L1, Tumour Growth and Development Flashcards
What proportion of death in the UK did cancer make up in 2000 vs 2019?
- 2000: ~25%
- 2019: ~30%
What is cancer?
- Outline the basic features
- Carcinomas and their prevalence
- Deaths worldwide, 2020
- Collection of over 200 different diseases
- Abnormally proliferating cells capable of spreading into surrounding tissue and other parts of the body
- Carcinomas are derived from epithelial cells; >80% of cancers
- 10 million deaths worldwide
Describe the trends in cancer with age:
- Cancer incidence increases with age (longer life = more opportunity to acquire mutations in proto-oncogenes/tumour suppressors)
- This is the case in almost all cancers
- Exception: Leukeamia; peak in infancy; inherited mutations
- See FC
How may a cancer karyotype differ from a normal cell?
- Cancers are genetically unstable
- Could have aneuploidy (wrong number of chromosomes)
- Often extensive chromosomal rearrangements
Vogelstein model:
- Model for colorectal cancer development (multi-step; clinical progression driven by acquisition of genetic changes)
1. Normal epithelium
<-Loss of APC
2. Hyperplastic epithelium
<-DNA hypomethlyation
3. Early…IM…Late adenomas
<- activation of K-ras….loss of 18q TSG
<-Loss of p53
4. Carcinoma
5. Invasion and metastasis
Why are cancers hard to detect early?
- Issue arises in the detection of tumours of a small size
- Tumour must reach 10^8 cells before it can be detected via X-ray
- Death of patient occurs by 10^12 cells; small window for detection
Why is vascularisation a key factor for tumour growth?
- Tumour cells require a lot of nutrients since they are proliferating rapidly
- Growth is thus limited by how far oxygen can diffuse from nearest circulation
- Tumours will grow to a maximum of ~1mm in diameter without new blood vessel growth
How does angiogenesis differ in healthy vs cancerous cells?
Describe the process of ‘Angiogenic Switch’
- In wound healing, angiogenesis is required but occurs in a very regulated manner
- In cancer, however, this process is dysregulated to promote proliferation:
Angiogenic Switch
1. Perivascular detachment and vessel dilation
2. Onset of angiogenic sprouting
3 Continuous sprouting, new vessel formation + maturation, recruitment fo perivascular cells
4. Tumour vasculature (Characteristic chaotic organisation with gaps in capillary wall to permit plasma fluid -> high hydrostatic pressure)
Give examples of inhibitors vs activators of angiogenesis:
Activators: (Typically RTKs)
- VEGF-A, -B, -C
- FGF1, 2
- other FGFs
Inhibitors:
- thrombospondin-1, -2
- interferon alpha/beta
- angiostatin
- endostatin
- collagen IV fragments
What is metastasis? What must happen for it to take place?
- Escape of cancer cells form primary site, establishment at distant secondary sites
- ~90% cancer mortality
- Must escape basement membrane (acellular structure comprised of extracellular matrix proteins; lamins, collagen, proteoglycan)
Outline the steps in metastasis:
- Local invasion (+EMT)
- Intravasion and transport through circulation
- Arrest and extravasation
- Colonisation
How does a primary tumour invade local cells and breach the basement membrane? How is this beneficial to the tumour?
- Secretion of proteases (e.g. matrix metalloproteases) by tumour cells or adjacent stroma allows breach of basement membrane
- Tumour can thus invade local stroma (no longer benign)
- The extracellular matrix also serves as a reservoir for growth factors; degradation of basement membrane permits access and facilitates further proliferation
What is the EMT? (Why is it useful, what changes occur…)
Which transcription factors are involved?
- EMT: Epithelial to mesenchymal transition
- More motile and invasive phenotype adopted by tumour cells
- More fibroblastic phenotype, more resistance to apoptosis
- Cells repress expression of e-cadherins, upregulate expression of n-cadherin (weaker links)
- Governed by expression of Twist, Snail (SNAI1), Slug (SNAI2)
- Often induced in stroma (i.e. TME)
Why may transport through circulation threaten tumour cells?
