer cell types

Scientists have known for some time that metabolic differences exist even within the same type of tumor analyzed (biochemical heterogeneity). For example, MCF-7 and MDA-MB453 breast cancer cells have a different glycolytic flux, being higher in the former and this can be correlated to the different enzyme expression and regulation in the two cell lines. MCF-7, in fact, have higher levels of PFK-1, GA-3-PDH and pyruvate kinase enzymes than the others; in both lines these enzymes and enolase increase strongly with cell density; however, glycolytic flux is reduced at high densities in MDA-MB453 cells but remains unchanged in MCF-7.

Both lines consume glutamine in the same quantity, because they have the corresponding enzymatic set in an identical way; the only difference is the enzyme malic dehydrogenase (MDH), which is seven times higher in MCF-7 cells and causes more NADH to be produced, which serves as an enzyme cofactor. In MCF-7, glycolytic flux increases glutaminolytic flux; therefore in conditions of lower glycolysis the consumption of glutamine is reduced and that of glutamate increases; everything on the contrary happens for MDA-MB453 cells, in which glutamate production is stimulated at high glucose concentrations. This different cellular behavior correlates with the different nutrient demand: MCF-7 are incapable of growing in the absence of glucose.

On the contrary, MDA-MB453 specifically requires galactose as an energy source. MCF-7s have greater amounts of NADH due to the abolition of the glycerol-3-phosphate shuttle. High levels of NADH thus inhibit the enzyme UDP-galactose epimerase, which regulates the conversion glucose-6-phosphate=galactose-1-phosphate. In MDA-MB453 cells, epimerase promotes the flux of galactose glucose-6-P for glycolysis, while galactose has more of a structural role (glycoproteins and surface antigens). Saccharide nutrient specificity leads also in possible changes in intracellular signaling, which is associated with cellular replication and malignancy.

In both MCF-7 and MDA-MB453, the proliferative block induced with cyclic AMP derivatives or sugar deprivation (glucose for one, galactose for the other), correlates with a reduction in the cellular content of proteins phosphorylated on tyrosine. Among other things, intermediate metabolites such as fructose-1,6-diphosphate and 5-phosphoribose pyrophosphate influence the activity of certain protein kinases, while glycerol-3-phosphate can influence that of protein serine phosphatases (PP-1, PP2A, etc.). Instead, metabolites such as glucose-6-phosphate, ribose-5-phosphate and O-phosphoserine can negatively affect phosphotyrosine phosphatases (PTPs). Aside from directly deactivating tyrosine kinases, PTPs also partially deactivate the mitogenic pathway of MAP kinases (ERKs), which is required by all tumor cells for their duplication.

They also deactivate other MAP-kinases involved in either cellular stress (JNK and p38RK) induced by metabolic reprogamming, osmotic stress, radiation exposure and, of course, chemotherapic drugs. This means that nutrient availability and selectivity dictates the possibility to use specific drugs to treat certain forms of cancers rather than others. Glutamine analogues (es. azaserine and DON) have been emplyed in the past and then abandoned for their excessive toxicity. In the last decade a renewed interest in this molecules has been risen again, with versions of the drugs modified for a lesser toxicity, like the derivative now studued at the Johns Hopkins University scientists. Aside base synthesis, glutamine enters in the sythesis of glutathione, the major cellular antioxidant. Knocking out cellular redox defenses, enhances chemotherapy effectiveness.

Dietary interventions and cancer

The impact of dietary interventions on diseases, including cancer, can be deciphered better with a thorough understanding of the metabolic pathways of macronutrients such as proteins, fats, and carbohydrates. Systemic metabolism can be modulated by regulating the macronutrient intake and influencing the metabolic pathways utilized by these macronutrients. Special diets such as ketogenic diets, caloric restriction diets, high-fat diets, fasting-mimicking diets, and even high-salt diets, as well as dietary restrictions, are based on the concept of systemic metabolism modifications through macronutrient intake modulations. The researchers also reviewed studies that evaluated the role of dietary factors in cancer treatment, especially the use of nutritional interventions to improve the efficacy of immunotherapy and other cancer treatments.

Caloric restrictions were found to increase the response of T cells to immunotherapy. In contrast, using caloric restriction mimetics has improved the effectiveness of chemotherapy and immunotherapy. Caloric restriction has also been found to be effective in modulating the tumor microenvironment when combined with radiotherapy for cases of triple-negative breast cancer. Ketone bodies produced by fasting or Keto-diet style are powerful immune regulators: they act in a way similar to short-chain fatti acids (SCFAs) like propionate and butyrate to regulate gene expression either by receptors or direct modulation of nuclear histone modification. Butyrate and beta-hydroxybutyrate are direct inhibitors of histone deacetylases (HDACs), which regulate gene espression. Drugs directed toward these enzymes (es. voninostat, panabnostat, etc.) are currently explred and employed as anticancer drugs.

Finally, sudies found that alterations in the gut microbiome diversity and composition due to dietary interventions change the levels of metabolites derived from microbiota that directly influence antitumor activity. Many studies have now discovered that cancers like lung carcinoma pancreatic carcinoma, melanoma, breast cancer and colon cancer have better outocomes with immune checkpoint therapy (es. anti-PD L1) when microbiota is more balanced with probiotic species like Lactobacillus, Bifidobacterium, Leuconostoc, Akkermansia, etc., which produce SCFAs. Similar scenarios are recepitulated by animal administration fo SCFAs themselves, indicating possibly that these biomolecules are the main mediators of antitumor immunity in man. Polyphenols and flavonoids are other powerful regulators of probiotic species; their presence in beneficial diets (e.g. mediterranean diet) may justificate the positive effects that a good diet may have over the tumoral condition.

  • edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Xiao Y et al. Signal Transd Target Ther. 2024 Mar 11; 9(1):59.

Li L et al. Front Cell Infect Microbiol. 2024 Feb; 14:1341032.

Xin Y, Liu CG et al. Front Immunol. 2024 Feb; 15:1343450.

Gwangwa MV, Joubert AM et al. Biol Res. 2019; 52(1):15.

Otto AM et al. J Cell Biochem. 2015 May; 116(5):822-835.

Drabovich AP et al. Mol Cell Proteomics. 2012; 11(8):422-34.

Guppy M, Leedman P et al. Biochem J. 2002; 364(Pt 1):309.

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Dott. Gianfrancesco Cormaci
Dott. Gianfrancesco Cormaci
Laurea in Medicina e Chirurgia nel 1998, specialista in Biochimica Clinica dal 2002, ha conseguito dottorato in Neurobiologia nel 2006. Ex-ricercatore, ha trascorso 5 anni negli USA alle dipendenze dell' NIH/NIDA e poi della Johns Hopkins University. Guardia medica presso la casa di Cura Sant'Agata a Catania. In libera professione, si occupa di Medicina Preventiva personalizzata e intolleranze alimentari. Detentore di un brevetto per la fabbricazione di sfarinati gluten-free a partire da regolare farina di grano. Responsabile della sezione R&D della CoFood s.r.l. per la ricerca e sviluppo di nuovi prodotti alimentari, inclusi quelli a fini medici speciali.

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