Oncological Functional Nutrition: Phytochemicals and Medicinal Plants

Oncological Functional Nutrition: Phytochemicals and Medicinal Plants presents the anticancer activities, metabolism, mechanism of action, doses, and sources of various phytochemicals and medicinal plants.

Broken into five parts, this book addresses cancer epidemiology, molecular and therapeutic bases of cancer, macro and micronutrients in cancer prevention and treatment, phytochemicals in the cancer treatment, and medical plants as potential functional foods or resources for the obtention of metabolites with anticancer activity.

Written for nutritionists, food scientists, health professionals, oncologists, endocrinologists, natural product chemists, ethnobotanists, chemists, pharmacists, biochemists, and students studying relating fields, Oncological Functional Nutrition: Phytochemicals and Medicinal Plants will be a useful reference for those interested in learning more about functional nutrition and cancer.

• Discusses functional nutrition as alternative therapy
• Provides recommendations and intervention strategies related to the consumption of phytochemicals, food, and medicinal plants
• Addresses cancer epidemiology, the molecular and therapeutic bases of cancer, phytochemicals in the cancer treatment, and medical plants

• Language: English
• Publisher: Academic Press
• Release date: Aug 20, 2021
• ISBN: 9780128198292

Book preview

Oncological Functional Nutrition

Phytochemicals and Medicinal Plants

Edited by

Maira Rubi Segura Campos

Food Science Laboratory, Chemical Engineering Faculty, Universidad Autonoma de Yucatan, Mérida, Mexico

Armando Manuel Martin Ortega

Universidad Autonoma de Yucatan, Mérida, Mexico

Table of Contents

Cover image

Title page

Copyright

List of contributors

Chapter 1. Cancer epidemiology

Abstract

1.1 Introduction

1.2 Theoretical framework

1.3 Endogenous exposure

1.4 Exogenous exposure

1.5 Cancer and obesity

1.6 Cancer factors according to affected body site

1.7 Conclusions

Acknowledgments

References

Chapter 2. Molecular and therapeutic bases of cancer

Abstract

2.1 Introduction

2.2 Grow promotion and cell death suppression

2.3 Cell signaling

2.4 Replicative immortality and telomere dysfunctions

2.5 Mechanisms of cell death: cell cycle checkpoints and DNA damage response

2.6 Invasion and metastases

2.7 Metabolic reprograming in cancer

2.8 Microenvironment

2.9 Inflammation

2.10 Epigenetic of cancer

2.11 Cancer and the circadian clock

2.12 Treatment

2.13 New paradigms of old ideas

2.14 Conclusions

Acknowledgments

References

Chapter 3. Macronutrients and micronutrients in cancer prevention and treatment

Abstract

3.1 Introduction

3.2 Macronutrients in cancer

3.3 Micronutrients

3.4 Conclusions

References

Chapter 4. Phytochemicals in cancer treatment

Abstract

4.1 Introduction

4.2 Phytochemicals

4.3 Conclusions

References

Chapter 5. Medicinal plants as potential functional foods or resources for obtaining anticancer activity metabolites

Abstract

5.1 Introduction

5.2 Medicinal plants with anticancer potential

5.3 Conclusions

Acknowledgments

References

Index

Copyright

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List of contributors

M.R. Segura Campos,     Facultad de Ingeniería Química, Universidad Autónoma de Yucatán, Mérida, México

J.R. Caamala Cauich,     Facultad de Medicina, Universidad Autónoma de Yucatán, Mérida, México

D. Chamorro-Plata,     Escuela de Medicina, Universidad Anáhuac-Mayab, México

G.R. Fajardo-Orduña,     FES Zaragoza, Universidad Nacional Autonoma de México, México

Yelda A. Leal,     Centro Institucional de Capacitacion y Registro de Cancer (CICyRC), Unidad Medica de Alta Especialidad (UMAE) del Instituto Mexicano del Seguro Social (IMSS), Merida Yucatan, Mexico

L.A. Victoria Monroy,     Facultad de Medicina, Universidad Autónoma de Yucatán, Mérida, México

A.M. Martín Ortega

Facultad de Medicina, Universidad Autónoma de Yucatán, Mérida, México

Facultad de Ingeniería Química, Universidad Autónoma de Yucatán, Mérida, México

Chapter 1

Cancer epidemiology

Yelda A. Leal,    Centro Institucional de Capacitacion y Registro de Cancer (CICyRC), Unidad Medica de Alta Especialidad (UMAE) del Instituto Mexicano del Seguro Social (IMSS), Merida Yucatan, Mexico

Abstract

The increasing number of cancer cases observed in the last decades is due in part to the epidemiological transition that has occurred in recent year as cancer has, become a global health problem, with 18.1 million new cases, 9.6 million of death related to cancer, in 2018. Several epidemiological studies have documented exogenous and endogenous factors that can influence cancer risks, such as chronic infection, genetic background, lifestyles, and obesity. Both cancer and obesity have convergence points; since the World Health Organization reported around 3.9% of total global burden cancer was attributable to excess body weight. Therefore it is necessary to join efforts for the control and prevention of both of these noncommunicable diseases.

