CHAPTER 1: Introduction to Diet, Nutrition and Cancer

Cancer is an enormous burden for both developed and developing countries. This is illustrated by data from GLOBOCAN 2012, produced by the International Agency for Research on Cancer (IARC),¹  indicating the worldwide occurrence in 2012 of approximately 14.1 million new cancer cases and 8.2 million deaths due to the disease.²  Cancer is a major global cause of death and the projected increase in the burden to societies is associated with growth and aging of population, as well as increased prevalence of established risk factors including smoking, reproductive changes, physical inactivity, obesity and poor diet.²  Thus, prevention should be a major focus for cancer control.³  In this context, dietary approaches are promising.⁴ 

Although it is frequently assumed that the hypothesis that nutrition could be a cause of cancer started to be considered around the 1940s, evidence indicates that professional interest in the diet, nutrition and cancer association can be traced back to the 1800s.⁵  A landmark publication in the field was the article by Doll and Peto from 1981, where they estimated that 35% of cancer was attributed to diet.⁶  Although some⁷  have reviewed this original estimate and proposed lower figures (i.e., 20%), Doll and Peto’s findings were key to increase awareness of the influence of nutritional factors on cancer development. Since then, intense research has been conducted at the epidemiological, clinical and experimental levels.^8,9  Accumulated data indicate that diet and nutrition and cancer association is very complex and several aspects are yet not clear. For example, it has been pointed out that the estimation of dietary influence on cancer risk should further take into account early life nutrition, as developmental stages such as in utero life, early childhood and puberty may represent particularly vulnerable periods for cancer development in adulthood.¹⁰  According to the World Health Organization,³  30–50% of all cancers are preventable through reduction of exposure to risk factors (tobacco, environmental pollution, occupational carcinogens, infections and alcohol) and adoption of healthy lifestyles (physical exercise, healthy diet and weight).

In addition to the timing of food consumption, other factors that further complicate the elucidation of nutritional modulation of carcinogenesis include the great diversity of dietary components (i.e., more than 5 000 flavonoids have been identified in fruits and vegetables), the concentrations of which in foodstuffs can vary according to farming, harvesting, transporting and cooking conditions.^11,12  Furthermore, for those nutritional factors associated with decreased (fruits and vegetables, vitamin D, folic acid, selenium, zinc, polyphenols and carotenoids, among others) or increased (red and processed meat, alcohol, saturated fatty acids and obesity, among others) cancer risk, the exact underlying cellular and molecular mechanisms are still not clear.^13–22  More recently, nutrient–gene interactions (nutritional genomics), including epigenetics,^23–25  stem cells as cellular targets^26,27  and the intestinal microbiota,^28,29  have emerged as key factors that should be considered in order to better understand diet, nutrition and cancer and thus establish nutritional recommendations for cancer prevention.

Ingestion of fruits and vegetables is associated with cancer prevention.^30–32  These protective effects have been ascribed to the presence of several bioactive compounds.^33,34  In Chapter 2, the role of bioactive food compounds in cancer prevention is covered. These natural substances are widely distributed in plant-based foods such as fruits, vegetables, whole grains and beans. They originate from the secondary metabolism of plants, belong to different classes, such as polyphenols, terpenoids, allyl compounds and isothiocyanates, among others, and exert different cancer preventive effects. The molecular mechanisms underlying their protective effects are discussed and include modulation of phase I and II carcinogen metabolizing enzymes, regulation of gene expression through activation of nuclear receptors, interference with cell signaling pathways and modulation of epigenetic processes such as DNA methylation and histone post-translational modifications. Such complex mechanisms of action by bioactive food components could be associated with the cancer prevention effects of whole grains, fruits, vegetables and beans. Major limitations concerning establishing recommended levels of intake of these compounds are discussed and include limited information on their levels in foods and their bioavailability, which is influenced by individual genetic backgrounds and intestinal microbiota.

