Cancer Flashcards
What are tumours/neoplasms
arise from normal tissue but are unorganised, divided into benign and malignant
What is a benign tumour
non-invasive, localised and can maintain normal function
What is a malignant tumour
invasive, metastatic so spreads to sites distant from the origin, tissues show loss of form and function
What are the 4 main groups of tumours and what are they classified based on
based on cell type of origin
epithelial
mesenchymal
hematopoietic
neuroendodermal
What are epithelial cells
line walls/cavities or form a covering like skin
secrete proteins to form the basement membrane
What are tumours from epithelial cells known as and what percentage of tumours form them
carcinomas
reponsible for 80% of known tumours
What are squamous cell carcinomas
tumours from the protective layer or epithelial cells
What are adenocarcinomas
tumours from secretory epithelial cells
What are mesenchymal tumours and what percentage of tumours are they
responsible for 1% of tumours
derived from connective tissue cell types - originally from embryonic mesoderm
What are sarcomas
a type of mesenchymal tumour. mutiple types such as osteosarcoma (from osteoblasts) and liposarcomas (from adipocyte cells)
What are haematopoetic tumours and 2 examples
derived from cell types in blood-forming tissues
around 7% of tumours
eg
leukaemia - malignant cell derivatives that move freely in the circulation
lymphoma - solid tumours of T or B cells
What are neuroendodermal tumours and examples
responsible for around 1.5% of tumours
derived from components of the CNS / PNS
such as glioblastomas, neuroblastoma, schwannomas, astrocytomas
What are the two of benign tumours
hyperplastic, metaplastic, dyplastic
What are hyperplastic benign tumours
excessive cell number, cells are nomral and form structures
What are metaplastic benign tumours
displacement of normal cells with other normal cells not found in tissue. often found in the epithelial transition zone. can be premalignant
What are dyplastic benign tumours
cytologically abnormal cells, variable shape and crowded. hyperchromatic nuclei and lack of differentiation markers. the officially the premalignant state
What makes a tumour malignant
when cells breach the basement membrane and invade the surrounding stroma. cells are abnormal with poor differentiation and spread to different sites
What are the two types of tumour growth
monoclonal = one cell is abnormal and becomes replicated
polyclonal = multiple cells are abnormal and all replicate
Why should we screen for cancer
detect cancer in early stages, makes it easier to treat and more successful treatment
What are the screening criteria categories by WHO
condition must be a major problem with risk factors
the test must be safe reliable and specific
the treatment must be effective
screening programme must reduce morbidity and be effective and viable
What are the changes in a cell that transform a normal cell to a cancer cell
proliferative signalling
evade growth suppressors
avoid immune destruction
enable replicative immortality
activating invasion and metastasis
inducing angiogenesis
resist cell death
deregulating cell energetics
How do cancer cells sustain proliferation via growth signal autonomy
enhancing external stimulation such as mutation in growth factor receptors or increased growth factors
losing dependency on growth factors by:
mutations in signal transduction components such as PI3-kinase, Ras and Raf
mutations in cell cycle components
How do cancer cells evade growth inhibitory or suppressive signals
loss of activity of tumour suppressor genes such as p53, PTEN and Rb
aberration in development of signalling pathways such as hedgehog, Wnt and TGFB which all promote growth and metastasis
How do cancer cells evade apoptosis
mutations that affect the intrinsic apoptosis pathway such as loss of p53, upregulation of anti-apoptotic members of BCL2 family, down regulation of pro-apoptotic members of the BCL-2 family
mutations that affect the extrinsic pathway such as aberrations in death receptor regulation
What is angiogenesis
the formation of new blood vessels. tumours require vascularization to grow into a mass and prevent necrotic cell death. facilitates metastasis
What are the stages of angiogenesis
dormant blood vessel
perivascular detachment and vessel dilation
beginning of angiogenic sprouting of vesssles
continuous sprouting and recruit pericytes to stabilise the new sprout
tumour vasculature
What is VEGF
a proangiogenic molecule. is a growth factor. regulated by hypoxia and oncogenic signalling pathways. result in abnormal tumour vasculature
How do cancer cells maintain replicative immortality
normal cells have telomeres that shorten and limit the divisions that can take place. cancer cells produce telomerase that maintains telomere length and immortality. excessive length in cancer cells causes instability and promotes mutations
What are telomeres
composed of repetitive sequences of DNA - TTAGGG and associated proteins
protects ends of chromosomes and controls chromosome length
shorten by 100-200 bp each DNA replication round due to the limited of DNA polymerase needing an RNA primer
What are Cancer stem cells (CSCs)?
