Cancer: Causes, Genetics, and Tissue Microenvironment

• Cancer is an abnormal growth that results from uncontrolled proliferation and serves no physiological function.
• Cancer is derived from the Greek word "karkinoma" meaning "crab."
• Cancer is also referred to as a neoplasm or "new growth."

Key Associations and Causes of Cancer

• Key Associations and Causes of Cancer include: sun exposure, reproduction, occupational hazards, ionizing radiation, infections, post-menopause, tobacco, alcohol, indoor and outdoor air pollution, lack of fruit and vegetables, processed/red meat, lack of fiber, lack of physical exercise, overweight, and hyperglycemia/diabetes.

Genetics, Epigenetics, and Tissue

• Environmental factors, lifestyle behaviors, and genetic factors contribute to the development of cancers.
• Genetic alterations and changes in epigenetic regulation drive cancer
• Tissue microenvironment or stroma is involved in cancer development and progression.
• Infiltrating immune cells can cause chronic inflammation, which creates a permissive environment for tumor progression.
• Epigenetic processes influence cancer initiation, progression, and treatment.
• Factors that influence cancer risk include detoxifying enzymes, DNA repair genes, immune/inflammatory systems, a cell's immediate environment, and metabolic/hormonal factors.
• Prenatal and early-life exposures impact susceptibility to cancer
• Parental exposures before conception, nutrition, DES exposure, and gene-environment interactions are conditions that increase susceptibility to cancer.
• Developmental plasticity refers to the degree to which development is contingent on its environment.
• Reducing cancer risk must start early in life though avoiding sun exposure during peak hours, covering the skin, increasing physical exercise, and avoiding high-risk sexual practices.

Incidence and Mortality Trends Canada

• Overall cancer rates are higher for men than women in Canada.
• The highest cancer rates are observed in Denmark.
• Declines in lung cancer correlate with decreased tobacco use in Canada.
• Cancer rates have increased for ages 0-19 in Canada.
• Cancer deaths have decreased in men, women, and children.
• Liver cancer is the most predominant cancer.
• Mortality rates from liver cancer in men are more than double the rate for women.
• 2 in 5 Canadians will develop cancer in their lifetime.
• 1 in 4 Canadians will die from cancer.
• Cancer is the leading cause of death among Canadians.
• Lung cancer is the leading cause of cancer death in Canada, responsible for more deaths, compared to colorectal, breast and prostate cancer combined.
• There has been a substantial drop in the lung cancer death rate in recent decades.
• Cancer survival has also increased.
• About 90% of cancer diagnoses occur among Canadians who are at least 50 years of age.
• In 2019, cancer was the leading cause of disease-related death in children under 15 years in Canada
• Across Canada, cancer incidence and death rates are generally higher in the east than in the west.

