Cancer Flashcards
1
Q
Why is cancer a genetic disease?
A
- There are a number of environmental factors that cause cancer, but these act through genetic modifications e.g. activation of oncogenes
- Additionally 5-10% of cancers are due to inherited mutations
2
Q
What proportion of cancers are attributable to modifiable risk factors?
A
- 30-40% of cancers are preventable due to modifiable variables such as low fruit/veg intake, lack of physical activity, high BMI, alcohol and tobacco use
- Smoking is the most important risk factor in terms of cancer mortality
3
Q
What is the trend in cancer incidence and mortality in developed countries?
A
- The incidence of cancer is rising (due to aging population) and the mortality is decreasing
- This combines to increase the prevalence
4
Q
What proportion of cancer deaths occur in low and middle income countries?
A
- 70%
5
Q
What is attributable vs avoidable burden?
A
- The attributable burden can be estimated if the past prevalence of population to the risk factor and their relative risk of association with a cancer disease are known
- The avoidable burden is the burden of disease averted as a result in exposure reduction
6
Q
What are the main risk factors for cancer?
A
- Tobacco smoking
- leading cause of cancer death worldwide - Alcohol:
- 22% of mouth and oropharynx cancers in men and 6-20% of breast cancers in women - Diet, overweight and obesity:
- Linked with cancers of oesophagus, colo–rectum, breast (19%), endometrium (40%) and kidney - Hepatitis B and C:
- Cause of hepatocellular cancers - Human papillomavirus:
- Cause of all cervical cancer, 90% of anal cancer and 40% of cancers of the external genitals - Environmental pollution:
- Pollution of air, water and soil with carcinogenic chemicals - Occupational carcinogens
e. g. asbestos - Radiation exposure:
- X-rays and ionizing radiation
- UV radiation
7
Q
What are the 4 strategies to deal with cancer?
A
- Prevention:
30-40% of cancer deaths are preventable - Screening:
- aims to detect ‘pre-cancerous stage’
- should meet WHO criteria for screening program - Treatment
- Pallative care
8
Q
What are the features of a good preventative campaign?
What are some examples?
A
- Multi-dimensional approach
- Ingenuity
- Communication
- Patience
- Sustainability
- Creation of new norms
- Persistence
Examples:
- Sun exposure campaigns
- Preventing sale of alcohol to minors
9
Q
What are the WHO criteria for introducing a screening program?
A
- Condition should be important heath problem
- There should be a recognisable latent or early symptomatic stage
- The natural history of the disease should be adequately understood
- There should be an accepted treatment for the disease
- The test should be acceptable to population
- There should be an agreed upon policy as whom to treat as patients
- Facilities for diagnosis and treatment should be available
- The cost of screening should be economically balanced in relation to possible expenditure on medical care
- The screening should be a continuous project
10
Q
What are the 6 hallmarks of cancer?
A
- Resisting cell death
- Sustaining proliferative signalling
- Evading growth suppresors
- Activating invasion and metastasis
- Enabling replicative immortality
- Inducing angiogenesis
11
Q
How does resisting cell death lead to cancer?
A
- In normal cells a cellular stressor such as DNA damage will activate tumour suppressor programs e.g. p53 that will initiate the apoptosis (controlled cell death) of the damaged cell
- In cancer cells a cellular stressors such as DNA damage may occur, but the tumour suppressor gene e.g. p53 may be mutated, or antiapoptotic proteins such as Bcl2 may be overexpressed. This means that apoptosis is not initiated and the cancer cell survives and is allowed to accumulate mutations
e. g. B-cell lymphomas: a chromosomal translocation resulting in an immunoglobulin promoter being next to the Bcl1 gene leads to the cells becoming resistant to apoptosis and contributes to them becoming malignant
12
Q
How does sustained proliferative signalling lead to cancer?
A
- In normal cells growth and division are tightly constrained by both extrinsic factors such a growth factor and cytokine stimulation and hormone dependency and cell intrinsic factors such as intracellular signalling pathways and cell cycle regulators
- In many cancerous cells these proliferative signalling pathways are abberantly upregulated
e.g. B-cell sustained proliferate signalling in lymphomas: B-cells should only proliferate when they receive antigen-dependent proliferative signals. Mutations in B-cell receptor signalling leads to the constitutive activation of the BCR and thus abberant proliferation in B-cell lymphomas
13
Q
How does evading growth suppressors lead to cancer?
