Cancer
- Heterogenous group of diseases
- Creation of abnormal cells that grow beyond their natural boundaries
- Cancer cells can escape from normal regulatory mechanisms controlling cellular biology
Cancer cells must acquire key attributes to transition from normal to malignant
- Genetic instability and mutation
- Autonomous growth
- Insensitivity to anti-proliferative signals
- Resistance to apoptosis
- Unlimited potential for cell division
- Angiogenesis
- Locally invasive behaviour
- Evasion of immune system
- +/- ability to metastasise and thrive in distant organs
Tumour suppressor genes negatively regulate cell growth and are also important in DNA repair and cell signalling – dysfunction leads to uncontrolled cell growth and malignancy
- Loss of function of both copies/alleles of a TSG is typically required for carcinogenesis (“two-hit hypothesis”
Oncogenes are positively associated with cellular proliferation – mutated forms of normal genes (proto-oncogenes)
- Proto-oncogenes can be converted to activated oncogenes by mutation (causing excess production of whatever it makes i.e. growth factor), gene amplification or chromosomal rearrangement
Cell cycle
Cell division is tightly regulated so production of new cells balances those lost, maintaining tissue homeostasis.
Complex series of growth inhibitory signals and growth stimulatory signals are balanced by the cell resulting in cell division or quiescence.
In cancer – activated oncogenes and TSGs alter the balance to continuous proliferation
Quiescent cells – default state – G0
Signalled to proliferate -> start unidirectional cycle
G1 (gap 1) -> S (synthesis) duplication of DNA -> G2 (gap 2) -> M (mitosis) with segregation of each genomic complement to two daughter cells.
Checkpoint mechanisms closely monitor DNA integrity and critical cell cycle events.
- If problems are detected – cell cycle is paused for repair.
- If repair is not possible -> apoptosis.
- Many oncogenes and TSGs interfere with these checkpoints and apoptotic mechanisms -> allowing cancer cells to continuously divide
- In particular, the loss of ability to prevent damage DNA from replicating -> genetic instability -> increased further mutations -> cycle of carcinogenesis
Factors contributing to cancer development:
- Infectious agents – e.g HPV
- Smoking
- Alcohol
- Dietary factors
- Reproductive history and prolonged oestrogen exposure
- Carcinogens exposure – arsenic, asbestos, UV rays, aniline dyes
- Age (accumulation of mutations)
- Chronic inflammation
- Precursor lesions
- Immunodeficiency
- Inherited predisposition
Oncological terms
Synchronous
Second or multiple tumours thought to occur around the same time (within 2 – 6 months of primary tumour)
Metachronous
Second or multiple tumour occurring distinctly after a primary (6 months +)
Dysplasia
Disordered growth – loss of uniformity and architecture – may be pre-malignant but not always
Metaplasia
Replacement of one cell type with another, usually associated with tissue damage and repair