Keywords

Cancer; control; epidemiology; noncommunicable disease; obesity; prevention

1.1 Introduction

Cancer is a global health problem that tends to have a long duration and is associated with a combination of genetic, physiological, environmental, and behaviors factors. Consequently, children, adults, and elderly people are vulnerable to this chronic and often life-threatening disease. Approximately 30% of cancer deaths are associated with behavioral and dietary factors and habits, including high body mass index (BMI) and obesity, reduced intake of fruits and vegetables, lack of physical activity, and tobacco and alcohol consumption (Willett & Romieu, 2014). Variations in the prevalence of associated factors lead to different cancer profiles. There are observable differences in incidence and mortality rates between different geographical areas. Although more incident cases are detected in high-income countries, mortality rates are similar between low- and high-income countries (Bray et al., 2018). By 2040 there will be 29.5 million new cases and 16.3 million deaths; 60% of these will occur in developing countries, according to a World Health Organization (WHO) projection (IARC-WHO, 2019).

Worldwide changes in the epidemiological profile of overweight and obesity haves been observed in the last decades; the convergence of these two chronic diseases can further exacerbate the health problem (Collaborators, 2017). Furthermore, it is important to know and reduce the associated modifiable factors. The aim of this chapter is to review the epidemiological behavior of cancer among the geographical areas and the convergence of cancer and obesity that have increased significantly in the last decades, as well as to describe the factors related to cancer, emphasizing exogenous and endogenous exposure and the distribution of the protective and risk factors according to the affected site of the human body.

1.2 Theoretical framework

1.2.1 Global cancer epidemiology

Epidemiology is a science that provides many tools to study the causes and effects of diseases, find means of prevention and control, and aid in generating new ideas and hypotheses. Cancer epidemiology is the branch of epidemiology concerned with the disease of cancer; in this sense, cancer epidemiology and epidemiology in general, are based on the comparison of groups of people, because the epidemiological studies are concerned not only with the people who get a disease, but also with those who do not, and in particular with how these two groups may differ. Therefore the primary units of concern are groups of people, not separate individuals; this is what differentiates epidemiology from clinical medicine. Thus epidemiology is concerned with events that occur in populations. In particular, cancer epidemiology is concerned with the study of the distribution of cancer in populations. Its goal to identify risk factors that may point toward the early introduction of effective preventive measures (dos Santos-Silva, 1999).

Currently, epidemiology is riding a wave with transforming features, such as molecular epidemiology, which is the incorporation of exposure biomarkers, early effects, and susceptibility to elucidate mechanisms and enhance the biological plausibility of statistical association, since genetic and molecular factors can play an important role in individual susceptibility and response to carcinogen exposure (Spitz & Bondy, 2010; Vineis & Perera, 2007). Many studies have demonstrated polymorphisms in genes that code for specific drug-metabolizing enzymes, and mutations in these genes can lead to impaired drug metabolism and altered drug action in patients. The degree of cancer risk associated with inheriting a mutation depends on gene penetrance, which is the probability that an individual carrying a mutation will develop the disease. Gene penetrance may be modified by a combination of genetic and environmental factors (Malhotra, 2014). Interestingly, a great variety of environmental factors can influence the metabolism of drugs and carcinogenic in humans, including diet, smoking habit, alcohol ingestion, drug administration, ingestion of herbal remedies, exposure to environmental pollutants, infection diseases, and lifestyle (Wogan, Hecht, Felton, Conney, & Loeb, 2004). Thus molecular epidemiology is one area of epidemiology that focuses on the contribution of genetic and molecular factors, the environmental risk factors, and the interplay between them at the cellular and molecular levels. Hence the molecular epidemiology has recently been used in the field of molecular biomarkers to determine exposure to potential carcinogens and identify populations that are at risk. On the basis of those concepts, this chapter briefly describes the distribution of the burden of different types of cancer in the general population.

Cancer remains a huge burden and a leading cause of morbidity and mortality worldwide, with an annual incidence of 18.1 million new cases, 9.5 million deaths related to cancer, and an estimated prevalence in the last 5 years of 43.8 million sick people, according to a 2018 WHO report (Bray et al., 2018).

Disparities between developed and developing countries have been documented. For example, 57% of cancer cases (8 million) and 65% of cancer deaths (5.3 million) occurred in developing countries. Although more cases are detected in countries with a high or very high human development index, mortality rates are similar in both low- to middle-income countries and high- to very-high-income countries. This could be related to their health systems’ capacity for the timely diagnosis, management, and treatment of patients as well as the underreporting of new cancer cases. The WHO estimates that if this trend continues, by 2040 there will be 29.5 million new cases and 16.3 million deaths, and 60% of them will occur in developing countries. The situation in Latin America and the Caribbean is similar. In 2018, 1.4 million cases were documented, and 0.6 million deaths were reported in that region, and it is estimated that by 2040, 2.5 new cases will occur with 1.3 million deaths related to cancer (Bray et al., 2018; Ferlay et al., 2019; IARC-WHO, 2019).