A
- Tumour suppressor programs are commonly inactivated in cancer
e. g. P53: - Integrates signals from cellular stressors to induce cell growth and arrest and allow DNA repair, if DNA cannot be repaired it induces cell death
e. g. Rb (retinoblastoma protein) - Central regulator of cell cycle (regulates the G1 checkpoint which is an important barrier to abnormal proliferation)
- Inhibited by phosphorylation which is done by cyclin-CDK complexes
e. g. Mantle cell lymphoma:
- Immunoglobulin promoter is translocated next to cyclin D1 (due to t(11;14))
- This leads to overexpression of cyclin D1 which inhibits the action of Rb and thus leads to unconstrained cell proliferation (no G1 checkpoint)
14
Q
How does enabling replicative immortality lead to cancer?
A
- Normal cells have a replicative mortality ‘Hayflick limit’ that is the number of times the cell will divide before cell division stops ‘replicative senescence’
- The replicative mortality is due to the loss of genetic material on the lagging side, this is capped with telomeres, which are synthesised by TERT enzymes
- The TERT enzyme is tightly controlled so the telomeric ends will only be lengthened appropriately (within the Hayflick limit)
- TERT can become activated in cancers via mutation of its promoter region which leads to the upregulation of the enzyme and thus the overcoming of the Hayflick limit making the cell have replicative immortality
15
Q
What are the cancer enablers/emerging hallmarks?
A
Emerging hallmarks:
- Deregulating cellular energetics
- Avoiding immune destruction
Enabling characteristics:
- Genome instability and mutation
- Tumour-promoting inflammation
16
Q
How does deregulating cellular energetics lead to cancer?
A
- The deregulation of cellular energetics in cancer cells is known as the Warburg effect:
- Tumour cells are more likely to undergo glycolysis (anaerobic respiration) if in the presence of sufficient amounts of oxygen
e. g. IDH2 mutation in T-cell lymphoma:
- IDH2 is an enzyme that convert isocitrate into a-ketogluterae in the CAC
- When IDH2 is mutated the CAC cycle is broken and this causes the cancer cell to undergo glycolysis even when there is sufficient methylation
17
Q
How does avoiding immune destruction lead to cancer?
A
Cancer cells are able to avoid immune destruction by:
- Downregulating MHC expression and reducing costimulatory molecule expression
- Expressing inhibitory ligands (e.g. PDL1 and PDL2) and immunosuppressive cytokines to exhaust host T-cells
e.g. overexpression of PDL1 in Hodgkins Lymphoma
18
Q
How does genome instability and mutation enable cancer?
A
Mechanisms:
- Inactivation of tumour suppressor genes regulating DNA repair
- Telomere loss leading to karyotypic instability
- Hijacking of physiological mutation prone states e.g. B-cell somatic hypermutation
- Gives intra-clonal heterogeneity
- Iatrogenic changes can be evoked by cytotoxic therapy/radiotherapy
Consequences:
- Tumour clonal proliferation
- Acquisition of a more aggressive disease phenotype
- Resistance to therapy
19
Q
How does venetoclax therapy work?
A
- Venetoclax is a Bcl-2 antagonist that binds to the Bcl-2 and allows apoptosis to occur
- It is able to overcome the ‘evasion of cell death’ hallmark of cancer
- Used to treat CLL
20
Q
How does Ibrutinib therapy work?
A
- Ibrutinib is a drug (kinase inhibitor) that targets B-cell receptor signalling
- Ibrutinib initially pushes lymphocutes out of the lymph nodes where they eventually die
- When combined with ventoclax, an excellent treatment for relapsed refractory CLL
21
Q
What is the difference between instrinsic apoptotic stimuli and extrinsic apoptotic stimuli?
A
Intrinsic apoptotic stimuli:
- DNA damage
- Via a mitochondrial pathway
- When DNA damage is induced, p53 is upregulated which promotes the permeabilisation of the mitochondrial membrane and apoptosis
Extrinsic apoptotic stimuli:
- Immune mediated deletion
- Via a death receptor pathway which activates intrinsic and executioner pathways
22
Q
Describe the extrinsic apoptotic pathway:
A
- When cytotoxic lymphocytes e.g. NK cells and CD8+ T cells recognise hazerdous antigens on cells an immune synapse is formed and they will release granzyme and perforin from cytotoxic granules
- The perforin creates holes in the target cell membrane
- Granzymes activate caspases to induce apoptosis
- Involves death receptors: initiation of cell death by Fas ligand binding to Fas receptor which activates caspase 8
23
Q
How do tumours develop resistance against extrinsic apoptosis?
