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๐˜พ๐™š๐™ก๐™ก๐™ช๐™ก๐™–๐™ง ๐™‹๐™–๐™ฉ๐™๐™ค๐™ก๐™ค๐™œ๐™ฎ ๐Ÿงซ COPY COPY > Mechanism of Oncogenesis > Flashcards

Mechanism of Oncogenesis Flashcards

1
Q

Outline some statistics related to Cancer?

A

โ€œIncidence:

  • Every 2 minutes someone in the UK is diagnosed with cancer
  • 990 cases every day

Mortality:
- Every 4 minutes someone dies of cancer

Risk:
- 1 in 2 people born after 1960 will be diagnosed with some form of cancer during their lifetime

Cancer Survival:
- Half of people diagnosed with cancer survive their disease for 10 years or more.

Prevention:
- 4 in 10 cases are linked to lifestyle and they can be prevented through lifestyle changes.โ€

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2
Q

In which groups is Cancer more prevalent?

A

โ€œAdults ages 50-74 account for more than half of all new cancer cases.
Elderly people aged 75+ account for more than a third.
Slightly more cases in males than females.
There are more people aged 50-74 than aged 75+ in the population so the number is higher in 50-70s.โ€

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3
Q

What are the 4 characteristics of Cancer?

A

โ€œ1. Abnormal cell proliferation.

  1. Tumour formation.
  2. Invasion of neighbouring normal tissue.
  3. Metastasis to form new tumors at distant sites.โ€
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4
Q

List 3 types of Cancers:

A

โ€œ1. Carcinoma: Cancers derived from epithelial cells,
Approximately 85% of cancers.

  1. Sarcomas: Cancers derived from Mesoderm cells (bone and muscle).
  2. Adenocarcinoma: Cancers found in Glandular tissue. โ€œ
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5
Q

What are the 10 Hallmarks of Cancers?

A

โ€œ1. Self-Sufficiency in Growth Signals

  1. Insensitivity to Antigrowth Signals
  2. Evading Apoptosis
  3. Limitless Replicative Potential
  4. Sustained Angiogenesis
  5. Tissue Invasion and Metastasis
  6. Genome Instability and Mutation
  7. Tumor - Promoting Inflammation
  8. Reprogramming Energy Metabolism
  9. Avoiding Immune Destruction.โ€
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6
Q

Where does Cancer arise from?

A

โ€œCancer is a Disease of the Genome at the Cellular Level:

  • Carcinogens cause alterations to the DNA, potentially leading to mutations.
  • DNA from tumours has been shown to contain many alterations from point mutations to deletions.
  • The accumulation of mutations over time represents the multi-step process that underlies carcinogenesis.
  • This accumulation occurs only after the cells defence mechanism of DNA repair have been evaded.โ€
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7
Q

What happens if there is severe damage to the cell?

A

If there is severe cellular damage Cell Apoptosis is induced.

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8
Q

How do Cancerous cells evade the natural mechanisms blocking cancer?

A

โ€œMany mechanisms exist for blocking carcinogenesis.

However over burdening the system increases the possibility that cells will escape surveillance.โ€

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9
Q

Why is Cancer more prevalent with longer lifespans?

A

โ€œThe longer we live the more time there is for DNA to accumulate mutations that may lead to cancer.
Cancer is more prevalent as lifespan has increased.โ€

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10
Q

What is a Germ Line mutation?

A

If there is a mutation within egg or sperm.

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11
Q

How are Germ Line mutations linked to Cancer?

A

โ€œThey account for 5% of cancers.
They increase chances of developing cancer.
Rarely involved in causing cancer immedately.โ€

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12
Q

Significance of Somatic Mutations in Cancer:

A

โ€œSomatic Mutations constitute almost all mutations in tumor cells.
They are not heritable.
But they can be passed on to daughter cells as a result of cell division.โ€

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13
Q

How does the initiation of a Tumour occur?