The distribution of types of cancer affecting the general population, according to the 2018 WHO report, is as follows: With 2.09 million, lung cancer cases denote 11.6% of the total new cancer cases documented in 2018. followed by breast cancer, with 2.08 million cases (11.6%), colorectal cancer with 1.84 million cases (10.2%), prostate cancer with 1.27 million cases (7.1%), and stomach cancer with 1.03 million cases (5.7%). The main causes of cancer-related death are lung cancer with 1.76 million cases corresponding to 18.4% of the total, follow by colorectal cancer with 0.88 million cases (9.2%), stomach cancer with 0.78 million cases (8.2%), liver cancer with 0.78 million cases (8.2%), and breast cancer with 0.62 million cases (6.6%) (IARC-WHO, 2019).

A slight difference in gender is observed. A higher proportion of new cancer cases are found in men, 9.5 million compared to 8.6 million in women. A similar trend can be observed in mortality, with 5.4 million deaths related to cancer in men and 4.2 million in women. The profile of the most common cancers affecting women is breast cancer with 24.2%, followed by colorectal cancer with 9.5%, lung cancer with 8.4%, cervical cancer with 6.6%, and thyroid cancer with 5.1%; the most common causes of cancer-related death in women are breast cancer with 15.0%, lung cancer with 13.8%, colorectal cancer with 9.5%, cervical cancer with 7.5%, and stomach cancer with 6.5%. The corresponding profile of the most comment cancers affecting men is lung cancer with 14.5%, prostate cancer with 13.5%, colorectal cancer with 10.9%, stomach cancer with 7.2%, and liver cancer with 6.3%; the main causes of cancer-related death are lung cancer with 22.0, liver cancer with 10.2%, stomach cancer with 9.5%, colorectal cancer with 9.0% and prostate cancer with 6.7% (IARC-WHO, 2019).

1.2.2 Related factors to cancer

The increasing number of cancer cases observed in recent decades is due in part to the epidemiological transition that has occurred in the world, resulting mainly from the net growth of the population and the aging effect (Bray, Jemal, Grey, Ferlay, & Forman, 2012). Particularly, in developing countries an improvement in the health indices has been observed, resulting from the decrease in infectious diseases, malnutrition, and infant mortality, which has led to an increase in life expectancy and consequently to an increase in chronic disease, including degenerative cardiovascular disease and cancer (Bray, Jemal, Torre, Forman, & Vineis, 2015).

Although the etiology of cancer currently remains mostly unknown, several epidemiological studies have determined that only the 5%–10% of all cases of cancer are caused by inheritance of mutated genes and somatic mutation; the remaining 90%–95% of cases have been linked to lifestyle factors and environment. The plasticity of cancer patterns implicates environmental factors, nutrition, and physical activity as determinants of cancer; hence there are several associated factors that can influence the development of carcinogens (Aggarwal, Vijayalekshmi, & Sung, 2009). A program of the International Agency for Research on Cancer (IARC) continuously evaluates carcinogenic risks to human through the publication of monographs by an interdisciplinary working group of expert scientists who review the published studies and assess the strength of the available evidence that an agent can cause cancer in humans. Since 1971, more than 1000 agents have been evaluated, of which more than 500 have been identified and classified in three groups:

1. Group 1: Carcinogenic to humans, comprising 120 agents. There is strong evidence in exposed human and experimental animals.

2. Group 2A: Probably carcinogenic to humans, comprising 88 agents. There is at least some limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals. The evidence could involve exposure of humans or human cells or tissue.

3. Group 2B: Possible carcinogenic to human, comprising 313 agents. There is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. These agents include chemicals, occupations or working conditions, physical agents, biological agents, dietary constituents, and other exposures of everyday life (IARC-WHO; International, 2020).

Exposure to carcinogenic conditions can occur in two ways. Endogenous exposure occurs when the individual has a genetic susceptibility or are exposed to some pathophysiological product such as chronic inflammation. Exogenous exposure occurs when the individual is continuously exposed to certain chemicals, air pollution, contaminants in food and/or water, types of diet, habits, lifestyle, infections by some bacteria, viruses, and parasites that have been shown through epidemiological studies and/or experiments to have carcinogenic or mutagenic properties. Some reports have estimated that exposure to environmental carcinogens may contribute significantly to the causation of a sizable fraction, perhaps a majority, of human cancers when exposures are related to factors such as lifestyle, diet, tobacco use, alcohol, and obesity (Wogan et al., 2004).

All of these factors are generally present in different magnitudes across different populations. The variations in the prevalence of cancer risk factors led to different cancer profiles between different geographic areas; for example, infection-related and poverty-related cancers are common in developing countries, whereas in high-income countries the cancer profile is most often associated with lifestyle. According to Bray et al., the differing cancer profiles in individual countries and between regions signify that marked geographic diversity still exists, with a persistence of local risk factors in populations that are at different phases of social and economic transition (Bray et al., 2012).

