Major Molecular Mechanisms of Carcinogenesis
1. Initiation (Genetic Damage Begins)
The process starts when a carcinogen (chemical, radiation, viruses, or environmental factors) causes irreversible DNA damage or
mutations in a normal cell.
Functions:
Produces mutations in DNA sequence
Alters genes controlling cell growth
Creates abnormal cellular behavior
Damage may affect oncogenes or tumor suppressor genes
Examples of initiators:
Tobacco smoke chemicals
UV radiation
Ionizing radiation
Viral infections
Environmental toxins
2. Activation of Oncogenes
Normal cells contain proto-oncogenes that regulate growth and division. Mutations convert them into oncogenes, causing
excessive cell proliferation.
Functions:
Stimulate continuous cell division
Increase growth signaling
Reduce dependence on external growth factors
Common oncogenes:
RAS → controls signal transduction pathways
MYC → regulates cell proliferation
HER2 → promotes cell growth
BCR-ABL → causes uncontrolled kinase activity
3. Inactivation of Tumor Suppressor Genes
Tumor suppressor genes normally prevent excessive cell growth and repair DNA damage. Loss of function leads to uncontrolled proliferation.
Functions:
Regulate cell cycle checkpoints
Promote DNA repair
Trigger apoptosis if damage is severe
Major tumor suppressor genes:
TP53 ("guardian of genome")
RB1
BRCA1
BRCA2
4. DNA Repair Defects
Cells possess DNA repair systems to maintain genomic stability. Defects lead to accumulation of mutations.
Functions:
Detect DNA errors
Repair damaged DNA strands
Maintain genome integrity
Important repair mechanisms:
Mismatch repair
Nucleotide excision repair
Base excision repair
Double-strand break repair
Consequences:
Genomic instability
Increased mutation rate
Cancer progression
5. Evasion of Apoptosis
Apoptosis is programmed cell death that removes damaged cells. Cancer cells escape this process.
Functions:
Prevent elimination of abnormal cells
Allow survival of mutated cells
Promote tumor persistence
Important molecules:
BCL-2
Caspases
6. Sustained Angiogenesis
Tumors require blood vessels to obtain nutrients and oxygen.
Functions:
Supplies oxygen
Delivers nutrients
Supports tumor growth and metastasis
Major angiogenic factor:
VEGF
7. Invasion and Metastasis
Cancer cells acquire the ability to spread beyond the primary site.
Functions:
Break extracellular matrix
Enter blood and lymphatic systems
Colonize distant organs
Molecules involved:
Matrix metalloproteinases (MMPs)
Cell adhesion molecules
Integrins
8. Immune Evasion
Cancer cells avoid recognition by the immune system.
Functions:
Escape immune destruction
Suppress immune responses
Enhance tumor survival
Important immune checkpoint molecules:
PD-1
PD-L1
CTLA-4
Simplified Flow Diagram
Normal Cell
↓
Exposure to Carcinogen
↓
DNA Damage / Mutation
↓
Oncogene Activation + Tumor Suppressor Loss
↓
Defective DNA Repair
↓
Uncontrolled Cell Division
↓
Apoptosis Avoidance
↓
Angiogenesis
↓
Tumor Formation
↓
Invasion and Metastasis
This molecular progression explains how normal cells gradually acquire the characteristics known as the
“hallmarks of cancer,” leading to malignant transformation.
