Cancer Flashcards
Where is the incidence of cancer highest and lowest
Highest generally more developed countries (it is the 2nd largest cause of death after cardiovascular disease)
Lowest in developing countries, lowest in Africa as a continent
4 fold difference between them
What is the largest cause of cancer
Smoking (~30%)
What does metastasis mean
Spreading to other organs from the site of origin (primary tumour) to other sites (secondary tumours)
What are carcinomas
Malignant rumours of epithelial cells
What is carcinoma in situ
A pre-malignant change in which the epithelium shows malignant changes but does not invade underlying tissue
What are sarcomas
Tumours of tissue derived from the mesenchymal layer
What sí leukaemia
Abnormal proliferation of circulating white blood cells
How do the hallmarks of cancer arise
Why is it an old age disease
Through accumulation of mutations in the genome
There is an accumulation of mutations
How many bases and genes in the human genome
3x10^9
~ 20,000 genes
How close to a blood vessel must a cell be to avoid hypoxia
Why
~10 cells distance
Inadequate diffusion over long distances
What is angiogenesis
Growth of new blood vessels
What does bevacizumab target
It is A monoclonal antibody that targets VEGF
What is the vasculature in tumours like and what does this mean
Tumour neo-vasculature is usually leaky and tortuous with unstable blood flow patterns, leading to hypoxia and thus necrosis in the core
Are tumours clonal?
Yes but mutations result in them being heterogenous with multiple clones co-existing in the tumour. The predominant clone at any point will comprise superior fitness compared to the other clones
Which mutations give rise to cancer
Mutations in key signalling molecules that control cell fate
Give the 4 hallmarks of cancer
Mutation
Angiogenesis
Tumour expression
Invasion and metastasis
How many deaths in 2014 were caused by cancer
29%
True or false: the increased cancer incidence may be accounted for by increased longevity
True
More than a third of deaths from cancer were in people aged 75 or over
Cancer is mainly a disease of old age due to the accumulation of genetic changes over time
What are the top 3 environmental causes of cancer
Smoking (33%)
Obesity (20%)
Diet (5%)
Name an infection that causes cancer
Helicobacter pylori
Name 2 kinds of transmissible cancer
Tasmanian devil facial tumours
Canine transmissible venereal tumours
True or false: the most common cancers have a good survival rate
False
Several of the most common cancers have a very poor survival rate
Which are the four most common causes of cancer mortality
Lung
Bowel
Breast
Prostate
What is the largest preventable cause of cancer
Smoking
Why may large dog breeds be more susceptible to osteosarcomas
What evidence further backs this up
Highly active growth plates at these sites?
Primary osteosarcomas are generally restricted to children and young adults
What does mastinib do
It is a small molecule inhibitor that targets the c-Kit growth factor receptor in dogs
What are the key differences between benign and malignant tumours?
Benign: slow growing
Encapsulated
Non-invasive/ -metastatic
Differentiated
Malignant: fast growing
Invasive/ metastatic
Poorly differentiated
Which of the following are benign and which are malignant: Adenoma Sarcoma Fibroma Hyperplasia Carcinomas in situ Carcinoma Dysplasia Metaplasia
Only carcinoma and sarcoma are malignant
The rest (including carcinoma in situ) are benign
What is a sarcoma
Tumours of mesenchymal layer (connective tissue and blood vessels)
What is leukaemia
Abnormal proliferation of white blood cells
What is a neuroectodermal tumour
Tumours of the PNS or CNS
What kind of tumour are astrocytomas and meningiomas
Neuroectodermal tumours
Give the 6 cell intrinsic hall marks of cancer
Growth signal autonomy Resistance to inhibitory growth signals Unlimited replicative capacity Reprogramming of cell metabolism Resistance to apoptosis Genetic instability
Discuss the first 4 hallmarks of cancer
These are the major characteristics of tumour cells - uncontrolled proliferation
Discuss the hallmark of apoptosis resistance
Most incipient tumours die by apoptosis
Mutations that render cells resistant to apoptosis contribute to cancer
Why is the hall mark of genetic instability important in cancer
It can contribute to rapid accumulation of further mutations
What are the 3 cell extrinsic hallmarks of cancer
Induction of angiogenesis
Metastatic potential
Evasion from immune system
Why is angiogenesis important in cancer
Solid tumours need to develop a vasculature that supplies oxygen and nutrients
How does metastasis occur
Tumour cells invade surrounding tissue, enter the blood, or lymphatic system and lodge in distant sites
How do tumours avoid the immune system
Tumour cells and recruited normal cells produce cytokines that dampen the immune response to the tumour
How big are benign dormant micro tumours
~10^5 cells
What limits the growth of a microtumour
Growth requires a blood supply
Oxygen can diffuse 10 cells from source
This limits the size of an avascular tumour to 1-2mm
Angiogenesis is a cancerous process. True or false?
