Basic mechanisms in cancer biology Flashcards
Learn it
What is cancer?
Uncontrolled cellular growth
Possible issue with calling cancer “uncontrolled cell growth”?
Could be positive–>cell may pick up asn advantageous mutation and then do uncontrolled cell growth
Key properties of cancer cells?
Ability to replicate indefinitely, Ability to evade apoptosis
What kind of mutations could accelerate the early development of some cancers?
Mutations that inactivate DNA repair pathways, and mutations that increase the rate of cell division
What is a stem cell?
Cell types that can self renew or differentiate into a specialised cell type
What type of stem cell does each organ/tissue have?
One that is specific to the organ/tissue itself i.e. the brain will have stem cells that can differentiate into each type of neuron and any other brain cells
What is similar between stem cells and cancer cells?
The ability to replicate themselves indefinitely
What could happen to a stem cell to cause it to become a cancer stem cell?
If a mutation inactivated a DNA repair pathway, the cell would be able to pick up mutations fairly quickly
Why should cancer stem cells be a target for chemotherapeutic strategies?
Many cytotoxic agents would kill the tumour cells but leave the stem cells, meaning a relapse may occur
Why does cancer relapse sometimes?
The cytotoxic agents kill the tumour cells but the cancer stem cell survives, meaning the tumour can come back
What is an oncogene?
A gene that, when activated in a particular way, will promote cancer formation
What kind of mutation usually happens to an oncogene?
A gain of function mutation
What kind of mutation (dom/rec) usually happens to an oncogene?
Dominant
Why do oncogene mutations usually occur with no family history?
They only need to occur in a single copy of the geneas they are usually dominant mutations
What is a chromosomal translocation?
When two chromosomes swap portions of genetic material
What is the philadelphia chromosome?
When a short part of chromosome 9 is translocated onto a short part of chromosome 22
What gene from chromosome 9 is at the break point when the philadelphia chromosome is formed?
ABL gene
What gene from chromosome 22 is at the break point when the philadelphia chromosome is formed?
BCR gene
What happens on the philadelphia gene?
A fusion gene (BCR/ABL) gene is present
What is the role of the Abl gene?
It is a regulator of hematopoietic cell division
What happens to the Abl gene in the philadelphia chromosome?
It is locked into the “on” position
What happens as a result of the Abl gene being locked “on” in the philadelphia chromosome?
Uncontrolled hematopoietic cell division
What is a consequence of uncontrolled hematopoietic cell division?
Leukaemia
What is the function of the MYC gene?
It is a transcription factor that interacts with another transcription factor called Max
What do MYC and Max form?
A heterodimer
What does the Max-MYC heterodimer bind to?
They bind to an E box element (CACGTG)
What is the importance of the CACGTG E box element?
It is a promoter that can be found upstream of cell growth regulator genes
What happens when the MYC gene is mutated/amplified?
There is an overactivation of the genes that drive proliferation of early neural cells
Where do tumours form as a result of a MYC amplification?
The sympathetic nervous system–> neuroblastoma
What is a tumour suppressor gene?
A gene who carries out a function that suppresses tumour formation
What is biallelic inactivation?
Both genes need to be inactivated by mutation
Familial effect on tumour suppressor genes?
Associated cancers can more commonly display a family history
What is knudsons two hit hypothesis
For sporadic cases, there is no inherited mutations so both mutations would need to occur on the same gene in the same cell
Knudsons two hit hypothesis (but one hit)?
If one of the gene mutations is inherited, only one “hit” (mutation) would need to occur
Why are familial cases of TSG inactivation more common?
More likely that one mutation is inherited and one occurs during life than both mutations occuring during life
What are the major human breast cancer susceptibility genes?
BRCA1 and BRCA2
What is a DNA double strand breakage?
A break in the phosphodiester backbone on both strands of the DNA backbone
Effect of a double strand break on the DNA?
Can cause a section of damaged DNA to go missing
Issue with the Non-Homologous End Joining (NHEJ) method of fixing DNA?
It just connects the two ends of DNA, and doesn’t take into account the section that has gone missing
What is a better method of fixing a double stranded DNA break?
Homologous recombination
How does homologous recombination work?
Enzyme resects DNA, exposes a single stranded region. Single stranded region then looks for section of homologous chromosome that has sequence homology to it. That is then used to figure out what the missing section is
Benefit of homologous recombination?
The section of DNA that went missing is replaced in the fixed DNA
What does BRCA1 do?
Senses the DNA break and recruits BRCA2
What does BRCA2 do?
Recruits RAD51 and loads it onto the single stranded region
What does RAD51 do?
RAD51-single strand complex is required for strand invasion process (from homologous recombination)
What can mutations in BRCA2 cause (other than breast cancer)?
Fanconi’s anemia–> associated w/ bone marrow failure and leukaemia
How does the mutated BRCA2 work to get breast cancer?
One mutation is inherited from parents, while the other mutation occurs during life
How does the mutated BRCA2 work to get Fanconi’s anemia?
Both mutations are inherited from parents
Symptoms of Von Hippel-Lindau syndrome?
Fatigue, poor motor coordination and vision impairment
What kind of condition (dom/rec) is VHL?
Dominant condition, so only one copy of the gene needs to mutate
Differences in VHL syndrome depending on if you have one or both copies of the gene mutated?
There are different sets of symptoms for VHL
Normal role of VHL protein?
interacts w/ HIF-alpha transcription factor, causes it to be polyubiquitinated–> leads to degradation of HIF-alpha
HIF-Alpha under hypoxic conditions?
VHL doesnt bind to it, instead HIF-alpha binds to HIF-beta–> this complex can turn on genes that are involved in angiogenesisW
What is angiogenesis?
Blood vessel formation
What causes VHL syndrome?
VHL protein never binds to HIF-alpha so overstimulation of angiogenesis (it will occur in normal conditions a well as in hypoxic ones)
