11.2 From Notes - Cancer Etiology: Genes, Environment, Lifestyle

Cancer Etiology: Genes, Environment, and Lifestyle

• Cancers stem from the interaction of environmental, lifestyle, and genetic variables.
• Genetic and epigenetic modifications drive cancer development.

Genetic and Epigenetic Factors

• Genetic and epigenetic alterations change key cancer genes like oncogenes and tumor-suppressor genes.
• Epigenetic processes, particularly gene silencing of key regulatory genes, are crucial in cancer development.
• Different cancers exhibit distinct combinations of mutations and epigenetic modifications.
• Epigenetic regulation allows neoplastic cells to undergo dynamic and reversible changes between multiple phenotypic states.

Interacting Factors

• Detoxing enzymes, DNA repair genes, and the immune/inflammation systems influence cancer risk.
• The cell's surrounding biologic environment, including metabolic and hormonal factors, also plays a role.
• The tissue microenvironment/stroma participates in intricate signaling that facilitates tumor promotion and metastasis.
• Infiltrating immune cells induce chronic inflammation which can create a tumor-progressing environment, and initiate changes like inflammation-induced colon cancer.
• Chronic inflammation, caused by various factors, promotes cancers like colon, liver, and lung.
• Chronic inflammation promotes cancer development with continuous presence of cytokines, chemokines, reactive oxygen species (ROS), oncogenes, and activation of transcription factors.
• Researchers aim to understand individual cancer risk by connecting genotype, phenotype, and environment-lifestyle factors.

Incidence and Mortality Trends

• Cancer is projected to be a major global cause of morbidity and mortality.
• In 2012, there were an estimated 14.1 million new cases and 8.2 million cancer deaths reported.
• Cancer incidence has reportedly increased among people ages 0 to 19 years.
• In 2012, 28,012 people were diagnosed with liver cancer in the US.
• Men had about a threefold higher incidence rate of liver cancer than women.
• Liver cancer incidence rates were higher among people born between 1945 and 1965.

In Utero and Early Life Conditions

• Early life events can influence later susceptibility to chronic diseases.
• Developmental plasticity is the degree to which an organism’s development depends on its environment.
• Nutrition and environmental factors affect cellular pathways during gestation, leading to diverse adult phenotypes from a single genotype.
• Persistent epigenetic adaptations early in development are associated with increased susceptibility to cancer, linked to maternal/paternal nutrition and environment.
• The placenta controls growth and development in utero and is affected by exposures during pregnancy.
• Under-nutrition during the first trimester is particularly vulnerable to disease manifestation in adulthood, with associated increased heart disease, metabolic disorders, and possible breast cancer link.
• Maternal nutrition can cause phenotype changes in offspring through epigenetic mechanisms like gene silencing.
• Diethylstilbestrol (DES), a synthetic estrogen, is linked to increased risk of clear cell adenocarcinoma and potential breast cancer risk in daughters.
• Early life exposure to endocrine-disrupting chemicals (EDCs), including DES, can increase uterine fibroids.
• Small changes in the developmental environment can alter phenotypic changes, resulting in individual responses in adulthood, via epigenetic mechanisms.

Environmental-Lifestyle Factors

• Avoiding high-risk behaviors and carcinogen exposure can prevent many cancers.
• Lifestyle, dietary, and environmental factors contribute to cancer cases and deaths.

Tobacco Use

• Over 20 million Americans have died due to smoking-related illnesses since 1964, including non-smokers.
• Secondhand smoke (ETS) is a human carcinogen.
• Tobacco smoking is linked to cancers of the lung, upper aerodigestive tract, stomach, lower urinary tract, kidney, pancreas, cervix, uterus, myeloid leukemia, liver, and colorectal cancer.
• Secondhand smoke increases the risk of stroke and death in people with cancer and other noncancerous conditions, increases inflammation, and impairs immunity.
• Cigars have similar risks; regular cigar smoking increases the risk of cancers of the lung, esophagus, larynx, and oral cavity.
• Pipe smokers have increased risk of dying from cancers of the lung, throat, esophagus, larynx, pancreas, and colorectum.
• Electronic cigarettes (e-cigarettes) deliver nicotine with flavorings.
• Smoking results in epigenetic changes associated with development of cancer.
• Cigarette smoke induces an inflammatory response and other cellular changes that can lead to cancer and COPD.