1.3 Endogenous exposure

1.3.1 Cancer susceptibility

Susceptibility to carcinogen exposure either can be the result of inheriting high penetrance but rare germline mutations that constitute heritable cancer syndromes or can be inherited as common genetic variations or polymorphisms that are associated with low to moderate risk for development of cancer. These polymorphisms can interact with environmental exposures and can influence individual cancer risk through multiple pathways, including affecting the rate of metabolism of carcinogens or the immune response. Also, genomic instability plays an important role in both inherited and sporadic cancer (Malhotra, 2014). The action mechanism of carcinogenic damage to DNA is complex but can be described in two ways. One is characterized by covalent reaction with nuclear DNA, mainly through alteration in the structure, such as the development of covalent DNA adducts. The other type involves epigenetic (nongenotoxic) effects produced by modifications of cellular macromolecules that regulate gene activity or by perturbation of cellular regulatory processes (Kobets, Iatropoulos, & Williams, 2019). It is generally recognized that genetic alterations and epigenetic perturbations are equally important in the multistage development of cancer. Nevertheless, the different mechanisms of action for testing strategies and risk assessment have important implications.

1.3.2 Spontaneous mutations

Many processes damage DNA could contribute to so-called spontaneous mutagenesis. Mutations can be defined as a change in the nucleotide sequence of DNA. These can arise as a result of DNA damage or the incorporation of noncomplementary nucleotides during DNA synthetic processes. Sources of DNA damage can be broadly divided into two categories: those that result from exogenous agents, such as chemicals, viruses, and irradiation, and those cause by reactive molecules generated by normal cellular processes. Normal cellular processes that damage DNA include the generation of reactive oxygen and nitrogen species, alkylation, depurination, and cytidine deamination (Loeb, 1989). Most of the single-nucleotide polymorphisms (SNPs) have no functional consequence if they occur in a noncoding sequence; or they might have a modest effect that may interact with environmental factors to increase cancer susceptibility. Consequently, sufficient genetic alteration must occur by oncogenic mutations with gene dysregulation to yield a cell with abnormal phenotype and growth behavior (Kobets et al., 2019). Clinical and laboratory evidence suggests that carcinogenesis requires more than mutations, since for a cancer develop, the DNA repair mechanisms would have to be absent, defective, or inefficient. Furthermore, the inactivation of tumor suppressor genes is also involved in the cell transformation process (Brucher & Jamall, 2014). Therefore these genetic polymorphisms can account for some of the geographical differences seen in cancer prevalence between different populations.

1.3.3 Epigenetics

Epigenetic molecular changes can affect gene expression, leading to abnormal proliferation without altering structural changes in the DNA sequence. The process of carcinogenesis can lead to changes in the epigenome that can contribute to aberrant activation of silenced tumor-suppressor genes and lead to chromosomal and genomic instability. Thus genome-wide or gene-specific DNA methylation and lysine methylation of certain sites on histone proteins are often implicated in repression of transcription, while another histone modification, such as acetylation, phosphorylation, and arginine methylation, promotes transcriptional activation. Expression of noncoding regulatory RNAs (miRNA) is associated with posttranscriptional silencing of target mRNA (Kobets et al., 2019). The epigenetic mark that has been most highly studied is DNA methylation, involving the addition of a methyl group to the 5′ cytosine of C-G dinucleotides; referred to as CpG. These dinucleotides are often located near gene promoters and are associated with gene expression levels. In particular, DNA methylation can affect transcription factor binding sites, insulator elements, and chromatin conformation, resulting in multiple levels of control of expression (Jones, 2012).

Over the last few years, studies have focused on the relationship between epigenome and cancer. Some studies have reported that some cancers have unique methylomes that define distant molecular subtypes of cancer. For instance, a hypermethylator phenotype called the CpG island methylator phenotype (CIMP), which is seen predominantly in the elderly and in the right colon, can be identified in approximately 15% of cases of colorectal cancer. Gliomas, gastric cancer and its precursor intestinal metaplasia, acute myeloid leukemia, and recently esophageal adenocarcinoma also have unique methylomes (M. Yu, Hazelton, Luebeck, & Grady, 2020).

Currently, social epigenomics has emerged as an integrative field of research focused on identification of socioenvironmental factors, their influence on human biology through epigenomic modifications, and how they contribute to current health disparities. Using genetics-based approaches, researchers are focusing on epigenetic changes in response to environment (Mancilla et al., 2020).

1.3.4 Hereditary cancer

Since the advent of molecular biology in the 1980s, research on cancer susceptibility has seen tremendous advances. Several genomic aberrations have been identified, and researchers have studied their role in carcinogenesis, the understanding of molecular pathobiology in hereditary cancer syndromes. The Human Genome Project, which sequenced the DNA of the entire human genome, has been one of the most important developments in this field. More recently, the genome-wide association study (GWAS) approach has permitted the analysis of genetic variations and identification of new susceptibility genes relating to several diseases, including cancer. Usually, once a cancer has been ascertained to have a genetic component through familial aggregation studies, the next step is to identify the pattern of Mendelian inheritance (autosomal dominant or recessive) using segregation analysis. Then linkage analysis is used to localize the chromosomal region containing the susceptibility gene (Malhotra, 2014). Although hereditary cancer syndromes affects only a small proportion of all cancer patients, those patients may benefit from effective management because many molecular targeted therapies have been developed on the basis of the inherited genomic aberrations.

