Cancer Flashcards
What are the 6 hallmarks of cancer?
Sustaining proliferative signalling Evading growth suppressors Resisting cell death Inducing angiogenesis Enabling replicative immortality Activating invasion and metastasis
What are the 2 emerging hallmarks of cancer?
Deregulating cellular energetics
Avoiding immune destruction
What are the 2 enabling characteristics of cancer?
Genome instability and mutation
Tumour promoting inflammation
Explain how cancer cells sustain proliferative signalling
Normal cells require external stimulation/regulation from growth factors to drive entry to the cell cycle. Cancer cells have enhanced external stimulation or lost dependency on external signalling.
Enhanced external stimulation: mutations in GFRs can cause them to be constitutively active, an increase in receptors results in too much signalling, increased levels of growth factors causes over stimulation.
Loss of dependency on external stimulation: mutations in cell cycle components can enhance the molecules positively driving growth, or activating mutations in signal transduction components downstream from the growth factor can result in the cell cycle being activated regardless of growth factor presence.
Explain how cancer cells evade growth suppressors
Cancer cells have lost the ability to respond to inhibitor signals that regulate growth, differentiation, apoptosis, etc, due to:
- Loss of activity of tumour suppressor genes e.g. p53, PTEN, RB1
- Aberration in developmental signalling pathways e.g increased PIP2 → PIP3 → AKT leads to increased proliferation, mutated TGF-β loses its anti-apoptotic abilities and so supports metastases
Explain how cancer cells resist cell death
Cancer cells evade the apoptotic signals that usually induce death in cells with damaged DNA. They do this through mutations in the intrinsic pathway of apoptosis such as loss of p53 activity, down regulation of pro-apoptotic molecules in the BCL-2 family such as BAX, BAK, BAD and up regulation of anti-apoptotic molecules such as BCL-2 or BCL-XL. Cancer cells also evade apoptosis through mutations in the extrinsic pathway such as aberrations in death receptor regulation.
There is suggestion that cancer cells may benefit from tolerating some degree of cell death; necrotic cells release bio-active regulatory factors (e.g. IL-1α) which stimulate proliferation in neighbouring cells (Hanahan and Weinberg 2011).
Explain how cancer cells induce angiogenesis
Tumours need their own blood supply in other to grow larger than 1-2mm - allows growth and prevents death of the cells due to hypoxia. Tumours can lie dormant and then switch on angiogenesis. Percicytes come away from the blood vessel causing dilation, instability of the vessel and proteins start to leak out. Percytes are re-recruited but there are not enough to fully stabilise the blood vessel. This unstable, leaky, dynamic nature of blood vessels promotes angiogenesis which carries on for as long as the tumour grows. Cancer cell up regulate pro-angiogenic molecules including VEGF - makes the vessel dilate and leak which is the first stage of angiogenesis. Normal angiogenic regulatory processes are disrupted so tumour vasculature is abnormal.
Explain how cancer cells enable replicative immortality
Cancer cells express telomerase, which maintains telomere length through specialised DNA polymerase action and so allows an infinite number of cell divisions. 80% of cancer cells have extensive, unregulated telomerase. The telomeres of cancer cells are actually slightly too long, making the chromosome unstable, contributing to the mutation accumulation and genetic instability of cancer cells.
Explain how cancer cells activate invasion and metastasis
Cancer cells gain the ability to spread through the body by breaking cell-cell/cell-ECM attachment and changing shape to become more motile. They also induce angiogenesis to support secondary tumour growth. Less than 1 in 10,000 circulating cancer cells with survive to set up a secondary metastatic tumour. Some metastatic cells show organotropism in which certain cells show preferential spread to certain sites. Tumours can spread to close proximity sites or to distal sites (seed and soul or pre-metastatic niche hypotheses). Invasion, intravasation, transport, extravasation, colonisation, angiogenesis.
How many proven cancer driver genes are there?
299 (Bailey et al 2018)
How many proto-onco genes have been identified?
79 (Bailey et al 2018)
How many tumour suppressor genes have been identified?
95 (Bailey et al 2018)
Explain how cancer cells deregulate cellular energetics
Tumour cells utilise aerobic glycolysis to drive pyruvate into lactate (like normal diving cells do). This generates intermediates for biosynthetic pathways such as growth. Tumour growth depends on the expression of pyruvate kinase M2 - drives pyruvate to lactate, upregulated a little bit in normal dividing cells and a lot in cancer cells. Also depend on lactate dehydrogenase and glucose uptake through GLUT1. This excessive glucose metabolism via the Warburg effect can be exploited therapeutically/diagnostically.
Explain how cancer cells avoid immune destruction
The immune system can recognise and eliminate cancer cells through recognition of tumour antigens by tumour specific antibodies. Cancer cells avoid this by:
- Loss of tumour antigens
- Down regulation of antigen presenting molecules that would prime the T cells
- Overexpress PD-L1 ligand (immune checkpoint protein) that binds PD-1 receptors on T cells and reduces their cytotoxic action as they think the tumour cell is self.
The immune system can promote tumour formation via immunoediting: elimination of the cancer cells, equilibrium (selection by the immune system of the cells it can kill, immunogenic ones) so the less immunogenic cells escape the immune system.
Explain how genome instability aids cancer progression
Cancer genomes have many non-synonymous mutations.
Mutations in driver genes confer a growth advantage and contribute to the cancer phenotype, such as p53 or Ras. There are also multiple coincedental passenger mutations that occur due to the lack of DNA damage repair. Cancer cells often have aboral karyotypes: aneuploidy, polyploidy, translocations, deletions, duplications, chromothripsis. Acquisition of the other hallmarks depends on alterations of the genome.
