Carcinogenesis - Molecular Hallmarks of Cancer Cells Flashcards
What are the 6 main hallmarks of cancer cells?
- evading apoptosis
- self-sufficiency in growth signals
- insensitivity to anti-growth signals
- sustained angiogenesis
- limitless replicative potential
- tissue invasion and metastasis
What are the 10 hallmarks of cancer cells?
- sustaining proliferative signalling
- evading growth suppressors
- avoiding immune destruction
- enabling replicative immortality
- tumour-promoting inflammation
- activating invasion and metastasis
- inducing angiogenesis
- genome instability and mutation
- resisting cell death
- deregulating cellular energetics
What is meant by the “hallmarks of cancer”?
when cells progress towards a neoplastic state, they acquire distinctive capabilities
cancer cells acquire the hallmarks through mutations, which allow them to progress and spread
What is meant by cancer cells sustaining proliferative signalling?
this involves signals by growth factors that bind to cell-surface receptors, typically containing intracellular tyrosine kinase domains
intracellular signalling pathways regulate progression through the cell cycle, as well as cell growth
these signals influence other cell properties, such as survival and energy metabolism
Why is sustaining proliferative signalling perhaps the most fundamental trait of cancer cells?
it allows for self-sufficiency in positive growth signalling
What is the role of Rb protein?
How does it interact with growth factors?
Rb protein is a key regulator of the cell cycle as it prevents progression from G1 to S phase
negative Gfs inhibit progression of the cell cycle by activating Rb protein
How can cancer cells act to evade growth suppressors?
inactivation of Rb gene is a common event in tumours
this results in resistance to negative growth regulation
the gatekeeper between G1 and S phase is lost
How do cancer cells avoid immune destruction?
The tumour cell expresses PD1, which binds to PD-L1 receptor on T cells
When they bind, the T cell becomes silenced and is no longer destructive
How can cancer be treated, using the fact that it can evade the immune system?
Blocking PD-1 and PD-L1 prevents the interaction between the tumour cell and the T cell
this allows the T cell to resume killing the tumour cell
How can cancer cells have replicative immortality?
In normal cell division, the telomere becomes shorter with each division until it cannot divide anymore
cancer cells have telomerases which elongate and maintain the length of the telomeres
What is meant by ‘tumour-promoting inflammation’?
inflammation associated with the tumour helps to accelerate progression of cancer
knowing how the tumour behaves to inflammation can be used to determine if a patient would benefit from immune therapy
What is meant by activating invasion and metastasis of cancer cells?
- cancer usually becomes dysplastic and progresses from low-grade to high-grade dysplasia
- the cells break through the basal lamina
- the cells enter the bloodstream
- the cells adhere to the blood vessel and penetrate the capillary wall
- the cells then divide to form a tumour
What is meant by cancer cells inducing angiogenesis?
small tumour is growing and releases angiogenic factors
this stimulates capillaries to sprout and supply oxygen and nutrients to the tumour
this also allows for metastatic spread
Why do cancer cells want to have genome instability and mutations?
it is beneficial for cancer cells to have an unstable genome with lots of mutations present
this allows cancer to progress from a pre-malignant to an invasive form
it allows cancer cells to react quicker to changes and adapt
How do cancer cells resist cell death?
Bcl2 is not activated normally, allowing apoptosis to occur
If Bcl2 is upregulated, there is no apoptosis meaning that the cell does not die
What is meant by cancer cells deregualting cellular energetics?
cancer cells have a deregulated metabolism
this is anaerobic as tumour cells cannot be reliant upon limited oxygen supplies
they use up glucose and produce lactate
What are proto-oncogenes?
normal genes that promote cell proliferation, survival and angiogenesis
What are oncogenes?
mutated versions of proto-oncogenes that cause increased/uncontrolled activity of expressed proteins
What is meant by oncogenes being dominant gain-of-function genes?
1 mutant copy of the gene acts dominantly to the remaining normal parental gene
What are the 4 mechanisms of oncogene activation?
- translocation
- point mutation
- amplification
- insertion
What is meant by translocation as a mechanism of oncogene activation?
it involves translocation of an oncogene from a low to an active transcriptional site
this leads to aberrant expression of the oncogene
What is meant by point mutation as a mechanism of oncogene activation?
substitution of a single base within the amino acid sequence which produces a hyperactive oncoprotein
What is meant by amplification as a mechanism of oncogene activation?
insertion of multiple copies of an oncogene
this leads to increased expression
What is meant by insertion as a mechanism of oncogene activation?
insertion of a promoter or enhancing gene (by retroviruses) near an oncogene leads to increased expression
What are examples of oncogenes?
- RAS
- myc
- RAF
- HER2
- EGFR
What are the 3 genes in the RAS family of proteins?
KRAS
NRAS
HRAS
What types of molecules to oncogenes code for?
tyrosine kinase family
they are involved in growth and stimulation of cell division
over-expression leads to tumour growth and proliferation
What are the 2 categories of tumour suppressor genes and their functions?
gatekeepers:
- antioncogenes
- negative regulators of the cell cycle and proliferation
- positive regulators of apoptosis
caretakers:
- maintain genetic stability
What happens if there is a mutation in a tumour suppressor gene?
this results in loss of their function
How do carcinogens interact with tumour suppressor genes?
they induce molecular abnormalities in TSGs that cause reduced/lack of protein expression/function
What are the 4 mechanisms of TSG loss?
- inactivating point mutations
- deletions
- translocations
- epigenetic silencing
shutdown of gene expression via methylation of CpG sequences in promoter regions
What are the 5 tumour suppressor genes?
- APC
- p53
- RB
- BRCA1 and BRCA2
- hMLH1, hMSH2
What genes and tumours are implicated in the following cancer syndromes?
What is involved in a familial cancer syndrome?
inheritance of a mutant copy of a TSG or caretaker gene
caretakers maintain genetic stability
germline mutations cause genetic instability which predisposes individuals to developing cancer
What is the carrier risk associated with familial cancer syndromes?
carriers suffer from a risk of developing cancer
this is 70-90% depending on the syndrome
What is meant by the adenoma carcinoma sequence?
- oncogene activation and tumour suppressor gene inactivation occurs in a normal cell
- this develops into neoplasia (abnormal growth)
- this leads to malignant neoplasia, which leads to invasion and metastasis
What is the sequence of steps involved in carcinogenesis?
- telomerase expression allows for immortality and replication
- inactivation of TSGs removes growth inhibition
- oncogene activation leads to neoplastic transformation and excessive cell division
Which genes are involved in the following process?
What are the stages of this process?
What are the 4 clinical applications of tumour markers?
diagnosis:
- identification of type and sub-type
prognosis:
- certain mutations confer worse survival
therapy:
- predictive markers for therapeutic response
- development of targeted drugs or gene therapies
monitoring:
- response to treatment
- detecting relapse
What are the downsides of using serum markers in diagnosis and monitoring?
none have sufficient sensitivity or specificity to be used for general screening
What serum markers are used as an adjunct for diagnosis?
Which ones are used just for monitoring?
adjunct for diagnosis:
- AFP
- CA125
- hCG
- PSA
monitoring:
- CEA
- thyroglobulin
How can HER2 be used as a predictive and prognostic marker?
HER2 is overexpressed in 30% of breast cancers
only patients with HER2 overexpression have Herceptin treatment as patients without overactive HER2 receptors will have no beneficial effect
What are the predictive and prognostic markers in colorectal cancer?
50% of colorectal cancers have KRAS mutation
This binds to EGFR receptor
Cetumixab and Panitumumab block EGFR
