Mechanisms of Oncogenesis

Question 1

What is cancer?

Answer 1

A group of diseases characterised by:

• Abnormal cell division
• Tumour formation
• Invasion of neighbouring normal tissue
• Metastasis to form new tumours at distant sites

Question 2

What is a carcinoma?

Answer 2

Cancer derived in epithelial cells

Question 3

What is a sarcoma?

Answer 3

Cancer derived from mesoderm cells (bone and muscle)

Question 4

What is a adenocarcinoma?

Answer 4

Cancer found in glandular tissue

Question 5

What is a hallmark of cancer?

Answer 5

A characteristic that a normal cell has to acquire to become a cancer cell

Question 6

Provide some examples of hallmarks of cancer cells

Answer 6

• Sustaining proliferative signalling
• Evading growth suppressors
• Avoiding immune destruction
• Enabling replicative immortality
• Tumour-promoting inflammation
• Activating invasion and metastasis
• Inducing angiogenesis
• Genome instabillity and mutation
• Resisting cell death
• Deregulating cellular genetics

Question 7

Explain how age can affect cancer?

Answer 7

• Accumulation of mutations over time represent the multi-step process which underlies carcinogenesis
• Accumulation only occurs in cells if the cells defence mechanism has been evaded (avoided)
  
  • Many mechanisms exist for blocking carcinogenesis but over burdening the system increases the possibility that cells will escape surveillance
    
    • Hence the longer we live = more time for DNA to accumulate and mutations lead to cancers

Question 8

What is the effect of carcinogens on DNA?

Answer 8

Carcinogens will cause mutations in the DNA

Question 9

What are the two types of cells that can undergo mutations?

Which cell type can have more detrimental conquences.

Answer 9

• Germline mutation
• Somatic cell mutations

Question 10

What are germline mutations?

What is the consequence of these types of mutations?

Answer 10

Germline mutations are mutations within the egg and sperm cell

• Mutations can be passed onto offspring
• Accounts for 5% of all cancer cases
• Increased risk of developing cancer → however rarely involved in causing immediate cancer
• Inheritable mutation

Question 11

What is the consequence of somatic cell mutations?

Answer 11

• Mutations that affect somatic cells, cant be passed onto offspring
• Constitute to almost all mutations in tumour cells
• Only one cell needs to be mutated, then cancer initiation is clonal
• Tumour cells can evolve; sub-clonal selection allowing a growth advantage = explains heterogeneity of cells in a tumour

Question 12

How are cell numbers regulated

Answer 12

Growth, apoptosis and differentiation will regulate cell numbers:

• Cells will proliferate and grow
• They will differentiate
• They will perform a specific function
• They will undergo apoptosis

This pathway will be regulated by lots of different genes

Question 13

How is the difference between cell proliferation and cell apoptosis affected?

Answer 13

Mutations which alter the function of normal genes involved in this pathway

• Proliferation
• Differentiation
• Perform function
• Apoptosis pathway

We lose the abillity to regulate the processes involved in controlling cell number and cell number will continue to increase resulting in a clinically detectable tumour

Question 14

What are genes that have been actived to be oncogenic called?

Answer 14

Proto-oncogenes

Question 15

What is an oncogene?

Answer 15

An oncogene is a proto-oncogene that has been mutated in a way that it leads to signals which will cause uncontrolled growth (i.e. cancer)

Question 16

What are tumour supressor genes?

Answer 16

• Tumour supressor genes will inhibit both growth and tumour formation.
• They will act as braking signals during G1 phase of the cell cycle to stop or slow the cell cycle before S phase

Question 17

What happens if tumour supressor genes are mutated?

Answer 17

If tumour supressor genes become mutated then the normal brake mechanism will be disabled = uncontrolled growth i.e. cancer

Question 18

What are the two causes in which tumour cells arise?

Answer 18

• Activation of oncogenes
• Supression/ Mutations of tumour supressor genes

Question 19

What are the assumptions made of carcinogenesis?