No it is a normal process as new vessels are always needed, eg in wound healing
Give an example of a tumour hijacking the angiogenic process
Some tumour cells secrete VEGF
VEGF binds to specific receptors on endothelial cells that line blood vessels and stimulates secretion of MMPs, allowing tissue remodelling
The activated endothelial cells proliferate and migrate towards the source of the VEGF
these activates endothelial cells also secrete PDGF, a chemo attractant for smooth muscle cells
Is tumour vasculature stable?
No the neo-vasculature of tumours is often leaky and tortuous with unstable blood flow patterns
What does the unstable neo vasculature of tumours usually lead to
The centre of the tumour becoming hypoxic, forming a necrotic core
What are the 6 stages of angiogenesis in tumours
Hypoxia Proteolytic degradation Tip cell migration Tube formation Regulation of vessel size Tumour vascularisation
Why is hypoxia important for angiogenesis
Hypoxia induces HIF-1 expression and the consequent release of VEGF
What is the angiogenic switch
When the careful regulation of stimulants and inhibitors of angiogenesis is disrupted
Name 2 angiogenic inhibitors
Angiostatin
Endostatin
What is Avastin
A monoclonal antibody to VEGF
It is an anti-angiogenic drug with complicated side effects
It is no longer approved by the FDA
Other than VEGF, name 4 angiotensin activators
PDGF-BB
FGF
IGF
HGF
What does IGF stand for
Insulin like Growth Factor
What does HGF stand for
Hepatocyte Growth Factor
Name a cancer that does not require angiogenesis
Why does this present complications
PDAC
It is a tumour that is largely avascular and hypoxic
Lack of vasculature compromises the effective delivery of therapeutic drugs into the tumour
What is the most frequent characteristic of a malignant tumour
Invasion of surrounding normal tissue
What mechanism allows local tissue invasion of cancer
Tumour cells express proteases that degrade the basement membrane that defines the boundary of the tissue/ organ in which they originate
What do you call entering tissues that are distant from the primary tumour
Extravasate
True or false: metastic tumours possess the same genetic changes as the primary tumour from which they are derived
What does this suggest
True
Mutations conferring metastatic potential occur early and are not acquired
What kind of phenotype do both primary tumours and metastatic tumours exhibit
A de-differentiated phenotype
What is the Ames test
A test of the ability of a chemical to mutate the genome of salmonella
What correlation shows cancer is due to genetic mutation
There is a good correlation between the ability of a chemical to mutate DNA and chase tumourigenic transformation of cells
How do dietary carcinogens affect DNA
They react with nucleophilic sites in purines and Pyrimidine rings to form DNA adducts
Only mutations in which kind of gene lead to cancer?
Proto-oncogenes
Genes that control cell fate such as cell proliferation, survival etc
What genes are associated with HNPCC
MSH 2
MLH 1
HNPCC tends to occur when these are non functional
What are tumour suppressors
Genes whose inactivation promotes the incidence of cancer
OR
A gene whose protein product inhibits cancer
DNA repair genes are tumour suppressors
Why are tumours heterogenous
They are constantly evolving in response to intrinsic (eg hypoxia) or extrinsic factors (therapy)
Why do familial cancers require only 1 hit to a tumour suppressor
Patient already has 1 inactivated tumour suppressor allele
Why do sporadic cancers occur at lower frequency
Requires 2 independent hits to deactivate both copies of the tumour suppressor
What is a loss of heterozygosity often associated with
An inherited predisposition to cancer
3 epigenetic causes of cancer
Changes in chromatin
Post translational modification of proteins
Control of transcription or translation
What are epigenetic changes
Can these be heritable
Ones that do not involve mutation of the DNA itself
Yes they can pass from parent cell to daughter cell
Are miRNAs oncogenes or tumour suppressors
Different ones can be either
If there are increased miRNAs in a tumour it is an oncogene
Whereas increased miRNA in normal cells compared to the tumour suggests it is a tumour suppressor
What mediates the transformation from normal cell to tumour cells
The counter balance activities of oncogenes and tumour suppressors
How do tumours rise with oncogenes vs tumour suppressor genes
Oncogene: gain of function
Tumour suppressor: loss of function
Who discovered the first oncogene
How did he do it
What oncogene was it
Peyton Rous
Removed a chicken breast sarcoma and ground it up with sand. He passed this through a fine pore filter
He injected the filtrate into a young chicken and observed a sarcoma in the injected chicken
Rous Sarcoma Virus
How does the RSV cause cancer
It inserts a gene into the DNA leading to a replication defect
Does it take a single RSV cell to cause cancer
No
Transformation by RSV requires continuous maintenance by sarcoma gene activity
Transformation by RSV requires continuous maintenance by sarcoma gene activity. Give experimental evidence of this
Infect normal cells with RSV mutant at 37 degrees C
Cells transform
Shift temperature to 41 degrees C and the cells return to normal
Shift temperature back to 37 degrees C and the cells become cancerous again
What does retroviruses integration result in
The insertion of a potent LTR promoter at each end
What are the 2 general mechanisms to turn cellular genes cancerous ?