Give a mechanism that protects cells in this scenario
- Anoikis
- Hydrodynamic stress
- Cancer cells can interact with platelets to from microthrombi -> protects for stresses of circulatory system
How does extravasation take place? (Main and additional)
- Cells become lodged in a microvessel and can then extravasate
- Begins proliferating, typically involves MET
- Alternatively: Tether and roll model facilitated by HSPGs; hijacking a process normally used for dissemination of leukocytes in wound healing
What factors might dictate where a particular cancer metastasises to (with a key example)? What hypothesis does this relate to?
- Similar/favourable conditions to tissue of origin (‘Seed and soil’ hypothesis)
- Circulation (i.e. path taken
e.g. Panreatic primary tumours -> Liver (majority; first stop after colon in system)
-> Lungs (minority)
Describe the TNM system for cancer characterisation
- T: Size of tumour (T1 (small) to T4)
- N: Local Spread to lymph nodes (N0-3)
- M: Metastasis (0 or 1)
How are lymph nodes relevant to cancer progression?
- Often used to detect whether a cancer has spread
- Act as ‘sentinels’; is fluid draining from the tumour into a particular node?)
How might a cancer be imaged?
- CT/PET scan
- Typically use radioimaging; labelling areas of high glucose uptake for example
-> Warburg effect (high glucose uptake by cancer cells) - 18-Fluorine labelled FDG commonly used in PET scanning
Give the original 6 hallmarks of cancer:
(Hannahan and Weinberg)
- Sustained proliferative signalling
- Evading growth suppressors
- Activating invasions and metastasis
- Enabling replicative immortality
- Inducing angiogenesis
- Resisting Cell death
What 4 updates were added to the hallmarks of cancer in 2011:
(Hannahan and Weinberg)
- Avoiding immune destruction
- Tumour-promoting inflammation
- Genome instability and mutation
- Deregulating cellular energetics
+ What is anoikis and how is it carried out?
- Programmed cell death induced upon detachment form E-C matrix (Greek for ‘homelessness’)
- Critical for preventing adherent-independent cell growth and attachment to inappropriate matrix -> prevents colonisation
- Pathways for anoikis converge in caspase activation and subsequent activation of endonucleases, DNA fragmentation and cell death
+ How do cancer cells resist anoikis?
- EMT: Confers anoikis resistance (as well as anchorage-independent growth)
- Further mechanisms for resistance: change in integrins’ repertoire -> can grow in different niches, alongside various hallmark molecular features
- Tumour microenvironment also contributes to anoikis resistance in bystander cancer cells -> modulates matrix stiffness, enhances oxidative stress, pro-survival soluble factors, EMT etc
+ What two forms do anti-angiogenic therapies take?
- Antibodies
- Tyrosine kinase inhibitors
- Whilst a few of these drugs have been approved for use, they generally provide limited success; short term relief and only modest survival benefits -> see broad variety in mechanisms for angiogenesis both in healthy and cancerous tissue
+ What two ways can tumours become vascularised?
- Co-option of pre-existing vasculature
- Inducing new vessel formation
+ Outline 3 mechanisms for formation of new blood vessels in cancer:
- Intussuscpetive angiogenesis (new vasculature where a pre-existing vessel splits in two)
- Vasculogenic mimicry (vessel-like structures formed by tumour cells; more common in aggressively growing tumours)
- Transdifferentiation of cancer cells (Cancer cells -> CSCs -> Epithelial cells near vasculature)
- Neo-vascularisation in normal tissues and tumours occurs through one or more of various mechanisms
+ Angiogenesis is involved in what 3 processes in healthy tissues?
- Development
- Menstrual cycle
- Wound healing
+ Vasculature organisation in healthy vs cancerous tissues:
- Tightly controlled in all cases of healthy tissues -> ordered division of ‘vascular tree’
- Conversely, in tumours the organisation is chaotic with lacking maturation, heterogeneity in sizes of similar types of vasculatures, unregulated bloodflow etc -> areas of persisting or intermittent hypoxia
- Partial detachment of pericytes and uneven distribution of basement membrane -> fragility and risk of hemhorrage
+ Alternative routes for the tumour cell to invade beyond tissue of origin
- Whilst blood-borne cancers (hematogenous) are most common, cancers can also travel via the nervous system or along the basal side of endothelial cells
- They can travel through the lymphatic system
- They can travel along coelomic cavities
+ Broad types of mutation in development of cancer:
- Driver
- Passenger
- Hitchhiker
+ Are developmental and cancerous EMT equivalent?
- Whilst they share many features, they are not equivalent at a molecular level