Answer 19

• Requires malignant transformation of a single cell in order to initiate tumourigenesis
• Any cell is likely to be transformed as any other of the same type
• Once a malignant cell is generated the mean time to tumour detection is generally constant

Question 20

Summarise the Models of carcinogenesis

Answer 20

• There are 5 models (but non exclusive)
  
  • Non-exclusive as you can find compounds in different models
• Model 1 = Mutational (chemical carcinogens)
• Model 2= Genome instabillity
• Model 3 = Non-genotoxic
• Model 4 = Darwinian
• Model 5 = Tissue Organization

Question 21

Describe model 1 of carcinogenesis

Answer 21

• Cancder is a multi-step process which includes intiation, promotion and progession
• Chemical carcinogens will alter any of these processes by inducing irreversible DNA damage (mutations) and act in a genotoxic matter

Question 22

What are the types of carcinogens?

Answer 22

• Chemical
  
  • Bulk of the carcinogens
  • 10 groups: Polycyclic aromatic hydrocarbons, aromatic amines, azo dyes, nitrosamines, carbamates, halogenated compounds, alkylating agents
• Physical
  • Radiation (ionizing, ultraviolet)
  • Abestos
• Heritable
  
  • Predisposition - (inherited mutations)
• Viral
  
  • Hep B and Epstein Barr

Question 23

How do chemicals in smoke cause cancer?

Answer 23

Four major groups of polycyclic aromatic hydrocarbons, aromatic amines, nitrosamines and alkylating agents found in cigarette smoke will add functional groups onto DNA bases called DNA ADDUCTS

Question 24

What is the effect of benzo(a)pyrene on DNA?

Answer 24

• Benzo(a)pyrene is a polycyclic hydrocarbon found in cigarette smoke
  
  • Not itself carcinogenic (a pro-carcinogen)
• However it can easily enter cells and will interact with microsomal enzymes forming benzo(a)pyrene epoxide
  
  • This has the effect of changing G nucleotides to T within DNA (mutations)

Question 25

Describe that test can be carried out to determine whether a substance is carcinogenic?

Answer 25

**AMES TEST** * Test will determine the mutagenic activity of chemicals through observing if they cause mutations in simple bacteria e.g salmonella strain

Question 26

How can physical carcinogens cause cancer?

Answer 26

* Will impart energy into biological material * By imparting energy it will cause changes in bonding of molecules = biological effects

Question 27

What is the primary physical agent?

Answer 27

Radiation

Question 28

What are the types of radiation which can act as carcinogens?

Answer 28

Several types of radiation can act as carcinogens * Ionising radiation (X-Rays, nuclear radiation) * UV radiation

Question 29

What is the effect of radiation on DNA?

Answer 29

Will cause DNA damage by causing DNA breaks and pyrimidine dimers. These can be repaired, however if there is **failed repair** then it can cause **translocations** and **mutations**

Question 30

Describe heritable carcinogens and how they lead to cancer

Answer 30

* An **inherited germ-line mutation** has an increased risk of developing certain tumours but **rarely involved in causing cancer immediately** * In most known hereditary malignant syndromes, the elevated cancer risk is due to a mutation of a single gene (monogenic hereditary diseases) * The affected genes concerned usually have a controlling function on the cell cycle or the repair of DNA damage

Question 31

What are some syndromes predisposing cancer?

Answer 31

* **DNA REPAIR DEFECTS** * Ataxia telangietasia * Blooms Syndrome * Fanconi's anaemia * Li-Fraumeni syndrome * Lynch type II * Xeroderma pigmentosum * **CHROMOSOMAL ABNORMALITIES** * Down's Syndrome * Klinefelter's Syndrome

Question 32

What is ataxia telangiectasia

Answer 32

* Ataxia (poor coordination), telangiectasia (small dialated blood vessels) * Neuromotor dysfunction * **Mutation of the ATM gene** → involved in DNA repair, will normally code for a serine threonine kinase which is recruited and activated by dsDNA breaks = cell cycle arrest, DNA repair and apoptosis * Hence prevents repair of broken DNA and can lead to cancer * **_Cancer predisposition_** * lymphoma, leukaemia + breast cancer

Question 33

What is Bloom's Syndrome?