Here, we discuss three different hereditary cancer syndromes associated to cancer with high incidence in world population.

In 1996 a linkage analysis was conducted, studying 23 families with multiple individuals affected with early-onset breast cancer. This approach allowed identification of the BRCA-1 and BRCA-2 susceptibility. Positional cloning in the 17q21 region on the chromosome localized the BRCA-1 gene. BRCA-1 appears to be a nuclear protein, expressed a within subnuclear structure of unknown function and induced by signals that stimulate cell proliferation and differentiation, including estrogens and progesterone. It has been proposed to play a role in the maintenance of genome integrity, meiotic recombination, and potentially the inhibition of malignant growth. Two years later, BRCA-2 was identified on chromosome 13q12-13. It is a very large gene with 10,485 nucleotides, spanning more than 70,000 bases of genomic DNA and encoding a protein of 3495 amino acids; several inactivating mutations are distributed throughout the length of the gene, and over 90% of mutations result in premature truncation of the protein. Both genes are tumor suppressors, and mutations in BRCA 1 and 2 are associated with others malignancies besides breast cancer. Individuals with BRCA-1 mutations are also at risk of developing cervical uterine, pancreatic, stomach, and prostate cancer, whereas patients with BRCA-2 mutation are at increased risk of developing melanoma, gallbladder, bile duct, pancreatic, stomach and prostate cancer. Fewer than 10% of breast cancer patients have hereditary mutations, but the incidence is higher among individuals with a family history of breast cancer. The frequency of BRCA-1 mutations in the general population is estimated to be 1 in 500 to 1 in 1000; however, BRCA-1 is found in approximately 12% of young women and in 1% of women over 50 years of age. Data suggest that BRCA-2 has a lower age-specific penetrance in comparison to BRCA-1; in a study of 32 younger women, BRCA-2 showed a frequency of 2.7% compared to 12% reported for BRCA-1. The association between BRCA-2 mutations and cases of male breast cancer appears to be dependent upon family history (Ellisen & Haber, 1998). The factors that could modify the penetrance appear to be reproductive factors and exogenous hormones. The management of those patients includes risk-reducing surgery (mastectomy), chemoprevention, genetic testing, cancer screening, and surveillance.

Lynch syndrome, or hereditary nonpolyposis colorectal cancer syndrome, is an autosomal-dominant disorder caused by germline mutations in DNA mismatch repair gene system. This system is involved in recognizing and repairing base pair mismatches; in consequence, the inactivation of these genes leads to failure of DNA mismatch repair, resulting in increased mutations rates, most commonly in regions of repetitive nucleotide sequences called microsatellites. Nowadays, the microsatellite instability can be tested in tumors by using polymerase chain reaction. These aberrations were identified on MSH2 and MSH6 on chromosome 2p16, MLH1 on chromosome 3p21, and PMS2 on chromosome 7p22; germline mutations in EPCAM have also been linked to Lynch syndrome. The EPCAM is upstream of MSH2 and leads to loss of MSH2 expression by hypermethylating the promoter (H. T. Lynch et al., 1993; Yurgelun et al., 2012). Approximately 1%–4% of all patients with colorectal cancer have an underlying familial genetic syndrome such as Lynch syndrome. The incidence of extracolonic tumor is higher in patients with MSH2 mutations (Bonadona et al., 2011). Patients with Lynch syndrome have an increased risk for developing colorectal cancer and other malignancies, such as endometrial, ovarian, upper urinary tract, gastric, small bowel, biliary, and pancreatic cancers. The management of Lynch syndrome involves counseling, surveillance in carriers and families, and chemoprevention. Although the genetic mechanisms behind Lynch syndrome are understood, no target therapy has been development for the defective mismatch repair system (Koehler-Santos et al., 2011).

Cowden syndrome is an autosomal-dominant inherited syndrome involving different tumor types, including sporadic glioblastoma and prostate, kidney, and breast cancers. It was mapped in chromosome 10q23 by germline mutations in the MMAC-1 gene (mutated in multiple advanced cancer), and the PTEN gene (phosphatase and tensin homolog deleted on chromosome 10) compromises 9 exons encoding 403 amino acids by sequence analysis if the open reading frame demonstrated a protein tyrosine phosphatase domain and homology to tensin. Examination of the predicted amino acid sequence has shown two domains of homology with other known proteins, providing clues about the potential fiction of this gene. The first is a protein tyrosine phosphatase domain, which suggest a role in removing phosphate moieties from other cellular proteins; since the transforming effects of many oncogenes are linked to their ability to activate proteins through the addition of a phosphate group (i.e., tyrosine kinase activity); the observation that a tumor suppressor gene may function to remove such phosphate groups is of particular interest. The second functional domain is similar to chicken tensin and bovine auxilian proteins, suggesting a potential role for PTEN/MMAC in cell adhesion and signaling. Cowden syndrome is characterized by multiples hamartomas of the skin, breast, thyroid, oral mucosa, and intestinal epithelium; early-onset breast cancer and variable neurological manifestations; and early-onset uterine leiomyoma (Ellisen & Haber, 1998; E. D. Lynch et al., 1997). Females with Cowden syndrome have been reported to have as high as a 67% risk for fibrocystic disease of the breast and a 25%–50% lifetime risk of developing adenocarcinoma of the breast. For the management of Cowden syndrome there is an International Cowden Consortium for operational diagnostic and treatment criteria (Eng, 1998).