Are subpopulations within a tumour that are thought to initiate and maintain the cancer.
What are cancer stem cells responsible for?
Heterogeneity of tumours
Tumour plasticity
Migratory abilities
How can cancer stem cells be identified?
Stem cell markers e.g CD44 (breast and pancreas), CD133 (colon, prostate, brain)
Are cancer stem cells more likely or less likely to survive anti-cancer treatments?
More likely
How cancer stem cells arise?
From deregulation of self-renewal pathways e.g wnt and hedgehog
What is invasion and metastasis?
Cancer cells have gained the ability to invade and spread (metastasise) to distant sites by:
- Breaking cell- cell adhesion and cell- extracellular matrix (ECM) attachment
- Changing shape and becoming more motile
- degrading the ECM via proteases to allow invasion
- inducing angiogensis to support secondary tumour growth
What is a primary tumour?
Site of origin
What is a secondary tumour?
Metastases (traced back to primary tumour- same cell type)
What are the sites of spread?
• Close proximity to primary tumour- Direction of blood flow- Tumour cells get trapped in capillary bed
• Distal/ non-obvious- Seed and soil hypotheses (Paget) (cells need to match with optimum environment)- Premetastatic niche (Lynden)
(distant site is prepared via circulating tumour derived factors)
What are the steps involved in invasion and metastasis?
- Invasion
- Intravasation
- Transport
- Extravasation
- Metastatic colonisation
- Angiogenesis
What is the role of Src?
Mediates breakdown of cell: cell contacts and cell: EXM contact
What is epithelial- mesenchymal- transition (EMT):
- Reversible process
- Common in wound healing and early embryogenesis
- Reactivated in cancer
What are the cellular changes in EMT?
• Activation of transcription factors SNAIL and TWIST
• Loss of cell polarity and loss of cell adhesion molecules e.g. E-cadherin
• Changes in cell shape
• Increase in mesenchymal markers e.g. N-cadherin, vimentin
• Protease production
• Promotion of ‘stemness abilities’ i.e. early metastasising cells likely to be CSCs
What is the rationale for cancer cells to utilise aerobic glycolysis?
- Cancer cells are frequent hypoxic- Lack of oxygen for oxidative
- Process of glycosis also generates intermediates for biosynthetic pathways such as growth
How do cancer cells evade the immune system?
Loss of tumour antigens
Downregulation of antigen present molecule (APCS)
Over-expression of immune checkpoint proteins and anti-apoptotic proteins
What is the multi-hit model and what is it supported by?
A cell has to acquire several mutations before it’s going to transform a normal cell into a cancer cell.
Supported by:
- Genetic homogeneity in cells from a given tumour
- Cancer incidence increase with age
- Evidence of cooperative effects of mutations
What is a driver mutation?
Confers growth/ survival advanatage
What is a carcinogenic agent and give examples?
• Cause damage that is not repaired- mutations survive and propagate
• Radiation
• Chemicals
• Infectious pathogens
• Endogenous reactio
What is ionising radiation and what are the risk factors?
Ionising radiation e.g gamma rays , alpha and beta particles
• Direct DNA damage- ionisation of atoms comprising DNA
• Indirect DNA damage- Radiolysis of H20 and ROS generation, hydroxylysine radical (most reactive but unstable) , H202 (less reactive but stable-time to enter the nucleus and effect DNA, more problematic) ,Superoxide radical
• Risk factors: exposure to X-rays, living at altitude, plane travel
What are the types of UV radiation and their wavelength? HOW does it work?
