The beginnings of cancer

Cancer is typically a disease of old age and the increase in life expectancy in most countries, and particularly in developed ones, is clearly increasing the incidence of most types of cancersReference Parham¹. Patterns of the disease are not fully explained by known risk factors. Much progress has been made in understanding the molecular basis of carcinogenesis, particularly the near consensus that virtually all cancers arise from an accumulation of genetic mutations and the more recent recognition of the role of inflammation and the tissue microenvironment, in particular for hormone-dependant cancers. However, most genetic mutations that contribute to cancer are not inherited, and thus must be attributable to accumulation of somatic mutations and epigenetic changes, from as yet poorly understood environmental factors, that certainly cannot be explained entirely by tobacco, use and arise over the course of a lifetimeReference Davis, Donovan, Herberman, Gaynor, Axelrod, Van Larebeke and Sasco². Normal maintenance of any organism means that cells replicate by division to replace old cells and repair any damaged tissue areas. Cell division starts with DNA replication, which takes place in a normal human's lifetime approximately 10¹⁶ times. Even though the DNA replication system is extremely accurate, opportunities for errors occur and these may cause mutations. In addition to errors occurring during normal DNA replication, exposure to some chemical agents or radiation, as well as viral infections, may induce further changes in DNA.Reference Parham¹

Cancer may develop when a cell accumulates mutations in genes related to cell multiplication and survival. These genes are either proto-oncogenes that normally help initiate and execute cell division or tumour suppressor genes that prevent mutant cell proliferation. The accumulation of mutations appears with advanced ageing of the body and if the immune system is incapable of identifying and destroying the mutated cells.

Cancerous cells replicate at a higher rate than normal cells, thus increasing the likelihood of further mutations, and some of the damaged cells may migrate to other tissues, causing metastasis or tumour growth in a tissue other than the one of origin. The longer a cancer is allowed to continue growing, the fewer the possibilities for the immune system to be able to recognise the damaged cells and destroy them. When mutated cells are few, the immune system may recognise and proceed to destroy them as it would any bacterial or viral infection. However when a cancer grows, the different damaged cells may be so many that the system is incapable of destroying them all and it fails in its surveillance jobReference Parham¹.

Studies in animals have shown that epigenetic and metabolic adjustments caused by modifications in the nutritional environment during embryonic or foetal stages of development may have important effects on the genetics of cancer among other chronic diseases. Interactions between single nucleotide polymorphisms in various genes have been associated with metabolic responses to diet influencing the development of chronic diseases such as obesity, cardiovascular disease and cancer. Genetic inheritance allows individuals to develop any one of multiple phenotypes that are determined by metabolic and environmental conditions, such as nutritionReference Stover and Garza^3–Reference Lee and Go⁵.

One of the most thoroughly evaluated associations between nutrition and the immune system is that related to dietary fat. Although total fat intake has been found to increase the risk of various types of cancer, it is the type of fat that has a more important effect on the immune response and consequently on cancer developmentReference De Pablo, Puertollano and Alvarez de Cienfuegos^6, Reference Granados, Quiles, Gil and Ramírez-Tortosa⁷. Polyunsaturated fatty acids (PUFAs) have been shown to modulate cytokine production, lymphocyte proliferation, expression of surface molecules, phagocytosis, apoptosis and natural killer cell activity; these last two effects are closely related to cancer development. An increase in n-3 PUFAs helps control the production of proinflammatory eicosanoids as well as cytokine productionReference Sweeney, Puri and Reen⁸. It has been shown in vitro that palmitic acid is able to potentiate iron-mediated toxicity in endothelial cells, causing mitochondrial dysfunction, cell death, apoptosis, and DNA mutationReference Yao, Shi, Gou, Zhou, Yee-Aw, Zhou and Liu^9–Reference Atshaver, Storey, Petrescu, Greenberg, Lyuksvutova, Smith and Schroeder¹⁴.

The role of nutrition in cancer development

The immune system, when acting as the body's primary defence against pathogens and cancer cells, utilises pro-inflammatory cytokines, as well as reactive oxygen and nitrogen species. When the production of these substances is excessive it may lead to chronic inflammation and an increased risk of cancer, as inflammation has been linked to the promotion phase of carcinogenesis, by inhibiting cell to cell communication between normal and cancer affected cells. In this case, the organism's ability to counter-attack this effect is very important to stop the production of cancerous cells. Nutrients such as zinc, selenium, vitamins A and C, n-3 PUFAs and probiotics modulate the immune response or act as antioxidants, helping the immune system to work specifically against the cancerous cell and not against normal adjacent cellsReference Philpott and Ferguson^15, Reference Trosko¹⁶.