- Deregulated activity
2. Deregulated/ elevated expression
What does the c-src protein kinase look like in its inactive form
C-terminal Tyr is bound by internal SH2 domain, locking Src into inactive conformation
How does the c-src protein kinase become activated
Upstream signals displace SH2 domain, allowing adoption of active conformation
What do Ras proteins do
Connect receptors to the internal effectors of the cell
How are Ras proteins deactivated
Hydrolysis of GTP
Which Ras αα are mutated in many human cancers
12, 13, 61
Why is RSV unusual
In retains all the viral genes in addition to transducing the cellular src gene
What are the 2 ways of oncogene activation
- Mutation of the normal coding sequence
2. Gene amplification, chromosome duplication or truncation or promoter region mutation
Give an example of gene amplification causing cancer
Abnormal expression of MYC promotes cell proliferation
Lower levels of MYC correlate with a worse prognosis. True or false?
False
Higher levels of MYC lead to poor prognosis
Give an example of when c-MYC is deregulated
Non AIDS Burkitt’s lymphoma
What kinda of transcription factor is myc
Pleiotropic
Oncogenesis is a result of persistence. True or false?
True
Requires persistent deregulation
Is a single oncogenic mutation enough for cancer
No
Eg Land et al showed in Vitro that high levels of both Ras and Myc were needed for tumour growth
What is intrinsic tumour suppression
Give examples of intrinsic tumour suppression
A fail safe mechanism for high levels of a single oncogene activity
High levels of myc stimulate apoptosis
High levels of Ras stimulate cell cycle arrest
Normal cell + tumour cell=
Normal cell usually
What do Simian Virus, HPV, and Adenovirus 5 all do
Bind to p53 and p105^RB
Eg E6 binds to p53 and destroys It
What does p105^RB do
It is a pocket protein that binds and inactivated the E2Fs transcription factors that drive expression of cell cycle genes
It is A cell cycle inhibitor
What does p53 do
It is a transcription factor that responds to stress/ damage/ oncogenic signalling and induces cell cycle arrest or cell death
Why is cancer much more common in people with heterozygous Rb alleles
They have a high frequency of LOH (loss of heterozygosity)
There is exchange of genetic information between homologous chromosomes in the Rb heterozygote meaning the mutated and non functional copy becomes dominant
What kind of exchange of genetic information occurs in the Rb heterozygote
Mitotic recombination
Chromosomal non disjunction
Gene conversion
What does Rb do
In non phosphorylated state it sequesters E2F proteins, which stops cell cycle proliferation
Phosphorylation stops Rb
However, HPV and Adenovirus inhibit Rb but not by phosphorylating it
High levels of myc stimulate what to cause apoptosis?
p53
What does high levels of Ras stimulate
p16
p53
What do p53 mutations do
Inhibit DNA binding
What does p53 have to do to become active
It must bind with other p53 molecules to become a homo tetramer
DNA binds in the centre of the tetramer
What happens if p53 is a hetero tetramer
What does this mean
It is inactive
A mutant p53 would act as a dominant negative as only one mutation is needed to knock it out
What do oncogenes do that their normal counterparts don’t?
Nothing but their activity is no longer regulated
What will happen if a tumour suppressor is hypo-methylated
It is silenced and cancer can occur
Name a protein made active by a point mutation in its proto-oncogene
RAS
What activates cyclin B/ CDK1
CDK24
What is APC gene product involved in
G1/S checkpoint
