Tumour Growth + Development Flashcards
What is Cancer? (intro)
Collection of >200 diseases with no one cure
Characterised by abnormally proliferating cells capable of spreading into surrounding tissue another parts of the body
Most commonly derived from epithelial cells (>80% cancers = carcinomas)
Initiated + driven by mutation in genes involved in regulating cell growth and division
10 million die worldwide each year due to Cancer
Types of tissue disorganisation in cancer?
Epithelial cells = carcinoma
(e.g. invasive ductal carcinoma of breast)
Mesenchymal cells = sarcoma
(e.g. rhabdomyosarcoma in muscle)
Haematopoietic system = leukaemia , lymphoma
Retina = retinoblastoma
(can also have non-cancerous benign tumours)
Factors affecting global incidence of cancer?
Sex
= females = higher incidence of breast cancer, cervical cancer
= males = higher incidence of prostate cancer, lung cancer
Age
= incidence increases with age
= more likely to acquire mutations in proto-oncogenes and tumour suppressor genes
How to show examples of how cancers are genetically unstable?
FISH staining of karyotypes
= amplification / loss of whole chromosomes
= rearrangement of chromosomes
Brief progression of colorectal cancer?
= model of multi-step carcinogenesis
= clinical progression is driven by acquisition of genetic changes
= cells within tumour undergo large number of population doublings before tumour can be detected
Importance of vascularisation?
Continued tumour growth depends on access to circulation
Tumours grow to a max of 1mm in diameter without new blood vessel growth
Growth limited to how far oxygen can diffuse
What is the angiogenic switch?
Leads to growth of blood vessels
- Dormant
- Perivascular detachment and vessel dilation
- Onset of angiogenic sprouting
- Continuous sprouting, new vessel formation and maturation, perivascular cells
- Tumour vasculature
What are the mediators of angiogenesis?
Activators
= typically receptor tyrosine kinase ligands
= bind to their cognate receptors expressed on surface of endothelial cells
= stimulate proliferation , growth of blood vessels
= e.g. VEGF-A/B/C, FGF1/2
Inhibitors
= e.g. thrombospondin-1/2. interferon a/b, angiostatin, endostatin
Organisation of tumour vasculature?
Chaotic in tumour
= increased branching of blood vessels
= disorganised
= gaps in capillary wall = allows plasma fluids to seep into spaces between cancer cells
= generates high hydrostatic pressure
What is metastasis?
= the escape of caner cells from the primary site + their establishment at distinct secondary sites
= responsible for 90% of cancer mortality (impacts organ function)
What is the basement membrane? (+it’s function)
= acellular structure comprised of extracellular matrix proteins
(e.g. laminins, collagen, proteoglycans)
= separates epithelial cells from underlying tissue (stroma)
epithelial cells attached to basement membrane (+to each other)
What are the 4 steps of metastasis?
Local invasion
Intravasation and transport through circulation
Arrest and extravasation
Colonisation
What occurs in local invasion (of metastasis)?
= depends on secreted proteases either by tumour cells or adjacent stroma
e.g. MMPs - matrix metalloproteinases - upregulated
= allows cells to breach membrane and start invading local stroma
(now malignant)
= cells undergo EMT (epithelial to mesenchymal transition)
= governed by expression of prescription factors
(e.g. Twist, Snail (SNAI1), Slug (SNAI2)
= TME (tumour microenvironment) important
= EMT allows cells to be motile and invasive, adopt a fibroblastic phenotype, become more resistant to apoptosis
= cells repress expression of E-cadherin and upregulate N-cadherin (weaker links)
(Extra Reading = + more changes)
= reorganisation of the cytoskeleton = allow cancer cells to form protusions like filopodia and lamellipodia = help migration into nearby tissues
= activation of signalling pathways = e.g. Rho family GTPaes and integrin signalling = involved in cell migration and invasion
= evasion of immune surveillance = e.g. downregulate MHC class I molecules
What occurs in intravasation and transport through circulation (of metastasis)?
Intravasation (cells entering blood stream) not fully understood
Transport through circulation challenge for cancer cells
= may die through anoikis / hydrodynamic stress
= only 1 in 10,000 survive
Cancer cells interact with platelets
= forming microthrombi
= may partially protect them from the stresses
What occurs in arrest and extravasation (of metastasis)?
Cells become lodged in a microvessel + can extravasate (leave blood vessel)
Cancer cell begins proliferating at new site
= typically involved MET (mesenchymal to epithelial transition)