A

โ€œAll cells in a primary tumor arise from a single cell.
Initiation of the development of cancer is clonal.
Only 1 of 10^14 cells in the body need to be transformed to create a tumour. โ€œ

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14
Q

Why is there Heterogeneity in Tumour Cells?

A

โ€œ1. Continued accumulation of mutations.

  1. Tumour Cells can evolve.
  2. Which leads to sub - clonal selection.
  3. Allowing a growth advantage to certain Tumour Cells that have evolved appropriately.
  4. And explains heterogeneity of cells in a tumour.โ€
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15
Q

How can the same Tumour in two patients be different?

A

โ€œThe development of any specific tumour,

Is dependent on its interaction with other tumour cells and the tumour microenvironment.โ€

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16
Q

What two factors control the balance of Ceullular Proliferation:

A

โ€œ1. A cell will proliferate in response to lots of different signals.

  • Growth Factors: EGF, PDGF
  • Cytokines: Growth hormone, interleukins.
  • Hormones: Oestrogen
  1. There are also processes in the body that will counter - balance this:
    - Apoptosis: programmed cell death as a result of irreparable damage. โ€œ
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17
Q

Outline the normal pathway for the development of a Cell?

A 
"Normal Cells
        โ†“
Proliferation
(Division and Growth)
        โ†“
Perform Function
        โ†“ 
Apoptosis
(Programmed Cell Death)"
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18
Q

Why is the regulation of the normal pathway so important?

A

โ€œ1. If mutations are acquired in the genes that regulate these processes.

  1. So instead of being balanced between cell growth and cell death.
  2. The cells will just continue to divide.
  3. Continual division will eventually produce a clinically detectable tumour.โ€
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19
Q

What are the two classes of Genes that regulate Tumours?

A

โ€œ1. Oncogenes

2. Tumour Suppressor Genesโ€

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20
Q

What is an Oncogene?

A

โ€œProto-oncogene that has been mutated in a way that leads to signals that cause uncontrolled growth.
For Example: Cancer (like pushing on the gas pedal) โ€œ

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21
Q

What do Tumour Suppressor Genes do and what happens if theyโ€™re mutated?

A

โ€œTumour suppressor Genes inhibit both tumor growth and tumor formation.

  • They act as braking signals during the G1 phase of the cell cycle to stop or slow the cell cycle before S Phase.
  • If Tumour Suppressor Genes are mutated the normal brake mechanism will be disabled resulting in uncontrolled growth. โ€œ
22
Q

What 3 assumptions are made for the Multistage Carcinogenesis model?

A

โ€œ1. Malignant transformation of a single cell is sufficient to give rise to a tumour.

  1. Any cell in a tissue is as likely to be transformed as any other of the same type.
  2. Once a malignant cell is generated the mean time to tumour detection is constant.โ€
23
Q

What are the 5 Models for Carcinogenesis?

A 
"Model 1: Carcinogens.
Model 2: Genome Instability.
Model 3: Non Genotoxic.
Model 4: Darwinian.
Model 5: Tissue Organisation.

These are non exclusive and overlap each other.โ€

24
Q

How can Chemical Carcinogens induce Cancer?

A

โ€œ1. Cancer is a multistep process that includes:

  • Initiation.
  • Promotion.
  • Progression.
  1. Chemical carcinogens can alter any of these processes to induce carcinogenic effects.
  2. The presence of multiple mutations in critical genes is a distinctive feature of cancer cells.
  3. This supports that cancer arises through the accumulation of irreversible DNA damage.
  4. In the majority of instances chemical carcinogens can induce this DNA damage and act in a genotoxic manner.โ€
25
Q

What are the 4 Major Classes of Carcinogens?

A

โ€œ1. Chemical:

  • Polycyclic Aromatic Hydrocarbons.
  • Aromatic Amines.
  • Azo Dyes.
  • Nitrosamines.
  • Carbamates.
  • Halogenated Compounds.
  • Alkylating Agents.
  1. Physical:
    - Radiation: ionizing or ultraviolet
    - Asbestos.
  2. Heritable:
    - Genetic Predisposition
  3. Viral:
    - Hepatitis B
    - Epstein Barrโ€
26
Q

How do Carcinogens act on DNA?

