Cancer 1 Section4 Lessons10 Weeks
Cancer – Definition and Mechanism of Carcinogenesis
Definition
Cancer is a group of diseases characterized by:
- Uncontrolled proliferation of abnormal cells,
- These cells have the ability to Invade into surrounding tissues, and
- Potential to metastasize i.e. they can spread to distant organs.
- These abnormal cells escape normal regulatory mechanisms of cell growth, differentiation, and death, leading to the formation of tumors (ne oplasms), which may be benign or malignant.
Key Features
- Loss of growth control
- Loss of differentiation (anaplasia)
- Invasiveness
- Metastatic potential.
Key Terms
NEOPLASM: A new, abnormal growth of tissue.
BENIGN TUMOR: Non-invasive, localized, and usually non-lethal.
MALIGNANT TUMOR (CANCER): Invasive, capable of metastasis, and often life-threatening.
Mechanism of Carcinogenesis
Carcinogenesis is the multi-step process by which normal cells transform into cancer cells due to genetic mutations and epigenetic alterations.
It has 3 main phases:
- Initiation
- Promotion
- Progression
Initiation
- In this phase of cacinogenesis there is irreversible genetic damage (mutation).
- It may be caused by a carcinogen (chemical, radiation, viral).
- This damage affects proto-oncogenes, tumor suppressor genes and DNA repair genes.
- Cells remain morphologically normal but are primed for transformation.
Examples
- Polycyclic hydrocarbons,
- aflatoxin B1,
- UV radiation.
Progression
- This is a Reversible phase involving clonal expansion of initiated cells.
- The promoting agents (e.g. hormones, chronic inflammation) do not cause cancer but stimulate proliferation of initiated cells.
- This clonal expansion increases the chance of further mutations.
- There is no direct DNA damage, but this creates a pro-cancer environment.
- There is accumulation of additional mutations that cause:
- increased aggressiveness,
- invasiveness, and
- metastasis.
- The cells acquire hallmarks of cancer:
- sustained proliferative signaling,
- evading growth supressors,
- resisting cell death (apoptosis),
- enabling replicative immortality, inducing angiogenesis,
- activating invasion and metastasis.
Summary
Step
Initiation |
Promotion |
Progression |
Apoptosis defect |
Key Event
DNA mutation |
Clonal expansion |
Genetic instability |
Failure to remove damaged cells |
Example/Mechanism
Carcinogens, radiation |
Hormones, inflammation |
Oncogene activation |
p53 loss, Bcl-2 ↑ |
Clinical Correlation
- Bcl-2 overexpression → seen in Follicular lymphoma.
- p53 mutation → present in >50% of human cancers.
- HPV infection → inactivates p53 and Rb via viral oncoproteins (E6, E7).
Molecular Basis of Carcinogenesis
It involves 4 steps:
- Activation of Proto-oncogenes to Oncogenes cause:
- Gain of function mutations that leads to uncontrolled cell division e.g. ras myc, HER2
- Inactivation of Tumor Suppressor Genes cause
Loss-of-function mutations which in turn remove cell cycle brakes (e.g. p53, RB)
- Defective DNA repair genes.
Allow accumulation of mutations (e.g. BRCA1/2)
- Epigenetic changes.
lead to DNA methylation or histone modification silences tumor suppressor genes. This causes evasion of Immune Surveillance