Genes And Cancer

Definition of Cancer Cells:
- Disease characterized by uncontrolled cell division.
- Growth regulated by biological chemicals.
- Abnormal cells can invade nearby tissue and avoid apoptosis.
Cell Division Characteristics:
- Cancer cells can divide 50-60 times before death.
- Do not respond to inhibitory growth signals.
Immortalization and Morphology:
- Display altered morphology and dense nuclear regions due to genetic damage.
Causes of Mutation:
- DNA replication errors are common in normal dividing cells.
- Environmental factors and lifestyle choices contribute to DNA damage.
- Cancerous mutation is linked to gene changes that promote uncontrolled growth.
Cell Cycle Control:
- Malfunction of growth factors and receptors leads to increased proliferation.
- Abnormalities in DNA repair proteins and transcription factors can also contribute to cancer.
Vogelstein's Model of Carcinogenesis:
- Notes progression of cancer through gene mutations:
  - APC gene linked to colorectal cancer (CRC).
  - Loss of heterozygosity (LOH) refers to loss of function in both alleles.
  - K-ras mutation commonly found, relating to the MAPK pathway associated with growth.
  - p53 is a classic tumor suppressor protein.

APC Gene Function:
- Encodes a protein that regulates cell proliferation.
Mechanism of Action:
- Binding of B-catenin to E-cadherin promotes contact inhibition and regulates proliferation.
- Wnt signaling pathway drives B-catenin dissociation, stimulating proliferation.
Consequences of Mutation:
- Absence of functional APC leads to uncontrolled B-catenin-driven cell proliferation.
K-ras Mutation:
- Alters growth factor receptor signaling, contributing to cell proliferation via MAPK pathway.
- Can be activated through GTP; mutations can lead to constitutively active forms promoting cancer.
Progression in Colorectal Cancer (CRC):
- DCC acts as a tumor suppressor; loss of function accelerates cancer development.
- p53 mutation marks a critical turning point leading to carcinoma formation.

p53 Function:
- Acts as a guardian of the genome, inducing cell cycle arrest and apoptosis in response to DNA damage.
Genetic Aberrations in Cancer:
- Point mutations involve changes in individual base pairs.
- Chromosomal abnormalities include LOH in APC and DCC, and chromosomal translocations are significant (e.g., BCR-ABL fusion gene in CML).
- Gene amplification increases functional protein levels leading to altered cell activities (e.g., Her-2 in breast cancer).

DNA Replication Fidelity:
- Cancer risk correlates with errors in DNA replication and the body’s ability to recognize and fix them.
Aging and Risk Factors:
- Increased age leads to a higher likelihood of replication errors.
- Environmental exposures can increase cancer risk.
Genetic Factors:
- Only 5-10% of cancer risk is due to inherited genetic factors; most are lifestyle and environmental.
Genetic Epidemiology:
- Focus on understanding genetic factors related to cancer susceptibility and relapse.
- Population-based studies identify susceptibility genes and examine environmental interactions.

Chemical Exposures:
- Majority of cancers arise from chemical exposure.
- Risk assessment often based on animal models, lacking human exposure testing.
DNA Damage:
- Environmental and occupational chemical exposures significantly increase cancer risk.
- Example: 8-hydroxy-deoxyguanosine (8-OHdG) indicates oxidative DNA stress damage.

Role of Inflammatory Cells:
- Produce reactive oxygen and nitrogen species that can cause DNA damage.
Growth Factors and Cytokines:
- Inflammatory cells secrete substances that facilitate proliferation, resistance to apoptosis, and increased migratory behavior.
Chronic Inflammation:
- Can lead to a cancerous phenotype by perpetuating cell damage and aberrant growth.