A

โ€œFour of the major groups

  1. Polycyclic Aromatic Hydrocarbons,
  2. Aromatic Amines,
  3. Nitrosamines.
  4. Alkylating Agents

These all exert their effect by adding functional groups to DNA bases called DNA adducts. โ€œ

27
Q

When is Benzopyrene a Carcinogen?

A

โ€œBenzopyrene is not a carcinogen it is a pro carcinogen.

It only becomes a carcinogen when exposed to microsomal enzymes.โ€

28
Q

What is the Ames Test for?

A

A test to determine the mutagenic activity of chemicals by observing whether they cause mutations in sample bacteria.

29
Q

Give an example of an Ames Test?

A

โ€œ1. Salmonella strains require histidine to grow.

  1. If they are plated with little histidine there will not be many colonies.
  2. If a mutagen is introduced into the salmonella.
  3. If it is then plated onto a plate with minimal histidine.
  4. Many colonies will form because the of the mutation. โ€œ
30
Q

How do Physical Carcinogens work?

A

Unlike chemical carcinogens physical carcinogens act by imparting energy into the biological material.

31
Q

Outline the steps of radiation causing Cancer?

A

โ€œ1. Energy

  1. Changes in bonding of molecules.
  2. Biological Effects.โ€
32
Q

Give an example of Radiation causing mutations?

A

โ€œIonizing Radiation:

  • X-rays.
  • Nuclear radiation.
  • U.V. radiation.

Causes Damage

  • DNA Breaks.
  • Pyrimidine Dimers form.

Failed DNA Repair:
- Translocations Mutations.โ€

33
Q

What is the significance of syndromes predisposing to Cancer?

A

โ€œ1. Accounts for 5% of all cancers.

  1. An inherited germline mutation has an increased risk of developing certain tumours,
    but are rarely involved in causing cancer immediately.
  2. Monogenic Hereditary Diseases:
    - In most known hereditary malignant syndromes the elevated cancer risk is due to a mutation of a single gene.
  3. The affected genes concerned usually have a controlling function on the cell cycle or repair of DNA damage.
    A deficiency in DNA repair would cause more DNA damages to accumulate and increase the risk for cancer.โ€
34
Q

DNA Repair Defects that can predispose to Cancer:

A 
"Ataxia Telangiectasia
Bloomโ€™s Syndrome
Fanconiโ€™s Anaemia
Li-Fraumeni Syndrome
Lynch Type II
Xeroderma Pigmentosum"
35
Q

Chromosomal Abnormalities that can predispose to Cancer:

A

โ€œDownโ€™s Syndrome.

Klinefelterโ€™s Syndrome.โ€

36
Q

Ataxia Telangiectasia:

A

โ€œSymptoms:

  • Neuromotor dysfunction.
  • Dilation of blood vessels.

Mutation:

  • Mutation leading to a ATM gene.
  • Which codes for serine/threonine kinase.
  • Which phosphorylates p53 (tumour suppressor).
  • That is recruited and activated by dsDNA breaks leading to cell cycle arrest,
  • DNA repair and apoptosis - cell cycle arrest

Cancer Predisposition:
- Lymphoma, leukemia, breast cancer โ€œ

37
Q

Bloomโ€™s Syndrome:

A

โ€œSymptoms:
- Short stature, rarely >5ft, skin rash that develops after exposure to the sun

Mutation:

  • Mutation in BLM gene that provides instructions for coding a member of the RecQ helicase family.
  • That helps maintain the integrity of DNA.

Cancer Predisposition :
- Skin cancer, basal cell carcinoma and squamous cell carcinoma.โ€

38
Q

Lynch Type II:

A

โ€œSymptoms:
- No symptoms, the first sign is when symptoms of bowel and womb cancer develop.

Mutation:
- Mutations in DNA mismatch repair (MMR) genes, ML H1, MSH2, MSH6 and PMS2.