Answer 33

* Short stature, rarely excees 5 feet tall, skin rashes after skin exposure * **Mutation in BLM gene** which provides instructions for coding member of the RecQ helicase family that maintain the structure and integrity of DNA * Cancer predisposition = skin cancer, basal cell carcinoma and squamous cell

Question 34

What is lynch Type II

Answer 34

* Lynch syndrome doesnt cause any symptoms * Sometimes the first sign that a person has LS is when the symptoms of the bowel and womb cancer develop * Mutation in DNA mismatch repair (MMR) genes notably MLH1, MSH2 and MSH6 * Cancer predisposition colorectal cancer

Question 35

How do viruses act as carcinogens?

Answer 35

Most viruses will be proliferative inside a cell and exhibit cell lysis. From this can will infect cells, multiply and release their contents to further infect cells. Viruses can s**witch from a lytic cycle** and become **tumourigenic** allowing transformation of cells

Question 36

What are the properties of tumourigenic viruses?

Answer 36

* Stable association with cells * Chromosomal integration * Episome * Must not kill cells * Non-permissive host (virus cannot replicate) * Suppression of viral lytic cycle * Viral release by buddings * Must evade immune surveillance of infected cells * Immune suppression * Viral antigens not expressed at cell surface

Question 37

What are viruses associated with cancer?

Answer 37

* **DNA viruses** * Epstein-Barr Virus can lead to Burkitt’s lymphoma or nasopharyngeal carcinoma * Papilloma Virus associated with cervical carcinoma (also causes warts) * Hepatitis B and C leads to hepatoma * **RNA Retroviruses** * HTLV-I leads to Adult T cells leukaemia and lymphoma

Question 38

Describe model 2 of carcinogenesis

Answer 38

**Genome instabillity** At least two events are necessary for carcinogenesis and that the cell with the first event must survive in the tissue long enough to sustain a second event

Question 39

Describe model 3 of Carcinogenesis

Answer 39

**Non-Genotoxic Carcinogenesis** Non-genotoxic carcinogens are modulators of tumourigenesis which dont alter DNA directly but act as: * tumour promoters (1,4-dichlorobenzene), * endocrine-modifiers (17β-estradiol), * receptor-mediators (2,3,7,8-tetrachlorodibenzo-p-dioxin), * immunosuppressants (cyclosporine) or * inducers of tissue-specific toxicity and inflammatory responses (metals such as arsenic and beryllium)

Question 40

What is model 4 of carcinogenesis?

Answer 40

**Darwinian Model** = This is carcinogenesis by Mutation and Selection-Model of Clonal Expansion . It is based on the role of the environment in selecting cells that have some acquired advantage * Cells undergoing expansion will take into account selective pressure with an aim to try survive * If a normal cell during its life cycle accumulates a change/mutation due to exposure to a carcinogen there will be 1. Sequential accumulation of mutations due to exposure of carcinogens 2. Tumour cells will be selected FOR abillity to grow + invade 3. Selection will include resistance to therapy 4. Some mutations will be deleterious for tumour (rare)

Question 41

Describe model 5 of carcinogenesis

Answer 41

Tissue organisation * **Somatic mutation theory** _(single catastrophic events triggering carcinogenesis)_ * Cancer is derived from a single somatic cell which has successively accumulated multiple mutations * Those mutations damage genes which control cell proliferation and cell cycle * Thus, according to SMT, neoplastic lesions are results of DNA level events * **_Tissue organization field theory (TOFT)_** * States that carcinogenesis is a problem of tissue organization * Carcinogenic agents destroy normal tissue architecture thus disrupting cell to cell signalling compromising genomic integrity * The DNA mutations are random and the effect, not cause, of the tissue-level events * **Carcinogenesis as general deterioration of the tissue microenvironment due to extracellular causes**

Question 42

What is the immune response in cancer?

Answer 42

The immune system will: * Protect from virus induced tumours * Eliminate pathogens * Identify and eliminate tumour cells by immune surveillance Despite this, tumours can still arise = concept of cancer immunoediting

Question 43

Describe cancer immunoediting (Three Es)

Answer 43

* **Elimination** * the immune system is able to eradicate developing tumours * **Equilibrium** * when elimination is not efficient there may be incomplete removal and tumour cells can remain dormant and enter equilibrium. This can last up to 20 years after exposure to a carcinogen. The immune system will exert a potent and relentless pressure to contain the tumour. During this phase some of the tumour may mutate or give rise to genetic variants which will survive grow and enter the next phase * **Escape** * expanding tumour populations becomes clinically detectable