UVA- (Wavelength 320-380nm)
UVB- wavelength 290-320nm- most effective carcinogen
UVC (wavelength 200-290nm
Double bonds in DNA absorb UV- mutations cause bends in the DNA which are misread by DNA polymerase
What UV is the main cause of skin cancer and why?
UVB- - MAIIN CAUSE OF SKIN CANCER
• P53 tumour suppressor commonly affected
• Causes80% of skin cancers- squamous and basal carcinomas - not usually melanoma- mutations in raf (active in driving cell proliferation)
• Risk factors- over exposure to the sun i.e sunburn, sun edges
What are direct acting chemical carcinogens?
Uncommon
- Reactive electrophiles
- Interact with nitrogen and oxygen atoms in DNA
- Examples include dimethyl sulphate and nitrogen mustards
What are indirect acting chemical carcinogens?
• Unreactive and water soluble 0 When taken into the body they are processed into the electrophillic carcinogenic form by enzymes in our cells.
Common
• Electrophillic centre produced by enzyme modification e.g via processing by cytochrome p450 enzymes
• Interact with bases in DNA forming addicts
• Examples include polycyclic aromatic hydrocarbons (PAHs) (Cigarette smoke) and aromatic or heterocyclic amines (cooked meats)
Risk: smoking, diet high in cooked or processed meat, preservatives in process food
What is the general mechanism of action of chemical carcinogens?
• An electrophillic (or electron deficient) form reacts with the nucleophilic sites (sites that can donate electrons) in the purine and pyramiding rings of nucleic acids
What are oncogenic viruses?
• DNA tumour viruses
• Encode viral proteins that block tumour suppressor action
• Examples HPV- protein promotes degradation of RB protein leading to constitutive activation the cell cycle
What are influential factor in human carcinogenicity?
Environemnt
• Reproductive life
• Smoking
• Alcohol consuption
• Excerise
• Diet- carnogenic contaminants, dietary deficiencies, obesity nh
What are the normal genes implicated in the onset of cancer?
Proto-oncogenes
Tumour suppressor genes
Caretaker genes
What is the normal role of protooncogenes?
Positively promote cell proliferation of celll survival
What type of mutation occurs in proto-oncogenes?
Gain of function - dominant function
What is the normal role of tumour suppressor genes?
Inhibit cell survival or negatively regulate cell proliferation
What type of mutation happens in tumour suppressor genes?
Loss of function and recessive
What are the genetic events that can cause loss of function in TS gene?
• Loss of entire chromosome
• Chromosomal rearrangements- gene is disrupted or region contains normal gene is deleted
• Mutation in coding sequence which results in non-functional protein
• Gene activity is silenced by epigenetic changes
• Mutations in genes coding for chromatin remodelling complexes e.g SWI/SNF
What is the role of a care taker gene
Repair or prevent DNA damage
What types of mutations are caretaker genes?
Loss of function and recessive
What repair mechanisms are affected when there are mutations in caretaker genes?
DNA mismatch repair, nucleotide excision repair, double stranded DNA break
What are the cyclins associated with the cell cycle phases?
G1 Cyclins
G1/S cyclins
S phase
M phase
What are CDKs influenced by?
Cyclin binding
Phosphorylation and Dephosphorylation
Binding to CDK inhibitors e.g p15, p16, -21, -27
Where are the cell cycle checkpoints and what are their role?
G1 checkpoint- is environment favourable?
G2 checkpoint- is DNA replicated? Is all the DNA damage repaired?
Checkpoint in mitosis- Are all chromosome properly attached to mitotic spindle?
What is the p53 gene?
TF, binds DNA as a tertamer
Can binds promoter regions in 300 target genes
Multifunctional tumour suppressor
What does a mutation in p53 cause?
Promote the formation of the malignant phenotype and are seen in tumours
