Carcinogenesis

Question 1

Define carcinogenesis

Answer 1

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).

Question 2

Define cancer

Answer 2

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)

Question 3

What are two main causes of cancer?

Answer 3

Genetic - somatic, or germline (rare)

Environmental - can alter frequency & consequences of cancer-predisposing mutations.
- smoking
- checmicals
- UV radiation
- viruses

Question 4

What initiates cancer formation and then how do tumours grow and spread?

Answer 4

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.

Question 5

What is neoplasm?

Answer 5

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

Question 6

What are carcinogens? Examples?

Answer 6

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.

Question 7

What happens at the molecular level to cause cancer?

Answer 7

1. 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.
2. Cancers escape DNA repair processes so the changes are transmitted to all daughter cells forming a clone.
3. Mutations that give the cancer cell a growth or survival advantage will allow it to outcompete neighbouring cells.
4. Natural selection favours survival of most aggressive characteristics- this is called progression
5. 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.

Question 8

Name the type of mutations that occur in cancer cells

Answer 8

1. Substitutions- bases swap
2. Deletion - bases removed
3. Insertion - bases added
4. Copy number change - large chunk of genome is deleted or duplicated.
5. 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

Question 9

Explain what driver and passenger mutations do to the cell.

Answer 9

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.

Question 10

Define proto-oncogenes. Define Oncogenes

Answer 10

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

Question 11

Name 3 ways a proto-oncogene can convert into an oncogene.

Answer 11

1. Deletion or point mutation of coding sequence = hyperactive protein made in normal amounts.
2. Gene amplification= normal protein greatly over produced.
3. Chromosomal rearrangement= protein overproduced or hyperactive.

NOTE: view notes for diagram!

Question 12

Give 3 examples of oncogenes

Answer 12

1. 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

2. 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.
3. 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

Question 13

What does the MAP-kinase pathway do to proto-oncogenes? How does pathway work normally? Examples of drugs that target components of pathway?

Answer 13

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!!

Question 14

Define tumour supressor genes

Answer 14

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!

Question 15

Function of tumour suppressor genes

Answer 15

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

Question 16

Give 3 examples of gene mutations in tumour suppressor genes.

Answer 16

1. RB1
2. TP53
3. BRACA1 & BRACA2

Question 17

Explain the gene’s RB1 function and the disease it causes.

Answer 17

1. 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).

Question 18

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?

Answer 18

2. 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.

Question 19

Explain the gene’s BRACA1 & BRACA2 function and the disease it causes.

Answer 19

3. 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

Question 20

What is the normal role of apoptosis regulators?

Answer 20

• Stop normal cells from dying
• Promote cell death in mutated cells whose DNA cannot be repaired.

Question 21

How does apoptosis occur?

Answer 21

1. BCL2 prevents apoptosis by stabilising mitochondrial membrane & by blocking the release of cytochrome C
2. If BCL2 is disrupted, cytochrome c is released from mitochondria triggering apoptosis.

Question 22

What happens when BCL2 is over-expressed?

Answer 22

• 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

Question 23

What occurs in normal cell growth?

Answer 23

• 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

Question 24

What occurs in cancer cell growth?

Answer 24

1. Immortilisation - indefinite growth due to their own ability to sustain division.
2. Transformation - tumour cells become resistant to anti-growth signals
3. Metastasis & Invasion: ability to invade normal tissue & into the underlying basement membrane of the tissue of origin, & other organs to establish new colonies.

Question 25

What are the hallmarks of cancer? Explain how the cancer cell causes the hallmarks

Answer 25

1. Sustaining proliferative signalling
   - Cancer cells don’t need external signals (in the form of growth factors).
   They can do this by:
   - Producing GFs themselves (autocrine signalling).
   - Permanently activating signalling pathways.
   - Destroying the “off switches” that prevent excessive growth from GFs
   Also, cell division is deregulated because the proteins that control it are altered.
2. Evading growth suppressors
   - Growth suppressors are called tumour suppressor genes
   - In cancer, TMG are mutated so don’t work.
3. Resisting apoptosis
   May do this by:
   - Altering mechanisms that detect damage or abnormalities.
   - Having defects in the proteins involved in apoptosis e.g. BCL2 gene proteins stabilise mitochondria membrane so cytochrome C can’t leak out to kill the cell.
4. Enabling replicative immortality:
   - Non-cancer cells die after a certain no. of cell divisions due to shortening of telomeres.
   - Telomeric DNA shortens w/ every cell division.

Telomeres - the region of DNA at the end of chromosomes.

• When it becomes too short, it activates senescence (a process where a cell permenantly stops divinding but doesn’t die).
• Cancer cells bypass this barrier by manipulating the telomerase enzyme to increase the length of telomeres.
• The divisions limit can also be increased by disabling pRB & p53 tumour suppressor proteins.

5. Inducing angiogenesis
   - Angiogenesis= new blood vessels form.
   - Allows cancer cells to receive blood & oxygen.
   - Cancers commonly produce growth factors e.g. fibroblast growth factor & vascular endothelial growth factor
   - Chronic inflammation plays a role in inducing many types of cancer.
   - Inflammation leads to angiogenesis & increased immune response.
   - Degradation of the extra-celluar matrix, necessary to form new blood vessels, increases the odds of metastasis.
6. Activating invasion & metastasis
   - The ability to invade & spread to neighbouring tissues.
   - Start by invading neighbouring cells, then blood vessels, then they exit circulation & start dividing in a new tissue.
7. Deregulated metabolism
   - Most cancer cells use alternative metabolic pathways to generate energy.
   - E.g. up-regulate glycolysis & lactic acid fermentation in the cytosol.
   - Also prevent mitochondria from completing normal aerobic respiration
8. Evading the immune system
   - Cancer cells are able to avoid body’s immune system through the loss of interleukin-33 (IL-33).

Question 26

SBA Exam Questions

During an oncology department multidisciplinary team meeting, the oncologist mentions some medical terminology. Which of the following definitions is correct?

Answer 26

A. Dysplasia is a change from one type of differentiated epithelium to another.
B. Anaplasia is an almost complete lack of differentiation
C. Carcinoma is a benign tumour of epithelial derivation.
D. Metaplasia is the disordered development of cells with loss of organization.
E. Carcinoma in situ is a carcinoma with stromal invasion.

Answer: B

B = Anaplasia is the almost complete lack of differentiation of a cancer. It is associated with a poor prognosis and, by definition, an anaplastic cancer is high grade.

Dysplasia is the disordered development of cells resulting in an alteration in their size, shape and organization.

Metaplasia is the change from one type of differentiated epithelium to another and is an adaptive response to injury.

Carcinomas are malignant tumours derived from epithelial cells; benign epithelial are called adenomas.

Carcinoma in situ is severely dysplastic epithelium with all the features of malignancy except it hasnot invadedthrough the basement membrane.

Question 27

SBA exam question

Which of the following statements regarding cancers is correct?

Answer 27

A. Tumours arise from single cells.
B. Lymphomas are benign tumours of lymphoid cells.
C. Cells in a tumour are genetically identical.
D. Transcoelomic spread occurs through the lymphatic system.
E. Melanomas are benign skin tumours; malignant melanomas are malignant skin tumours.

Answer: 1. A

A= Tumours originally arise from single cells that proliferate to form a clone of cells. As they develop, additional mutations are acquired by different cells such that they are genetically heterogeneous.

Lymphomas are all malignant lymphoreticular tumours and melanomas are all malignant melanocytic tumours; neither has a benign counterpart.

Transcoelomic spread occurs across a body cavity, i.e., via the pleural, pericardial and peritoneal cavities.