Apoptosis or programmed cell death is the most important mechanism for the maintenance of normal tissues and organs. Cells that are cancerous have lost this ability to balance cell proliferation. Many dietary components may act as chemopreventive agents, interacting at the molecular and cellular level to modulate apoptosis, through selectively activating or inactivating gene expression. Although much of the recent research has been focused on identifying the specific effects of single nutrients or dietary components on gene expression, it is necessary to remember that the individual consumes a combination of nutrients within foods in the diet, and that the interaction of these components may not have the same positive or negative effect. A better understanding of these interactions may help identify the ideal combination of foods for cancer prevention. Low fibre and high red meat intakes, as well as an imbalance of n-3 and n-6 fatty acids have been associated with an increase in cancer riskReference Beruin, Min, Wu, Wu, Perry, Cline, Thomas, Thornburg, Kulik, Smith, Edwarrds, D'Agostino, Zhang, Wu, Kang and Chen^17–Reference Neuhouser, Barnett, Kristal, Ambrosone, King, Thornquist and Goodman¹⁹. Dietary components can alter gene expression and phenotypes of cells through various steps, thus influencing cancerReference Davis and Ross^20–Reference Martin²⁴.

Epidemiologic studies have shown that 30 to 40 % of all cancers may be preventable by maintaining a healthy lifestyle and adequate diet. Increasing fruit and vegetable intake may lower the risk of cancer, particularly breast, colon, rectum, prostate and lungReference Theodoratou, McNeill, Cetnarskyj, Farrington, Tenesa, Barnetson, Porteous, Dunlop and Campbell^25, Reference Kimura, Kono, Toyomura, Nagano, Mizoue, Moore, Mibu, Tanaka, Kakeji, Maehara, Okamura, Ikejiri, Futami, Yasunami, Maekawa, Takenaka, Ichimiya and Imaizumi²⁶. This effect may be due to a resulting decrease in total fat intake and through an increase in vitamins and minerals such as selenium, folic acid, vitamin B12, vitamin D, antioxidants such as carotenoids (alpha-carotene, beta-carotene, lycopene, lutein, cryptoxanthin), as well as phytochemicals (phenolic compounds, terpenoids, steroids, indoles and fibres) and pre- and probioticsReference Divisi, Di Tommaso, Salvemini, Garramone and Crisci^22, Reference Fernandez, Gallus and La Vecchia^27–Reference Nishino, Murakoshi, Mou, Wada, Masuda, Ohsaka, Satomi and Jinno³⁰.

For instance, it has been shown that intake of selenium in pharmacological doses ( ≥ 200 μg/day) may be protective against prostate, colon, and lung cancersReference Cui, Vogt, Olson, Glass and Rohan³¹. Iron metabolism has also been associated to breast and colon cancerReference Raje, Mukhtar, Oshowo and Ingham Clark^32–Reference Hance, Rogers, Hursting and Greiner³⁵. Vitamin E in addition to its well known anti-oxidant functions, modulates the activity of microsomal enzymes, inhibits protein kinase C and induces apoptosis, thus acting on tumour growth and cellular proliferationReference Weinstein, Wright, Lawson, Snyder, Männistö, Taylor, Virtamo and Albanes^36–Reference Flora⁴⁰. Vitamin D has antiproliferative effects, promoting cellular differentiation similar to neoplasic processes; it has also been associated to UV-radiation protectionReference Mullin and Dobs⁴¹.

Table 1 presents a list of nutrients that have been associated with the development of different types of cancers either by enhancing the immune system or by exerting an immunosuppressive effect. It is always important to note that although some of these effects have been observed with the use of supplements, most of them are related to the intake of the foods that contain these nutrients.

Table 1

Dietary components associated with cancer development or prevention

The role of nutrition in cancer therapy

Most of the research that has been done in the area of nutrition and cancer is related to identifying the causes and ways of preventing the onset of a neoplasic event. However, research has also been done on the use of nutrition to improve the outcome of a patient after surgical treatment of a tumour. Enhancing immunity through diet is generally done by adding n-3 fatty acids, arginine, and nucleotides to an otherwise nutritionally complete formula. There are several trials suggesting that pre-operative immunonutrition improves outcomes in patients with upper gastrointestinal (GI) cancer surgery and is cost-effective, as complications are reducedReference McCowen and Bistrian^50–Reference Malik, Afaq, Sarfaraz, Adhami, Syed and Mukhtar⁵².

Pre-operative immunonutrition may induce changes that modulate stress responses and improve the outcome of patients undergoing abdominal cancer surgery. Pre-operative enteral immunonutrition in patients with GI cancer improves nutritional status and immunity and decreases the incidence of post-operative complications and infections, by modulating inflammatory reactions. Pre-operative immunonutrition has been suggested to correct the impaired Th1/Th2 balance found in cancerReference Tsujinaka, Hirao, Fujitani, Mishima, Ikenaga, Sawamura and Kurata^53–Reference Moskovitz and Kim⁵⁷.

A specialised pre-operative oral formula with arginine, n-3 fatty acids, and RNA has been shown to be as effective as pre- and post-operative administration of immunonutrition in decreasing the incidence of post-operative infections and length of hospital stay. Pre-operative enteral nutrition has been suggested to provide better regulation of post-operative immune system restoration than parenteral nutrition. On the other hand, early post-operative enteral nutrition supplemented with arginine, omega-3 fatty acids and RNA has been proven to increase hydroxyproline synthesis and improve surgical wound healing in patients undergoing gastrectomy for cancerReference Ates, Yilmaz, Erkasap, Ihtiyar, Kaya, Pehlivan, Ustuner, Yasar and Kiper^58–Reference Sanford⁶⁰.

Conflict of interest statement

The authors have no conflict of interests. RVR and ADBA co-wrote the manuscript.