Diet, Nutrition, Obesity, Alcohol Consumption, and Physical Activity

• Lifestyle and nutrition are associated with the development or progression of tumors.
• The Mediterranean diet (MD) reduces mortality from chronic diseases, showing a 13% risk reduction in overall cancer mortality with higher adherence to the diet.
• Components of the MD have anti-cancer properties.
• Dietary components can interfere with mutagen elimination.
• Food components with cancer-preventive potential include polyphenols, selenium, methyl group donors, retinoids, isothiocyanates, allyl compounds, and mono- and polyunsaturated fatty acids.
• Dietary factors can alter microRNA expression, which are involved in several cancers.
• Food can affect cancer stem cell differentiation and DNA repair.
• The body has defense systems against xenobiotics, including detoxification enzymes and antioxidant systems.
• Food and nutrition can modify carcinogen metabolism.
• High red meat and processed meat consumption is linked to increased risk of colorectal cancer. and are classified as carcinogens and red meat as probable carcinogens by the IARC.
• Overweight and obesity increase the risk for cancers, and is recognized as a poor prognostic factor for cancer. There is Chronic inflammation and altered adipokines associated with it.
• Excessive alcohol consumption increases the risk of cancers of the mouth, pharynx, larynx, esophagus, liver, colorectal cancer, and postmenopausal breast cancer. It involves acetaldehyde, oxidative stress, and nutritional deficiencies.
• Physical activity is associated with a decreased risk of colon, postmenopausal breast, and endometrial cancers.
• The WHO recommends at least 600 MET minutes of total activity per week.
• Exercise releases myokines, which have benefits that include increasing insulin sensitivity and inducing apoptosis in breast and colon cancer cells.

Air Pollution

• Ambient air pollution increases mortality and morbidity from cardiovascular, respiratory disease, and lung cancer.
• The IARC has concluded that exposure to outdoor air pollution and particulate matter (PM) is carcinogenic causing lung cancer.
• Fine and ultrafine particles can be absorbed by the lungs and cause inflammation.
• Particulate matter adverse cellular effects of PM include oxidative stress, ROS generation, DNA oxidative damage, mutagenicity, inflammation, and cell senescence
• Diesel exhaust causes lung cancer and involves pulmonary inflammation, leading to oxidative stress, DNA damage, and tumor development.
• Indoor air pollution, particularly from environmental tobacco smoke (ETS), can cause DNA damage and is a human carcinogen.

Ionizing Radiation

• Human exposure to ionizing radiation (IR) includes emissions from the environment (radon), x-rays, CT scans, and radioisotopes.
• Exposure to IR leads to leukemia, thyroid, breast, lung, bone, stomach, esophagus, lymphoma, brain, and skin cancers.
• Low doses of x-rays can induce DNA damage and apoptosis.
• Chronic inflammation is implicated in radiation-induced late tissue injury.
• IR can cause somatic mutations and tissue alterations.
• The human embryo and fetus are particularly sensitive to IR.
• Misrepair of DSBs can lead to chromosomal instability.
• Nontargeted effects (NTEs) are important in IR-induced carcinogenesis.
• Radiation-induced cancer has latent periods.

Ultraviolet Radiation

• The principal source of UV radiation is sunlight.
• UV radiation causes basal cell carcinoma and squamous cell carcinoma.
• Intermittent acute sun exposure leading to sunburn increases the risk of melanoma.
• Pathogenesis of nonmelanoma skin cancers involves gene mutations, DNA methylation, histone modifications, oxidative stress, inflammation, and reduced immune surveillance.
• ROS induced by UV can activate transcription factors and increase levels of regulating genes that induce inflammation.

Electromagnetic Radiation

• Exposure to electromagnetic fields (EMFs) is widespread.
• The IARC classified EMFs as a possible cause of cancer.
• There is a possible increased risk of glioma with higher mobile phone usage.
• Children have increased vulnerability to radiation and longer potential use of cell phones.

Infection, Sexual and Reproductive Behavior, Human Papillomaviruses

• Infections contribute to cancer worldwide.
• The most significant infections linked to cancer include Helicobacter pylori, human papillomavirus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), and Epstein-Barr virus (EBV).
• HPV is the most common sexually transmitted infection, and can lead to cervical intraepithelial neoplasia (CIN), lesions, and invasive cervical cancers.
• Persistent HPV infections can lead to mutations and tumor formation.