Among different micronutrients with cancer prevention potential, vitamin D can be highlighted.^35,36  Chapter 3 covers the role of vitamin D in obesity, an established risk factor for cancer, and in cancer prevention itself. An overview of the nutritional/physiological roles of vitamin D is provided with emphasis on its metabolism. Evidence of the cancer preventive potential of vitamin D based on epidemiological and intervention studies is then discussed. Inhibition of cell proliferation, induction of apoptosis and cell differentiation, and inhibition of angiogenesis, migration and invasion of tumor cells have been indicated as potential vitamin D anticancer actions. The impact of different polymorphisms in the vitamin D receptor (VDR) gene on cancer risk is then discussed. This gene codes for the nuclear receptor that mediates the genomic actions of vitamin D. Alterations in VDR expression or conformation could impair the cancer preventive actions of vitamin D. In addition, the actions of vitamin D at the epigenetic level are presented.

Selenium represents one of the most studied nutrients with cancer prevention potential.^37,38  This aspect of selenium’s beneficial effects is covered in Chapter 4. Selenium is found in both organic and inorganic forms, which present different bioavailability and metabolic pathways. These aspects are first discussed. Nutritional recommendations, food sources and biomarkers of selenium status are then covered. Epidemiological evidence linking selenium and cancer prevention is also provided and conflicting results between outcomes from the two main randomized clinical trials – the Nutritional Prevention of Cancer and the Selenium and Vitamin E Cancer Prevention trials – are discussed. The different outcomes from these clinical trials could be related to differences in genetic background. Thus, polymorphisms in key genes involved in selenium’s cancer prevention actions, such as those coding different antioxidant glutathione peroxidases, are suggested to increase the risk of different cancers, including breast, prostate and colorectal cancers. Furthermore, the proposed mechanisms underlying selenium’s cancer preventive actions are discussed, including those at the epigenetic level.

Zinc represents another micronutrient with cancer prevention activity³⁹  and this is discussed in Chapter 5. The nutritional importance of zinc is first discussed. It is an essential micronutrient that exerts key biological functions at the structural, catalytic and regulatory levels, modulating oxidative stress response, genomic stability, immunological function, DNA repair, cell proliferation and apoptosis, all of which are deregulated during carcinogenesis. Thus, disturbances in zinc homeostasis could increase the risk of cancer development. The impact of zinc deficiency or supplementation in the context of breast, upper digestive tract and liver carcinogenesis is presented. Both experimental and clinical evidence is discussed. It is highlighted that understanding zinc deregulation in the context of breast, esophagus, stomach and liver cancer development will allow the design of novel interventional studies in prevention, diagnosis and targeted therapeutics.

Among nutritional factors that increase cancer risk, red and processed meat consumption can be highlighted.⁴⁰  This is the subject of Chapter 6. Epidemiological evidence that supports the association between red and processed meat consumption and high risk of some types of cancers is presented. Red and processed meat consumption is positively associated with cancer in several subsites (with strongest results found for colorectal cancer) and this association seems to be related to heme iron, nitrate, and heterocyclic amines. Epidemiological studies on the role of red and processed meat on cancer incidence in populations have provided evidence of benefits of the reduced intake of these food items. Conversely, increasing trends for red meat intake have been seen in developing countries, representing a challenge for cancer control.

Alcohol consumption represents another established risk factor for cancer.⁴¹  This association is discussed in Chapter 7. Epidemiological, in vivo and in vitro data are discussed, showing the impact of ethanol consumption on increased risk for oroesophageal, colorectal, hepatobiliary, pancreatic and gastric cancers. In addition, it is highlighted that upper gastrointestinal microbiota, gene polymorphisms associated with ethanol metabolism, nutritional deficiencies, oxidative stress and the presence of other carcinogenic compounds should be considered in the individual pathophysiology of alcohol-related carcinogenesis.

Increased consumption of fatty acids is also associated with increased cancer risk.^42,43  Chapter 8 focuses on alterations in fatty acids’ metabolism in cancer, with emphasis on de novo fatty acid synthesis. This is an essential process that is necessary for conversion of nutrients into metabolic intermediates for energy storage, membrane biosynthesis and generation of signaling molecules. Exacerbated de novo fatty acid synthesis is a feature of several cancers. This metabolic alteration is associated with upregulation of several lipogenic enzymes, including fatty acid synthase, and supports tumor growth.