Explain how inflammation promotes tumour formation
Many carcinogens cause cancer through chronic inflammation. Tumour cells secrete cytokines which attract tumour-associated-macrophages. These produce growth factors, cytokines, and ROS/RNS which can causes DNA mutations. Those cytokines activate transcription factors that drive proliferation and angiogenesis. Inflammation can contribute to multiple hallmark capabilities by supplying bioactive molecules to the tumour microenvironment including growth factors, proangiogenic factors, etc (Hanahan and Weinberg 2011).
Define neoplasm
“new growth” i.e. a tumour
Define dysplastic tissue
a transitional state between benign and pre-malignant, cells are abnormal but not specifically proliferative/hyperplastic. Variable shape, crowded, irregularly spaced, lack differentiation markers.
Are tumours monoclonal or polyclonal? Define the answer.
Monoclonal: tumours are derived from a single cell
How are tumours classified and what are the 4 main categories?
Based on cell type of origin
1. Epithelial: sheets of cells, coverings etc. Carcinoma.
2. Haematopoeitic: cell types in ‘blood forming’ tissues and the immune system. Leukaemia or lymphoma
3. Mesenchymal: sarcomas, connective tissue cells
4. Neuroendodermal: derived from the CNS/PNS
Not all cancers fit these groups i.e. melanoma
What is the major difference between benign and metastatic tumours?
Benign: non-invasive and localised
Metastatic: invasive and spreads to other sites
Describe the two types of benign tumours
Hyperplastic: excessive cell numbers due to dysregulated proliferation. Cells are normal and form structures/tissues that look reasonably normal. There’s just too many cells.
Metaplastic: displacement of normal cells with other normal cells not found in that tissue. One type of normal cell is replaced by another normal cell type but a type that is not normally seen there.
Benign tumours are often surrounded by a fibrous capsule.
Describe the properties of a metastatic tumour.
Abnormal cells with poor differentiation, breach the basement membrane and invade the surrounding stroma, then spread to distant sites.
Describe the 6 steps involved in invasion and metastasis
- Invasion: of the tissue. break down the basement membrane by inavadopodia, migrate towards the blood vessel using fibres and ECM, guided by EGF
- Intravasation: entry to the blood vessel. Change shape to squeeze through the holes. Known now as circulating tumour cells - inly 1 in 10,000 cells survive this, but only one needs to survive to set up a metastatic colony
- Transport through the blood vessel
- Extravasation: get out of the blood vessel
- Metastatic colonisation: invade the local tissue in that area and grow into a new colony
- Angiogenesis: trigger the formation of new blood vessels in order to grow exponentially
What is src and describe its role in cancer
A soluble tyrosine kinase. Can be activated by growth factor signalling. When activated causes the e-cadherin complex to break down, the cell loses contact and becomes more motile. When treated with a small molecule Src inhibitor the cells are slowed down.
What is a cancer stem cell?
A small proportion of the cell sin a tumour are cancer stem cells. These are responsible for the heterogeneity of tumours, tumour plasticity, and migratory abilities - they maintain the cancer phenotype. A normal differentiated cell can accumulate mutations which cause it to de-differentiate into a cancer stem ell, resulting in a cancer cell which can replicate indefinitely and differentiate which is huge problem in treatment.
Explain the development and metastasis of human colorectal cancer and its genetic basis
- Normal epithelium develops a driver mutation - loss of APC tumour suppressor gene. This leads to excessive epithelial proliferation.
- An oncogene such as Ras is activated, leading to formation of a small benign tumour.
- Another tumour suppressor gene is lost leading to formation of a larger dysplastic tumour.
- A third tumour suppressor is lost. Once p53 is lost the tumour becomes malignant/invasive and becomes difficult to stop.
- Rapid accumulation of mutations results in metastasis
How many mutations are needed in a cell to develop the average colorectal cancer?
11
How many mutations are needed in a cell to develop the average kidney cancer?
2
How many mutations are needed in a cell to develop the average stomach cancer?
4
How many mutations are needed in a cell to develop the average lung cancer?
6
How many mutations are needed in a cell to develop the average breast cancer?
4
How many mutations are needed in a cell to develop the average brain cancer?
6
List some categories of carcinogenic agents
Radiation, chemicals, infections pathogens, endogenous reactions
What are the two types of radiation that can cause DNA damage?
Ionising radiation
UV radiation
Describe the two ways in which ionising radiation can damage DNA
Direct DNA damage: ionisation of atoms comprising DNA
Indirect DNA damage: more common, the radiation hits a water molecule and causes radiolysis of H2O generating hydroxyl radicals, H2O2, and ROS. H2O2 is less reactive but more stable and so problematic. ROS can interact with and damage DNA
Describe the carcinogenic affect of UV radiation
UVB (λ = 290-320nm) is the most effective carcinogen and the main cause of skin cancer. Causes formation of cyclobutane pyrimidine dimers and 6-4- photoproducts. Mutations induced cause bends in the DNA which are misread by DNA polymerase.
What is an oncogenic virus?
DNA tumour virus: encodes proteins that block tumour suppressor action e.g. HPV
RNA tumour virus: encodes mutated forms of normal genes, e.g. HTLV-1 linked to leukaemia
List three things which support the multi-hit model of carcinogenesis
- Genetic homogeneity in cells from a give tumour due to monoclonal origin
- Cancer incidence increases with age: can take decades for a cell to accumulate enough mutations
- In vivo evidence of cooperative effects of mutations to drive cancer - different combinations of proliferation genes can cooperate to enhance tumour induction
List some risk factors of exposure to ionising radiation
exposure to X-rays, living at altitude, plane travel
What is the general action of chemical carcinogens on DNA?
Electrophiles react with the nucleophilic sites in the purine and pyrimidine rings of nucleic acids
