Cancer lecture 1 revision Flashcards
What is cancer?
- Collection of over 200 diseases
- Abnormally proliferating cells capable of spreading into surrounding tissue/organs
- Commonly derive from epithelial cells (>80% carcinomas)
- Initiated and driven by mutations in genes involved in regulating cell growth and division
- 10 million death/year
Cells of origin for cancer
Carcinomas - epithelial cells
Sarcoma - Mesenchymal cells
Leukaemia - Haematopoietic cells
Retinoblastoma - neuronal retinal cells
Melanoma - melanocytes
Most common cancer globally
Breast
Lung
Colorectum
Prostate
Most common cancers in UK
Prostate
Breast
Colorectum
Lung
What is the biggest risk factor for cancer
Age, as cancer incidence increases with age due to increased probability of mutations in proto-oncogenes and tumour suppressor genes
Human/Breast cancer/uveal melanoma karyotypes
Human karyotype - diploid
Breast cancer karyotype - Severe aneuploidy, chromosomal rearrangements
Uveal melanoma karyotype - defined aneuploidy
Progression of colorectal cancer
Well-established model of multi step carcinogenesis with clinical progression driven by acquisition of genetic changes
Normal colonic crypts -> early adenomatous crypt
Early adenomatous crypts -> Small tubular adenoma or villous adenoma
Small tubular adenoma -> Large tubular adenoma -> same tubular adenoma
Villous adenoma -> (same tubular adenoma/Large tubular adenoma->) Invasive carcinoma -> liver metastases.
Vogelstein model for colorectal cancer
Normal epithelium
-> (loss of APC)
Hyperplastic epithelium
-> (DNA hypomethylation)
Early adenomas
-> (activation of K-ras)
Intermediate adenomas
-> (loss of 18q TSG)
late adenomas
-> (loss of p53)
Carcinoma
->
Invasion/metastasis
What size are tumours first palpable
10^9 cells
What size are tumours visible on X-ray
10^8 cells
What size are tumours when they kill?
10^12 cells
What does continued tumour growth depend on?
Access to circulation
Tumours grow max of 1mm in diameter in absence of new blood vessel growth
Growth limited by how far oxygen can diffuse
The angiogenic switch in cancer
- Dormant stage- limited cancer cells due to limited oxygen/nutrients, anti-angiogenic factors prevent blood vessel formation
- Perivascular detachment and vessel detachment - caused by MMP9 caused pericytes to detach
- Onset of angiogenic sprouting - cancer cells begin to rapidly divide
- Continuous sprouting - Cancer cells continue to grow, new vessel formation/maturation, recruitment of perivascular cells
- Tumour vasculature forms
Activators of angiogenesis
VEGF-A,B and C
FGF1 and 2
Typically receptor tyrosine kinase ligands
Bind cognate receptors on endothelial cells - stimulates proliferation
Angiogenesis inhibitors
Angiostatin
Interferon alpha/beta
Endostatin
Collagen IV fragments
What is metastasis
- Escape of cancer cells from primary site and establishment at secondary site
- Causes 90% of cancer deaths
What do epithelial cells attach to?
Basement membrane - formed from matrix proteins like collagen, proteoglycan, laminins
Process of metastasis
- Local invasion depends of secreted proteases e.g. MMPs either by tumour cells or adjacent stroma
- Allows cells to breach basement membrane and invade local stroma
- Epithelial cell -> mesenchymal cell transition governed by Twist, Snail (SNAI1) and Slug (SNAI2)
- Tumour microenvironment important here
- EMT allows cells to become motile and invasive, adopt a fibrinoblastic phenotype, and more resistant to apoptosis
- Cells repress expression of E-cadherin and upregulate more N-cadherin (weaker links)
- Intravasion occurs (not well understood)
- Transport through circulation - only 1 in 10000 survive due to anoikis or hydrodynamic stress
- Cells lodge in microvessel and extravasate
- Cancer cells begin proliferating at new site - MET usually involved
- Colonisation occurs - least efficient step due to new growth and survival factors in tissue so cells need to adapt
Common sites of metastasis
Prostate - brain, lungs, liver, BONE MARROW
Pancreas - Lungs and LIVER
Breast - LUNGS and liver
Colon - LIVER, bone marrow and lungs
TNM system of cancer staging
T - size of tumour
T1 (small) and T4 (large)
N - spread to lymph nodes
N0 - no cancer cells in lymph nodes
N3 - many lymph nodes affected
M - metastasis
M0 - no metastasis
M1 - Metastasis
Stages of cancer in TNM system
Stage 1 - T1/2, N0, M0 - 90% survival after 5 years
Stage 2 - T3/4, N0, M0 - 82% survival after 5 years
Stage 3 - T1-4, N1/2, M0 - 45% surivial after 5 years
Stage 4 - Any T, any N, M1 - Less than 10% survival after 5 years
How can you detect metastases
- CT/PET scans
- Radiolabelled glucose