Environmental & Lifestyle Factors

• Cigarette smoking is a known carcinogen and the most important risk factor for cancer.
• Cigarette smoking is linked to cancers of the lung, mouth, lips, nasal cavity and sinuses, larynx, pharynx, esophagus, pancreas, kidney, uterus, cervix, colon and rectum, liver, and acute leukemia.
• Environmental tobacco smoke second hand smoke increases the risk for lung cancer.
• Dietary components can act directly as mutagens or interfere with the elimination of mutagens.
• Xenobiotic chemicals found in human diets can be toxic, mutagenic and carcinogenic
• Lack of Glutathione-S-transferases (GSTs) may increase risk of cancer
• Interfering with defense mechanisms, affects the cell cycle.
• Primary dietary potential donors of DNA methylation include folate, choline, B vitamins
• Dysregulation of DNA methylation impacts risk of cancer
• Altered micro-ribonucleic acid (miRNA) predisposes an individual to cancer.
• Suppressing cancer stem cell renewal decreases risk of cancer
• Consuming kiwi fruits, cooked carrots, or supplemental coenzyme Q10 can improve DNA repair.
• Obesity is associated with cancers like endometrial, colorectal, kidney, esophageal, breast, pancreatic, and other cancers.
• Obesity is correlated with the body mass index (BMI).
• Energy expenditure involves resting metabolic rate, thermic food effects, and physical activity.
• Consuming alcohol increases risk for cancers of the oral cavity, pharynx, larynx, esophageal, liver, colorectal, & breast cancers.
• Combination of cigarette smoking & alcohol consumption increases risk for malignant tumours.
• Air pollution is linked to lung cancer.
• Smog increases daily mortality.
• Particle pollution causes pulmonary inflammation, oxidative stress and oxidation of DNA, nonfatal heart attacks, irregular heartbeat, and decreased lung function.
• Indoor air pollution is worse than outdoor pollution, cigarette smoke, and radon causes lung cancer.
• X-ray machines, radioisotopes, and other radioactive sources are examples of ionizing radiation
• Ionizing radiation can cause acute leukemias; increased frequencies of thyroid and breast carcinomas; lung, stomach, colon, esophageal, and urinary tract cancers, and multiple myeloma
• Ionizing radiation enters cells and randomly deposits energy in tissues leading to oncogeneactivation, tumor-suppressor genes deactivation, Chromosomal aberrations and DNA damage
• UV radiation comes principally from sun light source
• UV radiation causes basal cell carcinoma, squamous cell carcinoma, and melanoma
• Electromagnetic radiation (EMR) is energy in the form of transverse magnetic and electric waves
• Infections can contribute to Cancer
• Human papillomavirus (HPV) causes Cervical cancer
• Hepatitis B and C together cause Liver cancer
• Helicobacter pylori causes Stomach cancers
• Epstein-Barr virus (EBV) causes Cancers of the nasopharynx and stomach, Hodgkin disease, and non-Hodgkin lymphoma
• Human herpes virus type 8 causes Kaposi sarcoma
• Human T-cell lymphotropic virus type 1 causes Leukemia and lymphoma
• HPV is the most common sexually transmitted virus.
• HPV types 16 and 18 cause majority of cancers
• HPV is associated with cervical and anal cancers and cause almost one-half of vaginal, vulvar, and penile cancers
• HPV infects epithelial cells that leads to mutations and cancer
• A number of occupational carcinogenic agents increase risk of cancers
• Asbestos causes mesothelioma and lung cancer
• Dyes, rubber, paint, aromatic amines cause Bladder cancer
• Explosives, rubber cement, and dyeing industries: causes Leukemia
• Physical activity decreases the risk of cancer
• Decreases insulin and insulin-like growth factors.
• Decreases obesity and inflammatory mediators.
• Decreases circulating sex/metabolic hormones and improves immune function.
• Regular exercise after a cancer diagnosis leads to improvements in cancer-specific and overall survival in early-stage breast, prostate, and colorectal cancers.

Pathophysiology of Cancer

• Cancer is a disease of cumulative genetic changes
• Genetic changes involve mutational and epigenetic mechanisms
• Mutation is an alteration in the DNA sequence affecting expression or function of a gene.
• Cancer is predominantly a disease of aging and requires multiple mutations.
• Clonal Proliferation Model Of Neoplastic Progression In The Colon - Genetic Event: Inactivation of APC - Cell Behavior: Cell seems normal but is predisposed to proliferate excessively & Genetic Event: Mutational activation of K-ras - Cell Behavior: Cell begins to proliferate too much but is otherwise normal & Genetic Event: Loss of DCC, over-expression of COX-2 - Cell Behavior: Cell proliferates more rapidly; it also undergoes structural changes & Genetic Event: Loss of TP53, activation of telomerase - Cell Behavior: Cell grows uncontrollably and looks obviously abnormal.
• Examples of the genetic changes that can occur include mutations, gene amplification, chromosome translocation, clonal proliferation, malignant transformation, and heterogeneity