1.3.5 Chronic inflammation

Since Rudolf Virchow in the 19th century observed the presence of leukocytes within tumor tissues and made a connection between inflammation and cancer, he suggested that the lymphoreticular infiltrate reflected the origin of cancer at sites of chronic inflammation. Over the past years our understanding of the inflammatory microenvironment of malignant tissue has supported Virchow’s hypothesis. Several studies have focused on the information about the cytokine and chemokine networks and pathways for the inflammatory role in the development of carcinogenesis (Balkwill & Mantovani, 2001). Nowadays, inflammatory response plays a decisive role at different stages of tumor development, including initiation, promotion, growth, invasion, and metastasis (Fernandes et al., 2015; Grivennikov, Greten, & Karin, 2010). Inflammatory response involves a well-coordinated response of an innate and adaptive immune system. Mediators of the inflammatory response, such as cytokines, free radicals, prostaglandins, and growth factors, can induce genetic and epigenetics changes. including point mutations in tumor suppressor genes, DNA methylation. and posttranslational modifications, causing alterations in critical pathways responsible for maintaining the normal cellular homeostasis and leading to the development and progression of cancer (Hussain & Harris, 2007).

Although acute inflammation that persists only for the short term mediates the host defense against infections; long-term chronic inflammation can predispose the host to various chronic illnesses, including cancer. Cells can initiate the inflammatory response by releasing cytokines, chemokines, matrix-remodeling proteases, and reactive oxygen and nitrogen species, leading to the elimination of pathogens and the repair of tissue damage. Furthermore, dendritic and natural killer cells can also active the adaptive immune response that requires antigen specificity; when the inflammatory response is deregulated or the precise control of immune components fails, the result can be chronic inflammation with the potential to cause injury, necrosis, and malignant transformation, and this may favor the initiation and progression of cancer (Fernandes et al., 2015; Hussain & Harris, 2007).

It has been well established that chronic inflammation is strongly associated with several human cancers. Chronic inflammatory conditions involving different organs and tissues have been found to put the individual at risk of progression to cancer, since a wide array of proinflammatory cytokines, prostaglandins, nitric oxide products, and matricellular proteins are closely involved in premalignant and malignant transition of cells. Epigenetic disorders such as point mutations in cellular tumor suppressor genes, DNA methylation, and posttranslational modifications are associated with transformation of normal cells into cancer cells (Aggarwal et al., 2009).

Generally, most cancers, especially solid tumors, are preceded by inflammation of a specific organ, such as cervicitis, gastritis, colitis, hepatitis, or bronchitis. People who smoke cigarettes are prone to develop bronchitis, and 15%–20% of them develop lung cancer. Similarly, people who frequently have colitis are at high risk of developing colon cancer, and infection with Helicobacter pylori can induce gastritis, which in its chronic form can lead to gastric cancer. In the inflammatory microenvironment, excessive reactive oxygen species (ROS) and reactive nitrogen species are produced in cells and may cause DNA damage as indicated by the breakage of DNA strands, DNA methylation, and the silencing of DNA repair enzymes. Mutations in cancer-related genes occur i.e., tumor suppressor genes such as p53 may be inactivated, while oncogenes such as Kras may be constitutively activated, which may cause malignant transformation of cells (Y. Zhang, Kong, & Jiang, 2017).

After the initiation of cancer, infiltrating inflammatory cells and proinflammatory cytokines in the tumor microenvironment are important for the survival, proliferation, invasion, and metastasis of cancer cells. Among the infiltrating inflammatory cells, tumor-associated macrophages (TAM) play the principal role. By releasing cytokines such as colony-stimulating factor 1 (CSF-1), cancer cells are able to recruit TAMs and will express and release excessive proinflammatory such as interleukin 6 (IL-6), interleukin 1 beta (Il-1β), tumor necrosis factor α (TNF-α), which may act on cancer cell in a paracrine manner; thus proinflammatory cytokines could stimulate multiple and interweaving signaling pathways in cancer cells, among which the nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) pathways are of importance and critical for progression of cancer. NF-κB and STAT3 are transcription factors. Upon activation they will translocate into the nucleus and stimulate the expression of target genes. They may interact at the protein level, their target genes overlap, and they may activate the transcription of target genes cooperatively (Y. Zhang, Kong, & Jiang, 2017). For instance, a proinflammatory stimulus such as TNF, IL-1, Il-6, cyclooxygenase 2 (COX-2), and 5-lipo-oxygenase, all regulated by the NF-κB pathways, have been shown to be expressed in inflammations such as bronchitis, colitis, cervicitis, and gastritis (Aggarwal et al., 2009).

