L21 - Carcinogenesis - molecular hallmarks of cancer cells Flashcards
what 2 mechanisms are responsible for the conversion of normal cells into nepotistic cells?
- oncogene activation
- tumour supressor gene inactivation
What do caretaker genes do?
Maintain genetic stability by repairing damaged DNA and replication errors
- DNA repair genes
- controlling accuracy of mitosis
What do mutated forms of caretaker genes cause?
genomic instability as unable to correctly repair damaged DNA
What are 2 types of TSG?
- gatekeepers
- caretakers
What do gatekeepers do?
Play important roles in regulating normal growth
- negative regulators of the cell cycle and proliferation
- positive regulators of apoptosis
- positive regulators of cell differentiation
What types of mutations occur in TSGs?
- point mutations
- deletions/insertions
- chromosomal rearrangements
- epigenetic silencing (promoter methylation)
Every cell in the body will carry the ‘1st hit’ in what circumstances?
In the case of familial cancer syndromes
Why is a ‘2nd hit’ required for complete loss of function of a TSG?
one copy of the gene is enough to control; cell proliferation/apoptosis/repairing DNA due to mutations within TSGs being RECESSIVE .
Both copies of TSG have to be mutated for inactivated for complete loss of function.
Familial cancer syndromes can involve inheritance of a mutant copy of what?
A gatekeeper or caretaker gene (TSG)
What is the risk of cancer for a carrier of a mutant copy of a TSG?
70-90% lifetime risk of developing cancer, depending on the syndrome
What TSG gene is involved in retinoblastoma cancer syndrome?
RB1 (gate)
What TSG gene is involved in Li-Fraumeni cancer syndrome?
p53 (gate/care)
What TSG gene is involved in Familial adenomatous polyposis cancer syndrome?
APC (gate)
What TSG gene is involved in Familial breast cancer syndrome?
BRCA1, BRCA2 (care)
What TSG gene is involved in Hereditary non-polyposis colorectal cancer syndrome?
hMLH1, hMSH2 (care)
What are the principal tumours in Li-Fraumeni syndrome?
Sarcomas
Breast
What are the principal tumours in FAP?
Colorectal
What are the principal tumours in HNPCC?
Colon
Endometrial
What are the stages from proto-oncogene to cancerous cell?
- proto-oncogene
- cancer-promoting agent (UV light, chemicals etc)
- oncogene
- cancerous cell
What do mutations in proto-oncogenes lead to?
Activated versions of or increased expression of proto-oncogenes (gain of function)
Oncogenes
What are the different types of mechanism of oncogene activation?
- translocation
- point mutation
- amplification
- insertion
What are the 10 hallmarks of cancer cells?
- sustaining proliferative signalling
- evading groet suppressors
- avoiding immune destruction
- replicative immortality
- promoting inflammation
- invasion and metastasis
- inducing angiogenesis
- genome instability and mutation
- resisting cell death
- deregulating cellular energetics
what is meant by the hallmark self-sufficiency in positive growth signals?
Tumour cells acquire the ability to grow in the absence of EGF (epidural growth factor) which would bind to its receptor to encourage a cell to grow and differentiate.
Which family is the oncoprotein RAS part of?
It is a member of a family of guanine nucleotide binding proteins called G-proteins
What does the Rb protein do?
It is a key regulator of the cell cycle by preventing progression from G1 to S phase
NB: -ve GFs inhibit progression of cell cycle by activating Rb
What is Rb protein activated by?
Negative growth factors
- they inhibit progression of cell cycle by activating Rb protein
What does Rb protein stand for?
Retinoblastoma protein
Give an example of a negative growth factor
Transforming growth factor beta (TGFbeta)
How can cancer cells escape inhibition of proliferation by negative growth factors?
They can acquire mutational inactivation, or epigenetic silencing, of the RB tumour suppressor gene.
What does P53 do?
Induces cell cycle arrest to allow repair of DNA damage
But also induces apoptosis if there is too much damage
What does TP53 inactivation lead to?