Obesity is a well-established risk factor for cancer.⁴⁴  Obesity and cancer risk is the subject of Chapter 9. Different mechanisms have been proposed to explain the influence of obesity on cancer risk. These are discussed and include adipose tissue dysfunction, which is accompanied by metabolic, inflammatory and hormonal alterations that can impact cancer initiation and progression. In addition, obesity-associated dysbiosis has been recently highlighted as an important factor in cancer development. Notably, as obesity prevalence increases in developed and developing countries, multidisciplinary approaches will be needed in order to promote weight loss and, thus, effectively reduce rates of cancer incidence.

Traditionally, epidemiological studies on the diet, nutrition and cancer association have focused on single nutrients.^14,45  However, diet is a complex mixture of several components such as macro and micronutrients and bioactive food compounds. In order to capture such complexity, studies with dietary pattern analysis approaches have been conducted.^13,46  Thus, Chapter 10 focuses on “Dietary Patterns and Cancer Risk”. Both a priori and a posteriori approaches are discussed in the context of cancer prevention. It is highlighted that, even with the known limitations for the assessment of dietary patterns, the existent evidence supports the promotion of diets rich in fruits, vegetables, legumes and whole grains and low in red and processed meat, sugary foods and drinks, salty snacks and fat.

Cancer risk is a reflection of gene–environment interactions.⁴⁷  Nutritional genomics is a post-genomic discipline that focuses on the health implications of gene–nutrient interactions.⁴⁸  Chapter 11 focuses on “Nutritional Genomics and Cancer Prevention”. The modulation of gene expression through distinct mechanisms by nutrients and bioactive food compounds is presented. In addition, the impact of genetic polymorphisms in the context of diet, nutrition and cancer is further discussed. Carcinogenesis involves progressive deregulation of both genetic and epigenetic processes.⁴⁹  The main epigenetic processes comprise DNA methylation and histone modifications. Because alterations at the epigenetic level are potentially reversible, great interest has been directed toward the role of epigenetics in nutrition and cancer prevention,⁵⁰  the topic covered in Chapter 12. The regulation of epigenetic processes in normal cells is first presented. Then, epigenetic deregulation at the level of DNA methylation (global genomic hypomethylation and gene promoter hypermethylation) is discussed. An overview is provided regarding the direct epigenetic effects exerted by several bioactive food compounds with cancer prevention potential. Examples include epigallocatechin-3-gallate, curcumin, resveratrol, ascorbate and butyric acid, among others. Indirect epigenetic effects by nutritional components are also provided and include the metabolism of S-adenosyl-l-methionine and acetyl-CoA. It is highlighted that elucidating the modulation of epigenetic mechanisms by nutrients, bioactive food compounds and dietary patterns may help in establishing innovative cancer prevention strategies.

Timing of exposure to nutritional factors is a key factor influencing cancer risk.¹⁰  Accumulating evidence indicates that maternal malnutrition during gestation and lactation can increase the breast cancer risk in female offspring during adulthood.^51–53  More recently, paternal malnutrition during preconception was shown to also increase disease risk in female offspring.^54,55  Thus, Chapter 13 covers “Maternal and Paternal Nutrition and Developmental Origins of Breast Cancer”. Epidemiological and experimental evidence is provided that supports a role for maternal exposures in the developmental origins of breast cancer. Examples of relevant nutrients and bioactive compounds include fatty acids (omega-3, omega-6, omega-9 and saturated fatty acids), folic acid, proteins, ethanol, dietary fiber, soy isoflavones and blueberry anthocyanins, among others. Potential underlying mechanisms are discussed and include alterations in mammary gland development, possibly through alterations at the epigenetic level targeting mammary stem cells. Novel experimental evidence on the impact of paternal interventions during preconception with high-fat, selenium-deficient or low-protein diets on female offspring susceptibility to breast carcinogenesis is discussed. Potential implicated mechanisms include the alteration of sperm epigenetic marks. It is highlighted that a life-course approach, where preventive measures are adopted throughout a woman’s life, could represent a valuable way to reduce breast cancer risk. In this case, preventive measures should focus on windows of susceptibility to breast cancer starting already in early life.