Epigenetic modifications cause genetic disturbance and changes in gene expression profiles. One of the common epigenetic changes is DNA methylation. It is conducted by specific enzymes that are present in all human cells. The enzymes needed for the addition of a methyl group (CH3) are named DNA methyltransferases. These enzymes maintain a methylation profile using S-adenosyl as the methylation donor. The methylation process stops the expression of genes, either by binding to transcription factors or by recruiting methylated DNA-binding proteins (Verma, 2015). For instance, hypermethylation of promoters leads to the transcriptional silencing of several tumor suppressor genes, including APC, p16, BRCA-1, Rb, and MDM2, and are associated with cancer development. CH3 addition at the carbon 5 position of the cytosine ring resulting in 5-methyl cytosine, along with 5′-methylcytosine (5mC), 5′-hydroxylcytosine (5hmC) associated with ten-eleven-translocation 2 also has been reported in cancer tissue samples. Methylated CpG sites are also prone to the deamination, leading to missense mutations in cancer-related genes (Hussain & Harris, 2007). Epigenetic perturbations (miRNA aberrations, altered DNA methylation) together with important steroid hormone metabolic changes (i.e., estrogens) or the altered vitamin D concentrations that may unbalance the immune-inflammatory response have been found to be linked to the risk and severity of several chronic inflammatory conditions as well as of cancer (Milagro, Mansego, De Miguel, & Martinez, 2013). The inflammation-mediated cytosine damage can alter the methylation pattern and critical gene regulation; that is, the proinflammatory cytokine IL-6 enhances and maintains hypermethylation of the p53 tumor suppressor gene a key component of the nucleotide excision repair, promoter in multiple myeloma cell line KAS-6/1; furthermore, IL-6 decreases promoter methylation of epidermal growth factor receptor, leading to the enhanced expression and growth of cholangiocarcinoma cells. These results suggest that DNA methylation is a mechanism that could contribute to inflammation-associated tumorigenesis (Hussain & Harris, 2007).

On the other hand, the human leukocyte antigen (HLA) genes encode proteins required for presentation of foreign antigens, including peptides, to the immune system for targeted lysis. For instance, Epstein-Barr virus (EBV) infection has been associated to gastric cancer and nasopharyngeal cancer. Individuals who inherit HLA alleles with a reduced ability to present EBV antigens may have an increased risk for developing those cancers, whereas individuals with an HLA allele that present EBV efficiently may have a lower risk (Malhotra, 2014).

1.4 Exogenous exposure

Exogenous factors, such as infections, environmental pollutants, food and water contamination, infections, habits such as alcohol and tobacco use, radiation, a high-calorie diet, and obesity, have been recognized as major risk factors for the most common types of cancer. Control and reduction of these agents are complex, as they may have numerous sources and widespread; consequently, this involves multisectoral efforts.

1.4.1 Infections

Infections with viruses, bacteria, and parasites have been identified as strong risk factors for specific cancers. In 2009, thirty-six scientists from 16 countries met at the IARC to reassess the carcinogenicity of the biological agents that had been classified as carcinogenic Group 1. They identified eleven infectious pathogens, seven viruses, one bacterium, and three parasites; the action mechanisms of these microorganisms include cell proliferation, inflammation, inhibition of apoptosis, immunosuppression, genomic instability, cell migration, inhibition of DNA damage response, transformation, oxidative stress, methylation, mutations, altered cellular turnover, and gene expression. Following are brief descriptions of the cancers for which there is sufficient evidence for their association with infectious agents: (1) Epstein Barr virus (EBV): associated with nasopharyngeal carcinoma, Burkitt lymphoma, non-Hodgkin and Hodgkin lymphoma, and extranodal NK/T cell lymphoma (nasal type); (2) hepatitis B virus (HBV): associated with hepatocellular carcinoma; (3) hepatitis C virus (HCV): associated with hepatocellular carcinoma and non-Hodgkin lymphoma; (4) human immunodeficiency virus type 1 (HIV): associated with Kaposi sarcoma, non-Hodgkin and Hodgkin lymphoma, cervical cancer, anal cancer, and conjunctival cancer; (5) Kaposi sarcoma herpesvirus (KSHV): associated with primary effusion lymphoma, Kaposi sarcoma; (6) human papillomavirus (HPV): associated with cervical, vulvar, vaginal, penile, anal, oral cavity, oropharyngeal, and tonsillar cancer; (7) human T cell lymphotropic virus type 1 (HTLV): associated with T cell leukemia and lymphoma in adults; (8) H. pylori: associated with noncardia gastric carcinoma and low-grade B cell mucosa-associated lymphoma tissue gastric lymphoma; (9) Clonorchis sinensis: associated with cholangiocarcinoma; (10) Opisthorchis viverrini: associated with cholangiocarcinoma; and (11) Schistosoma haematobium: associated with urinary bladder cancer. The four most important are HPV, HBC, HCV, and H. pylori because together they account for more than 90% of the infection-related cancer worldwide (Bouvard et al., 2009; de Martel, Georges, Bray, Ferlay, & Clifford, 2020). Convergent evidence from epidemiology, pathology, and oncology suggests that new viral etiologies for cancer still remain to be discovered (Chen et al., 2019).