Loss of apoptotic response
This is the most common genetic abnormality in human tumours (>50% of tumours)
Which syndrome does inherited mutation of TP53 cause?
Li-Fraumeni syndrome
Why is sustained angiogenesis important in cancer cells?
Tumours greater than 2mm need to stimulate a new blood supply (angiogenesis) or the cells in the middle of the growth will die from lack of oxygen/nutrients
How do cancer cells carry out angiogenesis?
Growth factors/angiogenic factors such as vascular endothelial growth factor are often produced by tumours and these stimulate growth of new vessels
What do VEGF do?
Stimulates growth of new vessels
Actively recruits endothelial cells that process to construct new capillaries and vessels
Tumour cells which are able to invade new tissues show which feature?
Loss of E-cadherin through mutation or hypermethylation of the gene
What does loss of E-caherin result in?
Epithelial-mesenchymal transition (EMT)
What does metastasis involve?
The spread of malignant cells via the blood/lymphatic system to secondary sites and the formation of secondary tumours
What is CA-125 serum antigen used for?
Used in the detection and monitoring of ovarian cancer - but not very sensitive or specific
Overexpression of which gene is found in around 30% of breast tumours? And what does it code for?
HER2
Codes for a positive growth factor receptor
So over expression causes cells to become more responsive to, or independent of, positive growth factors.
Which drug targets HER2 and what type of drug is it?
Herceptin
It is an antibody drug targeted to HER2
What does herceptin do?
It dampens the effects of an overactive HER2 receptor
what is a proto-oncogene?
Normal genes that promote cell proliferation,
survival and angiogenesis
what is an oncogene?
mutated versions/increased expression of proto-oncogenes,
causing
increased/uncontrolled activity of expressed proteins
what does on oncogene do?
- cause aberrant cell proliferation
- survival/inhibition of apoptosis
- angiogenesis [feeding the growing tumour mass]
do oncogenes allow for gain or loss of function?
Oncogenes are dominant gain-of-function: 1 mutant copy of the gene acts dominant to the
remaining normal parental gene
Explain how insertion allows for oncogene activation.
Insertion of a promoter or enhancing gene (by retroviruses) near an oncogene = increased
expression of porto-oncogene
what is a Antioncogene?
gatekeepers (tumour suppressor gene)
Carcinogens induce what molecular abnormalities in TSGs that cause reduced/lack of protein
expression/function?
- inactivating point mutations
- deletions
- translocations
- epigenetic silencing
are mutations within TSGs dominant or recessive?
recessive
what familial cancer is associated with loss of the APC gene?
(Familial adenomatous polyposis) -
colorectal cancer syndrome
what does the APC gene control?
a TSG that controls proliferation
what does the p53 gene control?
regulates apoptosis
what affect to negative growth factors have on a mutated or inactive Rb protein?
negative growth factors would have no affect and so proliferation/growth would continue
inactivation of Rb gene is common in tumours, what does this result in?
- resistance to negative growth factors
- continuous proliferation
what is the mechanism that allows the hallmark avoiding immune destruction?
binding of PD-1 antigen on T cell and PD-L1 receptor on tumour cell inhibiting T cell from killing tumour cell
What is the PD-1/PD-L1 pathway?
The PD-1 (programmed cell death-1) receptor (also known as CD279) is expressed on the surface of T cells. Its ligands, PD-L1 (CD274) and PD-L2 (CD273), are commonly expressed on the surface of dendritic cells or macrophages. PD-1 and PD-L1/PD-L2 and act as co-inhibitory factors, which halt the development of the T cell response.
PD-1/PD-L1 interaction ensures that the immune system is activated only at the appropriate time in order to minimize the possibility of chronic autoimmune inflammation.
what is the role of PD-1/PD-L1 in cancer cells?