Aging is an independent cancer risk factor.⁵⁶  Importantly, diet, aging and cancer are interconnected factors. Thus, the topic of Chapter 14 is “Eating Habits and Their Impact on Aging and Cancer”. Evidence linking dietary regimens and aging is first presented, with special reference to caloric intake. In addition, the emerging topic of time-restricted feeding schedules as a means to delay aging is also addressed. Age-induced alterations in the tissue fitness landscape are further discussed for their possible relevance in the pathogenesis of neoplasia.

An emerging topic in diet, nutrition and cancer is represented by the impact of the gastrointestinal microbiota.⁵⁷  The subject of Chapter 15 is “Nutrition, the Gastrointestinal Microbiota and Cancer Prevention”. The role of the gastrointestinal microbiota on maturation of the immune system and regulation of epithelial cell proliferation and differentiation is discussed. The mechanisms through which an altered intestinal microbiota could lead to deleterious outcomes, such as local and systemic inflammation, pathogenic colonization and consequently cancer are then discussed. The role of bacteria in colorectal carcinogenesis is described, with some being the cause (driver bacteria) and others being the consequence (passenger bacteria) of cancer development. The interaction of the gastrointestinal microbiota with dietary factors is bi-directional. Among all these bacteria, some could metabolize food components leading to the production of tumor-suppressor or pro-carcinogenic molecules. On the other hand, food components could also affect the gastrointestinal microbiota profile.

The cellular origin of cancer is a key topic in cancer research.⁵⁸  Accumulating evidence indicates that stem cells play an important role in this context.⁵⁹  Thus, nutritional interventions targeting stem cells could represent a promising approach for cancer prevention.⁶⁰  The topic of Chapter 16 is “Nutrition, (Cancer-)Stem Cells and Cancer Prevention”. The relevance of cancer stem cells for cancer development is first discussed according to the “Hierarchical Model of Tumor Evolution”. The nutritional impact on cancer stem cell signaling pathways is then presented. Examples include the Wnt, Hedgehog and Notch pathways that can be targeted by food compounds such as curcumin, resveratrol, genistein, quercetin and lycopene.

Colorectal, liver, breast and prostate cancers represent the most frequent cancers.²  Accumulating epidemiological, clinical and experimental evidence shows the association of nutritional factors and risk for these cancers. Thus, these aspects of diet, nutrition and cancer are covered in Chapters 17 (“Nutrition and Colorectal Cancer Prevention”), 18 (“Nutrition and Liver Cancer Prevention”), 19 (“Nutrition and Breast Cancer Prevention”) and 20 (“Nutrition and Prostate Cancer Prevention”). These chapters provide an overview on the pathophysiology of these different cancers. Food components that increase or decrease risk are then discussed and the associated mechanisms presented.

A better comprehension of the different topics of the diet, nutrition and cancer association covered in the different chapters of this book, ranging from epidemiological to molecular aspects, will contribute to establish more specific dietary recommendations for cancer prevention. Currently the most robust recommendations for cancer prevention are those established by the World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR) in their third report on “Diet, Nutrition, Physical Activity and Cancer: a Global Perspective” from 2018,⁶¹  available at dietandcancerreport.org:

1. Be a healthy weight.

2. Be physically active.

3. Eat a diet rich in whole grains, vegetables, fruits and beans.

4. Limit consumption of “fast-foods” and other processed foods high in fat, starches or sugars.

5. Limit consumption of red and processed meat.

6. Limit consumption of sugar-sweetened drinks.

7. Limit alcohol consumption.

8. Do not use supplements for cancer prevention.

9. For mothers: breastfeed your baby, if you can.

10. After a cancer diagnosis: follow these recommendations, if you can.

In addition, the WCRF/AICR indicate that not smoking and avoiding other exposure to tobacco and excess sun are important in reducing cancer.⁶¹