Definition of Carcinogenesis
Carcinogenesis (oncogenesis or tumorigenesis) is a multistep process by which normal cells transform into malignant tumor cells through genetic and epigenetic changes.
1 Initiation
Definition: The first, irreversible genetic change (mutation) in a normal cell.
Characteristics:
- Rapid, permanent DNA damage (mutation).
- Not sufficient alone to produce tumor —needs further promotion.
Causes:
- Chemical carcinogens (e.g., polycyclic hydrocarbons, aflatoxin).
- Physical agents (radiation, UV light).
- Viral integration.
Mechanism:
- Activation of oncogenes (e.g., RAS), or inactivation of tumor suppressor genes (e.g., p53).
- DNA damage is "fixed" if not repaired before DNA replication.
2 Promotion
Definition: Clonal expansion of initiated cells by promoters, leading to proliferation and further genetic instability.
Characteristics:
- Reversible at this stage.
- Promoters alone do not cause mutations; they stimulate division of initiated cells.
Examples of promoters:
- Hormones (e.g., estrogens).
- Chronic inflammation.
Mechanism:
- Induces cell proliferation, increasing the chance of additional mutations during DNA replication.
3 Progression
Definition: Acquisition of additional genetic and epigenetic changes, resulting in increased aggressiveness and malignant potential.
Characteristics:
- Irreversible.
- Increased genetic instability.
- Development of heterogeneity within the tumor (subclones with different properties).
Features:
- Loss of differentiation (anaplasia).
- Increased invasiveness and metastatic potential.
- Resistance to apoptosis.
- Angiogenesis.