PD-L1 expressed on the tumor cells binds to PD-1 receptors on the activated T cells, which leads to the inhibition of the T cells.
how can we use PD-1/PD-L1 against cancer in immunotherapy?
we block the ligand PD-L1, PD-1 cannot bind and so T cell is not inhibited and acts on tumour cell
what is the enzyme that allows the hallmark of replicative immortality?
telomerase
keeps building telomere so it doesn’t shorten
what is the mechanism that allows the hallmark of inflammation promotion?
inflammation destroys cells and so promotes more to grow back (unscheduled when tumour cells are promoting inflammation)
how are secondary tumours formed?
via metastasis
what is the mechanism that allows the hallmark of resisting cell death?
Over expression of anti-apoptotic BCL2 - puts a halt on apoptosis = cancer cell survives.
what does the BCL2 gene regulate?
cell death (apoptosis) by either inhibiting (pro-apoptotic) or inducing (anti-apoptotic) apoptosis.
what is the mechanism that allows the hallmark of deregulated metabolism?
the Warburg effect
what is the Warburg effect?
Cancer cells predominantly produce energy through a high rate of glycolysis followed by lactic acid fermentation even in the presence of abundant oxygen.
what is a possible explanation of the Warburg effect?
- damaged mitochondria due to the cancer
- an effect associated with cell proliferation. Since glycolysis provides most of the building blocks required for cell proliferation, cancer cells (and normal proliferating cells) have been proposed to need to activate glycolysis, despite the presence of oxygen.
Explain how translocation allows for oncogene activation.
chromosomal translocation which relocates a proto-oncogene to a new chromosomal site that leads to higher expression
Explain how point mutation allows for oncogene activation.
A mutation within a proto-oncogene, or within a regulatory region (for example the promoter region), can cause a change in the protein structure, causing:
- an increase in protein (enzyme) activity
- a loss of regulation
Explain how amplification allows for oncogene activation.
by insertion of multiple copies of an oncogene – increased expression
what are the 3 genes that code for the RAS family of proteins?
KRAS
NRAS
HRAS
list 5 oncogenes.
RAS MYC RAF HER2 EGFR
what are the 2 categories of TSGs?
antioncogenes/gate keepers
caretakers
what molecular abnormalities do carcinogens induce in TSGs?
- inactivating point mutations
- deletions
- translocations
- epigenetic silencing
this causes reduced/lack of protein expression/function
what is epigenetic silencing?
shutdown of gene expression via
methylation of CpG sequences (cytosine nucleotide is followed by a guanine) in promoter regions
what familial cancer syndrome does a mutated RB1 TSG cause?
retinoblastoma
what familial cancer syndrome does a mutated p53 TSG cause?
Li-Fraumeni
sarcomas, breast tumours
what familial cancer syndrome does a mutated APC TSG cause?
familial adenomatous polyposis
colorectal cancer
what familial cancer syndrome does a mutated BRCA1/2 TSG cause?
familial breast cancer
breast, ovarian tumours
what familial cancer syndrome does a mutated hMLH1/2 TSG cause?
hereditary non-polyposis colorectal cancer
colon/endometrial tumours
what serum marker can be used as an adjunct for liver/testicular cancer?
AFP
what serum marker can be used as an adjunct for ovarian cancer?
CA125
what serum marker can be used as an adjunct for testicular cancer?
hCG
what serum marker can be used as an adjunct for prostate cancer?
PSA
why is PSA no longer used to detect prostate cancer?
- many noncancerous conditions also can increase a man’s PSA level
- not sensitive or specific enough
- PSA elevates as a mans prostate grows with age
why should you always test for PSA before a prostate examination?
touching the prostate is enough for it to secrete PSA into the blood stream and you will get an elevated PSA result
which serum markers are not used as an adjunct for diagnosis but for monitoring a cancer?
- CEA (will not indicate which kind of cancer is present)
- thyroglobulin (thyroid cancers – both those confined to the thyroid gland and those that have spread to other parts of the body)
the KRAS mutation is associated with which type of cancer?
50% of colorectal cancers have a KRAS mutation
