Carcinogens and Tobacco Quiz

Biochemistry of Cancer

• Cancer is defined as a disturbance of growth characterized by excessive cell proliferation, unrelated to the physiological needs of the involved organs (UICC).
• Oncology encompasses the study of cancer's etiology, diagnosis, treatment, prevention, and research.

Etiology of Cancer

• Cancers have a multifactorial origin, encompassing genetic, hormonal, metabolic, physical, chemical, and environmental factors.
• Most human cancers arise spontaneously from a single aberrant cell, which proliferates to form a tumor mass.
• The frequency of mutations increases with age.
• Cancer is the second leading cause of death in developed countries, after cardiovascular disease.

Mutagens

• Substances that increase the mutation rate also enhance cancer incidence.
• All carcinogens are mutagens.
• Examples are X-rays, gamma-rays, and ultraviolet rays.

Chemicals

• Some human cancers result from chemicals introduced into the body through occupations (aniline, asbestos), diet (aflatoxins), or lifestyle (smoking).
• Chemical carcinogens act cumulatively.
• Common environmental carcinogens include tobacco, food additives, coloring agents, and aflatoxins.
• Thousands of chemicals are known mutagens and carcinogens.
• Methylcholanthrene is a potent carcinogen; even nanogram quantities can induce tumors in mice.

Aflatoxins

• Aflatoxins are chemically related compounds produced by the fungus Aspergillus flavus.
• The mold grows on rice, wheat, and peanuts when exposed to damp conditions.
• Aflatoxins can be ingested through contaminated cattle feed or milk.
• They are powerful carcinogens that induce hepatomas (liver tumors).

Cigarette

• Lung cancer is linked to cigarette smoking.
• Cigarette smoke contains numerous carcinogens, primarily benzo(a)pyrene, nicotine, carbon monoxide, nitrogen dioxide, and carbon soot.
• Non-smoking spouses of heavy smokers have a five-fold increased risk of lung cancer compared to non-smokers.
• Oral cancer is strongly associated with tobacco chewing.
• A deficiency in glutathione-S-transferase (GST), an enzyme involved in carcinogen detoxification, increases smoking-related lung cancer risk. (About 5% of the population lacks GST).

Alcohol and Diet

• Alcohol consumption increases the risk of oral, pharyngeal, esophageal, and liver cancers.
• Diets high in fat and cholesterol are associated with colon, breast, and prostate cancers.

Promoters of Cancer

• Most carcinogens require promoters for cancer development.
• Benzopyrene application to skin alone does not induce cancer.
• Croton oil application alone does not induce cancer.
• Croton oil (specifically TPA) acts as a promoter, inducing tumor formation when applied after benzopyrene.
• TPA activates protein kinase C, leading to membrane protein phosphorylation and malignant transformation.
• Carcinogens cause mutations, while promoters drive unchecked cell division.

Progression

• Tumor development (malignancy) progresses over time.
• Cells with faster growth exhibit a selective advantage.
• Cells with increased malignant characteristics are progressively favored.
• Familial adenomatous polyposis is a model of multistep progression.

Action of Chemical Carcinogens

• Chemical carcinogens are usually ingested as procarcinogens.
• Procarcinogens are metabolized (often in the liver) to become active carcinogens.
• A good example of this is 2-acetyl amino fluorene (AAF), which is metabolized to an ultimate carcinogen N-hydroxy-AAF sulfate ester.
• Enzymes of the cytochrome P-450 system activate procarcinogens.
• Direct carcinogens have a direct effect on target molecules (e.g., methylcholanthrene).

Mechanisms of Action of Chemical Carcinogens

• Most carcinogens are electrophiles that react with nucleophilic groups in DNA.
• Carcinogens bind covalently to cellular DNA.
• These changes lead to DNA alterations and increased mutation probability.
• Carcinogens cause mutations and can produce tumors at the site of exposure, metabolism, or elimination. (e.g. buccal cancer, skin cancer, liver cancer, bladder cancer).

Physical Carcinogens

• X-rays, gamma-rays, and UV radiation cause cancer through various mechanisms, including pyrimidine dimer formation, DNA break sites, and free radical/superoxide formation.
• Prenatal X-ray exposure increases childhood leukemia risk.

Antimutagens

• Antimutagens inhibit tumor promotion.
• Vitamin A and carotenoids reverse precancerous conditions.
• Vitamin E, a strong antioxidant, prevents free radical damage.
• Vitamin C prevents cancer in individuals exposed to aniline.
• Tubers, beans, leafy vegetables, curcumin (from turmeric), high fiber, low protein, low fat diets have antimutagenic properties.
• Green tea and yeast cell wall polysaccharides provide antimutagenic effects.

Oncogenic Viruses

• Viral gene integration into host DNA causes uncontrolled cell proliferation (viral transformation).

Functions of Antimutagens

• Prevent mutagenic compound transformation.
• Inactivate mutagens.
• Prevent mutagen-DNA interaction.

Oncogenes

• Oncogenes are normal cellular constituents that can cause cancer.
• Normal cells contain DNA sequences similar to viral oncogenes (V-src).
• Cellular oncogenes are called proto-oncogenes (e.g., c-src).
• Proto-oncogenes are important regulatory genes; viruses can pick them up accidentally. Over 100 human proto-oncogenes are known; they are located on specific chromosomes.