A
- Downregulation of Fas receptor (death receptor)
- Decoy receptors expressed
- Silencing (e.g. methylation) of genes required to transduce death signals
- Overespression of negative regulators of death receptor
- Overexpression of inhibitor of apoptosis proteins
24
Q
Describe the intrinsic apoptotic pathway:
A
- p53 is one of the most important regulators of the intrinsic apoptotic pathway
- p53 works by protein-protein interactions so it is difficult to devise ways to restore its function
- p53 is upregulated in the event of DNA mutation/cellular stressors and it upregulates proapoptotic proteins to induce apoptosis
25
Q
Describe apoptosis and co-operative oncogenesis:
A
- In a normal cell, c-Myc (oncogene) activation would cause the upregulation of pro-apoptotic proteins such as Puma and Noxa
- c-Myc promotes genome instability and then cooperates with the suppression of tumour suppressor genes such as a mutation in p53 or an overexpression of Bcl2 to form cancer
26
Q
What is oncogene addicition?
A
- Oncogene addiction is when the activation of an oncogene is necessary for the survival and growth of a tumour
e. g. A tumour that is Myc-driven is Myc oncogene addicted can be targeted with Myc inhibitors
e. g. CML has an oncogene addiction to BCR-Abl, so switching off this oncogene cures the diseases
27
Q
What is epigenetic regulation?
A
- Epigenetic regulation refers to the differential expression of genes due to changes that do not affect the DNA sequence
e. g. chromatin remodelling (histone modification) and DNA methylation - Epigenetic mechanisms can be used to reverse cancer phenotypes, e.g. epigenetic silencing of a tumour suppressor gene can be reversed
28
Q
Describe DNA methylation and its effect on gene expression:
A
- DNA methylation (especially at gene promoters) usually occurs on CpG motifs and silences genes by preventing the binding of transcription factors
- DNA methylation is due to the action of DNA methyltransferases
- These DNA methyltransferases can be inhibited therapeutically inhibited using DNA hypomethylating agents such as 5-Azacitidine which traps DNMT1 and causes it to be degraded
- These drugs have been used off-label to treat T-cell lymphoma
29
Q
How are histones modified and how does this affect gene transcription?
A
- Histone tails can undergo acetylation, methylation and phosphoryation
- Overexpression of enzymes that cause these modifications are commonly seen in malignancies
- Histone deacetylase (HDAC) inhibitors allow global acetylation and reading of genes to occur which can upregulate apoptosis
- Only really effective in haematologic malignancies
- BET-bromodomain (reader) inhibitors mimic acetylated lysine residues e.g. JQ1
- Bromodomain-containing proteins such as BDR4 are known to be of importance in midline carcinoma so inhibiting the reading of these genes can help treat cancers
- cMyc is an example of a gene regulated by BRD4, using a BET-bromodomain (reader) inhibitor such as JQ1 can treat malignancies driven by abberant cMyc
- However tumours can develop JQ1 resistance via upregulation of Bcl-2
30
Q
What are the primary roles of the immune system against tumours?
A
- Elimination or suppression of viral infections
- E.g. HPV elimination prevents cervical cancer - Elimination of pathogen and resolution of inflammation
- Immune surveillance:
- Elimination of tumour cells via detection of tumour specific antigens or molecules induced by cellular stress
31
Q
What are the tumour/host immunity dynamics?
A
- When normal cells become transformed into immortalised cancerous cells via activation of oncogenes e.g. cMyc, Ras or loss of tumour suppressors e.g. p53, Rb- the cell becomes stressed and immunogenic
- These stressed cells can then be:
- Eliminated:
- The innate and adaptive immune system may remove the cancerous cells before they can cause a malignancy - Equilibrium:
- The lymphocytes may be able to remove most of the tumour cells but some may survive in a quiescent state due to immunological control
- The genetic instability of the surviving cells means they may be able to develop more mechanisms the subvert/inhibit the normal immune response - Escape:
- The tumour cells are able to escape the immune system and develop into clinically apparent cancer
32
Q
What is clinical evidence of immunosurveillance?
A
Mouse studies:
- If a tumour is resected out of a mouse and transplanted into a different mouse of the same strain, the tumour will grow (as there is no immunological memory)
- If the tumour is transplanted back into the original mouse the tumour will regress/not grow and this mouse will have immunological memory against that tumour antigen
Evidence of micro-metastases:
- Even after someone is cleared of cancer, micro-metastases may persist that are not clinically evident, but they are controlled by the person’s immune system
- If an organ with micrometastases is transplanted into someone else, that person will develop cancer as they do not have sufficient immunological surveillance to keep the micro-metastases in equilibrium
