Carcinogenesis Flashcards
(27 cards)
Define carcinogenesis
describes how a normal cell evolves into an invasive cancer cell i.e. cancer development.
largely genetic & involves accumulation of a critical number of mutations in genes (oncogenes & tumour suppressor genes).
Define cancer
uncontrolled cell growth
Enabled by ability to stimulate cell growth, to stop inhibitory signals & prevent apoptosis
- Leads to the formation of a mass of cells called neoplasm or tumour
- Malignant neoplasms have ability to invade adjacent tissues & metastasise (spread)
What are two main causes of cancer?
Genetic - somatic, or germline (rare)
Environmental - can alter frequency & consequences of cancer-predisposing mutations.
- smoking
- checmicals
- UV radiation
- viruses
What initiates cancer formation and then how do tumours grow and spread?
initiated by damage to DNA in stem cells
- this damage overcomes normal DNA repair mechanisms but is not lethal.
DNA mutations eventually disrupt key regulatory systems allowing for tumour growth, invasion of the surrounding tissues or spread to other areas of the body (metastasis).
Disrupted systems include proto-oncogenes, tumour suppressor genes, regulators of apoptosis & genes which regulate interactions between the tumour & its host.
What is neoplasm?
Means “new growth” that is unregulated, clonal & irreversible.
persists in the absence of the initiating stimulus
Derives from a single cell of origin & is therefore clonal.
Any cell type can undergo neoplastic change but the most common cell is epithelial cell.
Can either be benign or malignant
What are carcinogens? Examples?
Agents that cause DNA damage increasing the risk of cancer.
Important carcinogens include:
1. Chemicals e.g. n-nitrosamine & benzene in cigarette smoke.
2. Infective agents:
- Bacteria e.g. helicobacter pylori which can cause adenocarcinoma of the stomach which is a gland forming stomach cancer & lymphoma, which is a malignant tumour of lymphocytes.
- Parasites e.g. liver flukes
- Viruses e.g. HPV, EBV, HCV & HBV.
3. Radiation- damages DNA & is associated w/ lymphoma, leukaemia, thyroid cancer & skin cancer.
What happens at the molecular level to cause cancer?
- mutation or epigenetic change occurs, caused by exposure to a mutagen or ageing.
- These changes involve genes which normally control cell growth, cell survival or cell senescence. - Cancers escape DNA repair processes so the changes are transmitted to all daughter cells forming a clone.
- Mutations that give the cancer cell a growth or survival advantage will allow it to outcompete neighbouring cells.
- Natural selection favours survival of most aggressive characteristics- this is called progression
- These mutations & epigenetic changes give cancers a set of properties called hallmarks which determine the natural history of the disease as well as its response to various therapies.
Name the type of mutations that occur in cancer cells
- Substitutions- bases swap
- Deletion - bases removed
- Insertion - bases added
- Copy number change - large chunk of genome is deleted or duplicated.
- Break points / chromosomal rearrangement / translocations - where the genome is split in 2 places & then joined.
⚡ For cancer to occur, genetic damage & mutations often need to accumulate
NOTE: view images for above mutations
Explain what driver and passenger mutations do to the cell.
Driver mutation- An alteration in the genome of a cancer cell that gives it a fundamental growth advantage.
Passenger mutation- Has no effect on the fitness of the cell but is detected as it happens to be in the same cell as a mutation in a driver gene.
Define proto-oncogenes. Define Oncogenes
Proto-oncogenes are normal genes which are needed for cell growth & differentiation
Oncogene is a mutated proto-oncogene.
- Gives tumour cells the ability to divide uncontrollably
- The protein expressed by oncogene usually has lack of regulation or increased activity
Name 3 ways a proto-oncogene can convert into an oncogene.
- Deletion or point mutation of coding sequence = hyperactive protein made in normal amounts.
- Gene amplification= normal protein greatly over produced.
- Chromosomal rearrangement= protein overproduced or hyperactive.
NOTE: view notes for diagram!
Give 3 examples of oncogenes
- Philadelphia chromsome
- Chromosomal translocation events often up-regulate expression of an oncogene.
- Does this by fusing the gene w/ a promotor region that is always switched on or active.
- In chronic myeloid leukaemia, discovered that chromosome 22 had its end chopped off & switched w/ the end of chromosome 9, resulting in cancer.
NOTE: view diagram on notes
- MYC family of oncogenes
- Amplifications can mean that there are10 to 100copies of an oncogene sequence.
- Multiple copies of the oncogene leads to increased expression of the protein. - RAS oncogene family
- Point mutation- a single nucleotide variant.
- Altered base sequence = altered amino acid sequence & protein.
- Insertion or deletion can cause frameshift.
NOTE: view notes for diagram
What does the MAP-kinase pathway do to proto-oncogenes? How does pathway work normally? Examples of drugs that target components of pathway?
NOTE: a kinase is a protein that can transfer a phosphate group to another protein, activating the protein.
The mitogen-activated protein kinase pathway contains several proto-oncogenes that can mutate.
How does MAP- kinase pathway work?
1. A growth factor binds to a receptor tyrosine kinase located on the membrane of a cell.
2. This activates protein located on the inner membrane called RAS
3. RAS activates a cytoplasmic protein called RAF.
4. RAF activates another cytoplasmic protein called MEK.
5. MEK phorphorylates ERK
6. ERK travels into nucleus*where it can activate several transcription factors.
7. The transcription factors can switch on several genes which are involved in the cell cycle, cell growth or cell metabolism.