The human microbiome project (HMP) is defined as the study of the commensal microorganisms (the microbiota) that live on all the surface barriers of our body and are particularly abundant and diverse in the distal gut. The cross-talk between the commensal microbes and the host is essential for the maintenance of physiological homeostasis, response to environmental changes, and survival. Evidence that has accumulated in the last few years suggests that the composition of the microbiota at the epithelial barrier affects systemic functions, including metabolism, energy balance, central nervous system physiology including cognitive functions, cardiovascular functions, nutrition, circadian rhythm, inflammation, innate resistance, and adaptive immunity. Disruption of the symbiotic relationship between the host and the microbiota is commonly referred to as dysbiosis. Dysbiosis leads to a failure to control pathogenic microorganisms, to a dysregulated inflammatory or immune response against commensals, and as a result to severe acute and chronic tissue damage, for example, in inflammatory bowel diseases such as Crohn and ulcerative colitis. Another example, chemotherapy or radiation in the intestinal mucosa, could allow transmucosal translocation of bacteria and contribute to therapy-induced dysbiosis (Dzutsev et al., 2017).

The composition of the microbiota at various anatomical sites is controlled by host genetics, particularly by the polymorphisms in immune-related genes, as well as by environmental factors, such as lifestyle and nutrition. For instance, the gut microbiota has functions in detoxification of dietary components, reducing inflammation, and maintaining a balance in host cell growth and proliferation. The most prevalent intestinal bacteria belong to the six phyla: Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria, Verrucomicrobia, and Fusobacteria (Garrett, 2015). The physiological interaction between the host immune system and the gut microbiota is important for preventing tissue-damaging inflammatory responses directed against commensals such as different species of Lactobacilli and Proteobacteria in the small intestine and Clostridia and Bacteroides in the colon while avoiding infection by pathogens such as Salmonella and Shigella and the uncontrolled growth of indigenous pathobionts such as Clostridium difficile and vancomycin-resistant Enterococci. The gut microbiota is characterized by temporal stability and resilience, including the ability to restore itself after perturbation (Dzutsev et al., 2017).

The HMP revealed that the microbiome is formed not only by bacteria (bacteriome), but also by virus (virome) and fungi (mycobiome). The ways in which microbes and microbiota contribute to carcinogenesis, whether by enhancing or diminishing a host’s risk, fall into three broad categories: (1) direct influence on the balance of host cell proliferation and death, (2) modulation of immune system function, and (3) Influencing and interaction with the host biochemistry metabolism (Bilski et al., 2020; Garrett, 2015). Recently, a comprehensive collection of whole-genome and whole-transcriptome data from cancer tissue has been generated within the International Cancer Genome Consortium project, providing a unique opportunity for a systematic search for tumor-associated viruses. Data from 2658 cancer across 38 tumor types were analyzed, and potential viral pathogens were identified by using a consensus approach that integrated three independent pipelines in 382 genomes; 68 transcriptome dataset viruses were detected, with a high prevalence of known tumor-associated virus (Zapatka et al., 2020).

The term bacteriotherapy came from an appreciation for the coadaptation between host and microbe. Revising this knowledge and using bacteria to trigger the immune system to attack and destroy cancer dates back to the 1850s, when several German physicians noticed that some cancer patients with active infections showed signs of tumor regression. Around 1900 this led Coley to test bacterial extracts in patients with bone cancers. Heat-killed cultures of Streptococcus pyogenes and Serratia marcescens, or Coley’s toxins, were one of the earliest forms of bacteriotherapy (Mellman, Coukos, & Dranoff, 2011).

Current chemotherapeutic agents have a narrow therapeutic window because there is interest in the microbiota’s modulation of the chemotherapy toxicity and efficacy. Because microbes not only trigger and reinforce proinflammatory immune circuits but also exploit or elicit immunosuppressive responses, microbes may take advantage of preexisting immunosuppression or elicit immune-dampening responses that can also contribute to impaired antitumor immunity (Garrett, 2015). Although both chemotherapy and radiation can modify the composition of the microbiota and exert toxicity, one of the most promising anticancer therapeutic approaches is the adoptive transfer of expanded, tumor-specific cytotoxic CD8+ T cells. In this case, some level of lymphoablation and myeloablation in the host is necessary for the survival of the incoming T cells and effectiveness of the transfer. Nowadays, in both patients and mice, total body irradiation increases the efficacy of the adoptively transferred tumor specific cytotoxic CD8+ T cells and favors dendritic cell activation and the production of homeostatic cytokines. The use of total body irradiation in the myeloablative conditioning regimen for adoptive T cell transfer therapy in cancer patients has been shown to increase the efficacy