Carcinogens Lecture Notes

Cancer Overview

• Cancer is characterized by abnormal tissue growth and the spread of abnormal cells.

• Examples of solid tumors: liver, lung, intestine, breast.

• Increased cancer incidence can be attributed to:

  • Increased age.

  • Increased exposure to carcinogens.

  • Other unidentified factors.

Carcinogens Defined

• A carcinogen is any substance that can cause normal cells to become cancerous.

• Carcinogenic agents fall into three groups:

  1. Physical: Radiant energy (e.g., UV rays).

  2. Chemical: Various chemical compounds.

  3. Biological: Certain viruses.

Mechanisms of Carcinogenesis

• Carcinogens may cause nonlethal genetic damage that leads to malignant cell division and tumor formation.

• Four classes of genes commonly affected:

  • Proto-oncogenes: Promote normal growth and division.

  • Tumor suppressor genes: Suppress cancer formation (e.g., p53).

  • DNA repair genes: Repair DNA damage.

  • Apoptosis-related genes: Induce programmed cell death.

Proto-oncogenes

• Normal genes that promote cell growth.

• Can mutate into oncogenes which overexpress growth and division, leading to cancer (e.g., MYC and RAS).

Activation of Oncogenes

1. Promoter insertion

2. Enhancer insertion

3. Chromosomal translocation

4. Gene amplification

5. Point mutations

Philadelphia Chromosome

• Example of a chromosomal translocation leading to oncogene formation.

• Involves BCR-ABL fusion which is associated with certain leukemias.

Tumor Suppressor Genes

• Function to inhibit cancer development by responding to DNA damage.

• When mutated or deleted, cancers can develop (e.g., p53, Rb).

• p53:

  • Encodes a protein (53 kDa) that regulates the cell cycle.

  • Triggers apoptosis in severely damaged cells.

  • Many tumors exhibit loss or mutation of p53.

• Retinoblastoma (Rb) gene:

  • Inhibits cell cycle progression.

  • Mutations allow uncontrolled division, leading to cancer.

Growth Factors

• Growth factors are glycoproteins that regulate cell growth by binding to cellular receptors.

• Excessive production can lead to uncontrolled cell proliferation.

• Can become oncogenic through mutations.

Important Growth Factors

• Epidermal Growth Factor (EGF): Stimulates epidermal and epithelial cell growth.

• Transforming Growth Factor-alpha (TGF-α): Similar to EGF, produced by tumor cells.

• Platelet-derived Growth Factor (PDGF): Accelerates wound healing.

• Erythropoietin (EP): Stimulates erythropoiesis from the kidney.

DNA Repair Enzymes

• Mutations in DNA repair enzymes can lead to rapid accumulation of mutations, increasing the risk of cancer.

• Examples include inherited mutations in BRCA1 and BRCA2 linked to breast cancer.

Ways Carcinogens Enter the Body

• Skin absorption: Some chemicals penetrate the skin directly.

• Ingestion: Consuming carcinogenic substances.

• Inhalation: Breathing in harmful gases or vapors, most common exposure route.

Factors Influencing Cancer Development

• Dose: Higher doses increase cancer risk.

• Environmental/lifestyle factors: Cigarette smoking, geographical factors, therapies that may act as carcinogens.

Radiant Energy as Carcinogen

• High-energy radiation (UV, X-rays) can induce DNA damage.

• UV radiation can form pyrimidine dimers, leading to mutations.

DNA Damage Mechanisms

• Ionizing radiation can cause damage directly or create free radicals (ROS) that contribute to mutations.

• Chemical carcinogenesis involves exposure to substances that may accumulate and cause DNA damage.

Stages of Chemical Carcinogenesis

1. Initiation: Rapid, irreversible DNA damage occurs.

2. Promotion: Slower phase where initiated cells proliferate abnormally (months to years), influenced by promoters.

Role of Viruses in Carcinogenesis

• Certain viruses (Hepatitis B, C, HPV) can induce cancer by integrating their genetic material into host DNA, altering gene expression and disrupting cell cycles.

Cancer involves abnormal cell growth and spread, with examples including liver, lung, intestine, and breast tumors. Key factors increasing cancer risk are age, exposure to carcinogens, and unidentified factors.

Carcinogens are agents that cause normal cells to become cancerous, classified into three categories: physical (e.g., UV rays), chemical (various compounds), and biological (certain viruses). They cause genetic damage leading to malignant cell division, affecting proto-oncogenes, tumor suppressor genes, DNA repair genes, and apoptosis-related genes.

Proto-oncogenes promote normal growth but can mutate into oncogenes causing cancer. Mutations can arise from mechanisms like enhancer insertion or point mutations, such as the Philadelphia chromosome associated with leukemias.

Tumor suppressor genes like p53 help prevent cancer by responding to DNA damage, with mutations leading to tumor development. Growth factors regulate cell growth; excess can result in cancer, with examples including EGF and PDGF.

Mutations in DNA repair enzymes, such as BRCA1 and BRCA2, can heighten cancer risk. Carcinogens can enter the body through skin absorption, ingestion, or inhalation, with exposure dose and environmental factors influencing cancer risk.

Radiant energy from sources like UV and X-rays can damage DNA, while chemical carcinogenesis involves exposure leading to DNA damage over stages: initiation and promotion. Certain viruses can induce cancer by altering host DNA and gene expression.