Proto-oncogenes

• Products of many proto-oncogenes (e.g., sis, PDGF) are polypeptide growth factors that are vital to wound healing.
• Some proto-oncogene products are receptors for growth factors (e.g., EGF).
• Other proto-oncogene products influence growth control and cellular events.
• Oncogenic viruses can introduce oncogenes (c-oncogenes), causing uncontrolled cellular activity, and leading to malignant transformation.

Oncogenes and Oncogens

• Oncogenes are genes causing cancer (lowercase).
• Oncogens are the chemicals which produce cancer (uppercase).
• Oncogenes in normal cells have "c" prefix, while oncogenes in viruses have a "v" prefix.

Factors Activating Oncogenes

• Various factors (viruses, chemical carcinogens, chromosome translocations, gamma-rays, spontaneous mutations) can trigger one biochemical change (oncogene activation), which leads to cancer.

Antioncogenes (Oncosuppressor Genes)

• These genes protect against cancer.
• p53, a crucial oncosuppressor gene located on chromosome 17, is encoded by a phosphoprotein (molecular weight 53,000).
• Normal p53 suppresses oncogenic virus transforming ability.
• p53 activates the expression of genes that inhibit cell proliferation and blocks cells with damaged DNA.
• p53 directs cells to undergo apoptosis (programmed cell death) when DNA damage is severe.
• Most tumors have an absence of p53 or mutated p53.

Growth Factors

• Many oncogenes trigger cancer development through growth factor production.
• Growth factors can cause cell division or differentiation (cell specialization).
• Growth factors may be considered local hormones.
• Numerous growth factors exist, including fibroblast growth factor (FGF), hepatocyte growth factor (HGF), keratinocyte growth factor (KGF), vascular endothelial growth factor (VEGF), interleukins, and interferons.

Differences Between Normal and Tumor Cells

• Normal cell cycles are completed within 18-24 hours.
• In normal tissue, only ~1% of cells are actively dividing; whereas in cancer tissues, 2 to 5% are actively dividing, which indicates the aggressiveness of the cancer.
• This difference is used in cancer treatments (cytotoxic drugs and radiation kill dividing cells).

Doubling Time Growth

• Doubling time is the time taken for a tumor to double in size; it is generally constant for a given tumor.
• Tumor doubling time varies greatly among different cancers.
• Doubling time depends on cellular proliferation rate and cell death. (A high ratio of proliferating cells to resting cells suggests a more aggressive cancer).

Malignant Transformation

• A normal cell becomes malignant (cancerous) when it acquires malignant characteristics.
• Normal cells typically form a monolayer; conversely, cancer cells display a multilayered appearance.

Contact Inhibition

• Normal cells stop dividing when they come into contact with other cells (contact inhibition).
• This is due to the tight junctions connecting cells and cell-to-cell communication.
• Cancer cells lose this property (contact inhibition), allowing them to continue dividing even when in close contact, thus forming multilayers.

Anchorage Dependence

• Normal cells require a substrate (e.g., the surface of a culture dish) to adhere to and divide (anchorage dependence).
• Cancer cells frequently lose this dependence, and can grow without attachment to a substrate.
• Oncogene products (like tyrosine kinase) can cause abnormal phosphorylation of vinculin (a protein involved in cell adhesion).

Sialic Acid and Sialylation

• Cancer cells often carry more negative surface charges than normal cells due to higher levels of N-acetyl neuraminic acid (NANA).
• The increased negative charge results in weaker cell-cell adhesion leading to a lack of cohesiveness.
• Sialic acid and sialylation are linked to a cancer cell’s malignancy and its ability to metastasize (spread).
• Human sialidases (sialic acid-removing enzymes) are related to malignancy and are potential cancer targets.

Cell Fusion

• Cell fusion (merging of cells) enables fertilization, immune response, tissue repair, and regeneration, but can also contribute to cancer initiation and progression.

Metastasis and Secondaries

• Cancer cells can detach from the main tumor and spread to other parts of the body (metastasis).
• Molecules like collagenase and stromolysin aid cancer cell penetration into surrounding tissue.

Metabolic alterations

• Cancer cells often have altered metabolic pathways, often favoring anaerobic glycolysis over the citric acid cycle.
• Other enzymes and entire metabolic pathways can be deleted in cancer cells, highlighting the disruption caused by uncontrolled cell growth.
• For example, asparagine synthetase can be deleted in lymphomas.

Why Cancer Cells are Immortal

• Cancer cells often have elevated and persistent telomerase activity to counteract shortening of telomeres. Telomeres are protective caps at the ends of chromosomes.

Apoptosis

• Apoptosis (programmed cell death) ensures a balance in normal organs.
• The number of cells produced should be equal to the number of cells that die via apoptosis.
• In apoptosis, cells undergo chromatin condensation, cell shrinking, DNA fragmentation, and final disintegration.

Tumor Immunology

• Cancer treatments leave behind residual cancer cells.
• The body's immune cells eliminate these residual cells through various mechanisms (T cells, NK cells, complement-mediated lysis, antibody-dependent cell-mediated cytolysis, and macrophages).

Test your knowledge on carcinogens, including their characteristics and sources. This quiz also explores the role of tobacco in relation to cancer. Challenge yourself with questions about chemical carcinogens and their impact on health.