Genomic Hallmarks

• Sustained proliferative signaling (e.g., proto-oncogenes, oncogenes) is a genomic hallmark.
• Evading growth suppressors (e.g., tumor-suppressor genes) is a genomic hallmark.
• Genomic instability is a genomic hallmark.
• Enabling replication immortality (e.g., telomerase absent) is a genomic hallmark.
• Cellular adaptations (e.g., angiogenesis) is a genomic hallmark.
• Resistance to programmed destruction is a genomic hallmark.
• Activating invasion and metastasis is a genomic hallmark.
• Uncontrolled cellular proliferation is a main tenet of Sustained Proliferative Signaling
• Cytoplasmic components of the receptors activate intracellular signaling pathways induction/activation of regulatory factors affecting DNA synthesis, entrance into the cell cycle, and changes in expression of other genes related to cell metabolism for optimal growth
• Example Sustained Proliferative Signaling: Epidermal growth factor (EGF) S
• Proto-oncogenes encode normal nonmutant genes that code for cellular growth.
• Oncogenes are mutant genes that, in their mutant state, direct protein synthesis and cellular growth.
• Tumour-suppressor genes encode proteins that, in their normal state, negatively regulate proliferation, and are also referred to as anti-oncogenes.
• Body cells are not immortal meaning they cannot divide only a limited number of times (Hayflick limit).
• Telomeres are protective caps on each chromosome that are held in place by the Telomerase enzyme.
• Telomeres become smaller and smaller with each cell division.
• Cancer cells can activate telomerase, leading to continued division.
• Cellular Adaptations is Tumor Induced Angiogenesis
• Angiogenesis = growth of new vessels and is also called neovascularization.
• Advanced cancers can secrete angiogenic factors to facilitate feeding of the tumor.
  • Vascular endothelial growth factor (VEGF).
  • Basic fibroblast growth factor (bFGF).
• Programmed cell death (apoptosis) is a mechanism by which individual cells can self-destruct under conditions of tissue remodeling or as a protection against aberrant cell growth that may lead to malignancy
• Apoptotic pathways are dysregulated in most cancers
• Example; TP53 gene suppress activation of apoptosis
• Chronic inflammation is an important factor in the development of cancer and known as Resistance To Destruction
• Active inflammation predisposes a person to cancer by stimulating a wound-healing response that includes proliferation and new blood vessel growth
• Examples of Susceptible organs in Resistance To Destruction include the gastrointestinal (GI) tract, pancreas, thryoid gland, prostate, urinary bladder, pleura, and skin
• Those with Ulcerative colitis for 10 years or more have up to a 30 fold increase in developing colon cancer, inflammation increases the risk of cancers.
• H.pylori increases the risk of stomach cancer
• Hepatitis B (HBV) Or Hepatitis C (HCV) increase the risk of liver cancer
• Immune surveillance hypothesis: developing malignances are suppressed by an efficient immune responsee
• Immunotherapy hypothesis: predicts that the immune system could be used to target tumour-associated antigens clinically
• Some viruses are associated with human cancer

Cancer Invasion & Metastisis

• Tumour cells and tissue characteristics include Anaplastic, Pleomorphic, Substantial stroma, Lacks a capsule and Capable of invading nearby vessels
• Metastasis is the spread of cancer cells from the site of the original tumor to distant tissues and organs.
• Tumors can be classified as Benign and Malignant
• Benign tumors have slow growth, well-defined capsule and are well differentiated, non-invasive and have does not metastasize
• Malignant Tumors have rapid growth, are not encapsulated, invasive and metastasize
• Characteristics of cancer include being anaplastic, pleomorphic, having substantial amount of stroma, lacking a capsule and capability of invading nearby vessels

Cancer Classifications

• Benign Tumours are named according to the tissues they arise from and include the suffix -oma, such as a Lipoma (Fat) and Leiomyoma (Smooth muscle)

• Malignant Tumours arise from cell types. Malignant epithelial tumours are Carcinomas, Adenocarcinoma (Ducts or glands), Malignant connective tissue tumours (Sarcomas), from lymphatic tissues (Lymphomas)

• Carcinoma in Situ involves preinvasive epithelial malignant tumours. These are tumours that have NOT crossed the basement membrane and are not considered malignant.

• Initial proliferation of cancer cells and enlargement of the tumor elicits the synthesis which then recruits immune cells in the Stroma.

• The process of cancer development involves initial proliferation to recruit inflammatory/immune cells,

• Stroma microenvironment surrounds and infiltrates tumor, promotes its progression and metastatic potential

• The hallmarks of cancer are consequences of cancer-stromal interactions.