Lecture 1 Flashcards
What percentage of deaths were from cancer in the UK in 2000?
25.9%
What percentage of deaths were from cancer in the UK in 2019?
30.6%
Better treatments for strokes, infectious disease etc so death rate reduced
What percentage of deaths were from cancer globally in 2000?
13.4%
What percentage of deaths were from cancer globally in 2019?
17.5%
What other diseases/conditions caused a greater percentage of death than cancer
Strokes, IHD
What is cancer?
- Over >200 different diseases
- Characterised by abnormally proliferating cells - capable of spreafing to surrounding tissues and others parts of body
Most commonly derived cells for cancer
Epithelial cells (>80% are carcinomas)
How is cancer initiated
Initiated and driven by genetic mutations involved in regulating cell growth and division
Causes 10 million deaths a year
Cancer cells of origin
Carcinomas - epithelial cells
Rhabdomyosarcoma cells - mesenchymal cells
Acute lymphocytic leukaemia - haematopoietic cells
Retinoblastomas - neuronal retinal cells
Malignant melanoma - melanocytes
Cancer sites
Most common cancer sites in world:
- Breast
- Lung
- Colorectum
- Prostate
Most common cancer sites in UK:
- Prostate
- Breast
- Colorectum
- Lung
Other most common cancer sites include skin, NHL and kidney in UK
Stomach, liver and cervix uteri in world
What is the biggest risk factor for cancers?
Age
Cancer incidence increases with age as more likely to experience mutations in proto-oncogenes and tumour suppressor genes the longer a person lives
Leukaemia is an anomaly and it can develop in young children
Normal vs breast cancer karotype
Normal human karyotype - Diploid
Breast cancer karyotype - Severe aneuploidy, chromosomal rearrangements
Uveal melanoma karyotype - defined aneuploidy
Colorectal cancer progression
Well-established model of multi-step carcinogenesis with clinical progression driven by acquisition of genetic changes
Normal colonic crypts -> Early adenomatous crypt
Early adenomatous crypt -> Small tubular adenoma OR villous adenoma
Small tubular adenoma -> Large tubular adenoma <-> Same tubular adenoma
Villous adenoma -> (same tubular adenoma->) invasive carcinoma -> liber metastases
Vogelstein model for colorectal cancer
Integrates molecular changes with phenotypic changes
Normal epithelium -> (loss of APC) -> Hyperplastic epithelium -> (DNA methylation) -) Early adenomas -> (K-ras activation) -> Intermediate adenomas -> (loss of 18q TSG) -> Late adenomas -> (loss of p53) -> Carcinoma -> Invasion and metastasis
Tumour cell number, size and detection
Tumour first visible on X-ray (10^8 cells)
Tumour first palpable (10^9 cells)
Death of patient (10^12)
Angiogenic switch
- Dormant
- Perivascular detachment and vessel dilation
- Onset of angiogenic sprouting
- Continuous sprouting, new vessel formation+maturation, recruitment of perivascular cells
- Tumour vasculature
Mediators of angiogenesis
Activators - VEGF-A, VEGF-B, -C, FGF1, FGF2, other FGFs
Inhibitors - Thrombospondin-1, -2, interferon alpha/beta, angiostatin, endostatin, collagen IV fragments
What are activators?
typically receptor tyrosine kinase ligand
bind to their cognate receptors expressed on the surface of endothelial cells, stimulating proliferation and the growth of blood vessels
Metastasis
Escape of cancer cells from primary site and their establishment at distant secondary sites
Responsible for 90% of cancer mortality
Basement membrane separates epithelial cells from underlying tissue (stroma)
Epithelial cells are attached to the basement membrane – an acellular structure comprised of extracellular matrix proteins – laminins, collagen and proteoglycan
Steps in metastasis - local invasion
Local invasion depends on secreted proteases e.g. matrix metalloproteases (MMPs) either by the tumour cells themselves or by the adjacent stroma
This allows the cells to breach the basement membrane and start invading the local stroma (the tumour was benign up to this point)
The extracellular matrix also serves as a reservoir for growth factors and its degradation can therefore facilitate proliferation
Steps in metastasis: (i) local invasion: EMT
- Cells undergo an epithelial to mesenchymal transition (EMT). Governed by expression of transcription factors e.g. Twist, Snail (SNAI1), Slug (SNAI2)
- Tumour microenvironment is often important here
- EMT allows cells to become motile and invasive, adopt a fibroblastic phenotype, and become more resistant to apoptosis’
- Cells repress expression of E-cadherin and upregulate expression of N-cadherin (weaker links)
Steps in metastasis (ii) – intravasation and transport through circulation
Process of intravasation is not completely understood
Transport through circulation is a challenge for cancer cells – may die through anoikis or hydrodynamic stress
Only about 1 in 10 000 will survive the process.
Steps in metastasis (iii): arrest and extravasation
Cells become lodged in a microvessel and can then extravasate
The cancer cell then begins proliferating at the new site, typically involving a mesenchymal to epithelial transition (MET)
Steps in metastasis:(iv) colonisation
Colonisation is the least efficient step in metastasis - the new tissue likely has different growth and survival factors
Cells need to adapt to successfully colonise – but some tissues will offer a more “friendly” environment (see Paget’s “seed and soil” hypothesis)
Common sites of metastases
Prostate -> lungs, brain, liver, bone marrow
Pancreas -> lungs, liver
breast -> Brain, liver, lungs, bone marrow
Colon -> Liver, lungs, bone marrow
Clinical manifestation of progression
Cancer staging (TNM system)
T: size of tumour (T1-T4)
T1 (small) to T4 (large)
N: local spread to lymph nodes (N0-N3)
N0 - no lymph nodes containing cancer cells
N3 - many lymph nodes affected
M: metastasis
M0 - the cancer has not spread to other organs
M1 - the cancer has spread to other parts of the body