Other Viruses and Microorganisms

• Parasites like Opisthorchis viverrini and Schistosoma haematobium are involved in carcinogenesis.

Chemicals and Occupational Hazards as Carcinogens

• Numerous synthetic chemicals are used, and toxicity information is limited.
• Chemical carcinogenesis involves genotoxic and nongenotoxic mechanisms.
• Asbestos exposure increases the risk of lung cancer, along with asbestosis and mesothelioma.
• Bladder cancer is linked to dyes, rubber, paint, and aromatic amines.
• Benzol inhalation is linked to leukemia.
• Diesel exhaust exposure causes lung cancer.

Etiology of Cancer

• Avoiding high-risk behaviors and decreasing exposure to individual carcinogens can prevent many types of cancer.
• Cancers stem from environmental, lifestyle, and genetic factors.
• Exposures in utero and early life conditions can significantly influence the risk of certain cancers.

Developmental Plasticity and Early Life Exposures

• Developmental plasticity is defined as how an organism's development depends on its environment.
• Nutrition and environmental factors affect cellular pathways during gestation.
• Epigenetic adaptations in early development are associated with increased susceptibility to cancer.
• Exposure to nutrition revealed that the first trimester of pregnancy is particularly vulnerable to disease outcome.
• Small changes in the developmental environment can lead to phenotypic changes resulting in adult responses.

Tobacco Use

• Cigarette smoking is carcinogenic and remains the most important cause of cancer and death from cancer.
• Elevated mutation burden in smoking causes lung adenocarcinoma, larynx, liver, and kidney cancer.
• Cigarette smoke induces an inflammatory response, leading to reactive oxidative oxygen species, resulting in oxidative stress, a risk factor for many diseases.

Nutrition

• Diet, weight, and physical activity significantly influence the risk of developing cancer.
• Epigenetic processes act synergistically with genetic changes during carcinogenesis and tumor progression.
• A reduction in risk of chronic illness and mortality is associated with the Mediterranean diet.
• Three main factors link obesity and cancer: the insulin/insulin-like growth factor axis, sex hormones, and adipocyte-derived cytokines.
• Obesity results in increased estradiol levels, which can promote the growth of estrogen-dependent cancers.
• Alterations in adipose tissue due to obesity lead to insulin resistance, hyperglycemia, dyslipidemia, hypoxia, and chronic inflammation.

Alcohol

• Alcohol increases the risk of cancer of the mouth, pharynx, larynx, esophagus, liver, breast, and colorectal cancer.
• Factors contributing to this increased risk are oxidative stress and nutritional deficiencies.

Physical Activity

• Physical activity is associated with a decreased risk of developing 13 different types of cancer and WHO recommends at least 600 metabolic equivalent minutes
• Physical activity reduces cancer risk by: decreasing insulin and IGF levels, decreasing obesity, altering inflammatory mediators, decreasing oncogene levels, decreasing levels of metabolic and sex hormones, improving immune function, and enhancing cytochrome P450 activity.

Air Pollution

• Long-term exposure to ambient air pollution increases mortality and morbidity from cardiovascular and respiratory disease as well as lung cancer.
• Particulate matter in the air causes increased oxidative stress, reactive oxygen species generation, DNA oxidative damage, mutagenesis, stimulation of pro-inflammatory factors, and induction of senescence.

Ionizing Radiation

• Induces apoptosis and senescent cells
• Associated with multiple cancers
• Can cause oncogene activation, tumor suppressor gene deactivation
• Chromosomal and mitochondrial alteration and disrupting cellular regulation

UV Radiation

• Is the most preventable cause of skin cancer
• Causes basal and squamous cell carcinoma and melanomas

Electromagnetic Radiation (EMR)

• The most common exposure to EMR is from wireless communication devices and equipment.
• There is concern for the effects in later life for children who start using mobile devices at a young age.

Infection

• Infection with viruses can directly lead to cancer.
• Vaccines have been developed for the most significant types of HPV.
• HPV is the most commonly sexually transmitted virus in the US, almost half of all vaginal, vulvar, and penile cancers are caused by HPV.