8. The proteins of the cell cycle are then switched off.
9. In cancers, these proteins can be mutated leading to them being permanently switched on causing uncontrolled transcription
Drugs that target components of pathway:
- Herceptin targets Her 2 is a tyrosine kinase receptor which can be amplified in breast cancer
- RAF inhibitors can be used to treat aggressive skin tumour called malignant melanoma
NOTE: view notes for diagram on pathway!!
Define tumour supressor genes
Genes which control cell division.
Mutated forms lead to uncontrolled cell division.
Knudsons two-hit hypothesis applies to tumour suppressor genes in that both copies (alleles) of the gene must be affected to cause disease i.e RECESSIVE.
e.g. p53 &retinoblastoma (Rb) are classic examples of tumour suppressor genes
NOTE: view note for diagram!
Function of tumour suppressor genes
Normal role of proteins produced by tumour suppressor genes is to stop uncontrolled cell division
i.e. the normal function is controlling the cell cycle so that any DNA damage can be repaired, or apoptosis triggered.
1. Slow down cell divison
2. Repair DNA mistakes
3. Tell cells to die (apoptosis).
So loss of the gene & its protein products is problem for maintaining normal cell growth controls
Give 3 examples of gene mutations in tumour suppressor genes.
- RB1
- TP53
- BRACA1 & BRACA2
Explain the gene’s RB1 function and the disease it causes.
- RB1
-RB regulates the progression of a cell from G1 to S phase.
- Retinoblastoma is a human childhood disease - involving a tumour of the retina.
- Caused by loss of both copies of the RB gene on Ch13.
Diseases:
Hereditary retinoblastoma: 1 chromosome has a deletion in the region containing RB in the germline & 2nd copy is lost by a somatic mutation.
Non-hereditary retinblastoma: In the sporadic form of the disease both copies are lost by somatic mutation events.
Causes OSTEOSARCOMA!
Somatic mutations occur during in the course of cell division.
Germ line mutations are inherited genetic alterations that occur in the germ cells (i.e. sperm and eggs).
Explain the gene TP53 function. When is It expressed? How does it stop cell cycle? What occurs when DNA damage is very severe? What disease does it causes?
- TP53
- Gene is involved in the synthesis of protein p53
- p53 regulates cell division by restricting uncontrolled cell growth & division
Causes OSTEOSARCOMA
When is p53 expressed?
1. G1 phase is the phase before DNA synthesis starts. The G1 checkpoint ensures DNA is not damaged before replication.
2. If DNA is damaged, this triggers expression of p53 gene which stops cell from entering S-phase of the cycle.
3. Allows DNA repair to take place by up-regulation of DNA repair enzymes.
NOTE: view cell cycle diagram on notes!
How does p53 stop the cell cycle?
1. p53 stops cell cycle by causing transcription of cyclin dependent kinase inhibitor called p21
2. p21 blocks the CDK4/Cyclin D complex. These complexes drive the cell cycle.
What occurs if DNA damage is very severe?
1. If DNA damage is severe that it cannot be repaired, p53 can:
- Stop the cycle
- Cause cell senescence
- Trigger apoptosis.
2. Apoptosis is triggered by up-regulating BAX.
3. BAX disrupts BCL2 protein which causes cytochrome c to leak from mitochondria triggering apoptosis.
4. BCL2 normally stabilises the mitochondrial membrane blocking release of cytochrome c.
Li-Fraumeni syndrome
- Caused by inherited mutations of TP53.
- A rare autosomal disorder characterised by increased risk of developing a number of cancer.
- 50% of people w/ LFS develop cancer by age 40.
Explain the gene’s BRACA1 & BRACA2 function and the disease it causes.
- BRACA1 & BRACA2
- BRCA = BReast CAncer gene
- Everyone has these genes - they stop our cells from growing uncontrollably.
- A mutation in either gene means cells can grow out of control.
Inheritance of faulty versions of these genes have increased risk of developing:
- Breast, ovarian, prostate & pancreatic cancers
What is the normal role of apoptosis regulators?
- Stop normal cells from dying
- Promote cell death in mutated cells whose DNA cannot be repaired.
How does apoptosis occur?
- BCL2 prevents apoptosis by stabilising mitochondrial membrane & by blocking the release of cytochrome C
- If BCL2 is disrupted, cytochrome c is released from mitochondria triggering apoptosis.
What happens when BCL2 is over-expressed?
- BCL2 is over-expressed in a form of lymphoma called follicular lymphoma
Lymphoma= malignant tumour of lymphocytes.
- Follicular lymphoma has translocation between chromosomes 14 & 18
- Moves BCL2 gene from chromosome 18 to the Ig heavy chain locus on chromosome 14 causing increased BCL2 production.
- This causes enhanced stabilisation of the mitochondrial membrane preventing apoptosis & allowing malignant lymphocytes to become immortal
NOTE: Patients w/ lymphoma present w/ enlarged rubbery lymph nodes
What occurs in normal cell growth?
- Signal molecules e.g. growth factors, steroid hormones or cell-to-cell interactions regulate the behaviour of normal cells.
- Signals exist for differentiation, cell growth & division, & cell death
- Cells usually need multiple signals
. - If deprived of signals, most cells undergo apoptosis
NOTE: view notes for diagram
What occurs in cancer cell growth?
- Immortilisation - indefinite growth due to their own ability to sustain division.
- Transformation - tumour cells become resistant to anti-growth signals
- Metastasis & Invasion: ability to invade normal tissue & into the underlying basement membrane of the tissue of origin, & other organs to establish new colonies.