Cancer Predisposition:
- Colorectal Cancer.โ€

39
Q

Which infectious agents can cause Cancer?

A

โ€œViruses capable of causing a wide range of human diseases from smallpox to the common cold.
Most harm is caused when viruses multiply inside the infected cell.
Kill the cell and release progeny to further infect other cells.โ€

40
Q

What properties must be seen to identify a Tumourigenic Virus?

A

โ€œ1. Stable Association with Cell

  • Chromosomal integration.
  • Episome.
  1. Must not Kill Cells:
    - If there is a non permissive host the virus cannot replicate.
    - Suppression of Viral Lytic Cycle.
    - Viral release by budding.
  2. Must Evade Immune Surveillance of Infected Cells:
    - Immune suppression.
    - Viral antigens not expressed at cell surface.
    - Non - immunogenic genes expressed.โ€
41
Q

What Viruses are associated with Cancer?

A

โ€œDNA Viruses:

  • Epstein-Barr Virus: Burkittโ€™s lymphoma or nasopharyngeal carcinoma.
  • Papilloma Viruses: Cervical carcinoma or warts.
  • Hepatitis B and C: Hepatoma.

RNA Retroviruses:
- HTLV-1: adult T cell leukaemia, lymphoma.โ€

42
Q

What is the Knudsonโ€™s Hypothesis for Hereditary Cancers:

A

โ€œRb1 the tumour suppressor gene that causes retinoblastoma when both copies are mutated.

Suggested that multiple hits were required to cause cancer.
If the first mutated allele was inherited the second mutation would lead to cancer.

Two Types of Retinoblastoma:
1. Inherited Type.

  1. Sporadic Type:
    - Developed the Tumour much later in life.
    - In Sporadic Forms of the tumour both mutations had to take place and hence could explain the difference of age at diagnosis.

At least two events are necessary for carcinogenesis.
The cell with the first event must survive in the tissue long enough to sustain a second event. โ€œ

43
Q

How do Non Genotoxic mechanisms cause cancer?

A

โ€œ1. Non-genotoxic is characterized by an emphasis on non-genotoxic effects.

  1. Several important modulators of cancer risk:
    - Diet.
    - Obesity
    - Hormones.
    - Insulin Resistance.
  2. Do not act through a structural change in DNA but rather through functional changes including epigenetic events.โ€
44
Q

What are some Non Genotoxic Carcinogens?

A

โ€œ1. Tumour Promoters (1,4-dichlorobenzene).

  1. Endocrine - Modifiers (17ฮฒ-estradiol).
  2. Receptor - Mediators (2,3,7,8-tetrachlorodibenzo-p-dioxin).
  3. Immunosuppressants (cyclosporine).
  4. Inducers of tissue-specific toxicity and inflammatory responses (metals such as arsenic and beryllium). (Also in Model 1)

In a high proportion of these Carcinogens,
Multiple pathways need to be altered for Cancer Induction. โ€œ

45
Q

What does the Darwinian Model explain?

A

โ€œCarcinogenesis by mutation and selection.
It is a model of clonal expansion.
The role of environment in selecting cells that have some acquired advantage.โ€

46
Q

Describe the order of events that can lead to selection?

A

โ€œ1. Sequenctial accumulation of mutations due to exposure to carcinogens.

  1. Tumour cells will be selected for ability to grow and invade.
  2. Selection will include resistance to therapy.
  3. Some mutations may be deleterious for tumour.โ€
47
Q

What are Tissues?

A

โ€œGroups of cells with similar function as known as tissues.

For Example: epithelial, connective, muscle and nervousโ€

48
Q

Why is Tissue Organisation important in Cancer?

A

โ€œTo understand the changes that occur during cancer.
It is important to understand the principles of cell and tissue organisation.
And mechanisms that control growth and structure.โ€

49
Q

What two theories explain the forces driving Carcinogenesis?

A

โ€œ1. Somatic Mutation Theory (SMT):
Single catastrophic event triggering Carcinogenesis.
- Cancer is derived from a single somatic cell that has successively accumulated multiple DNA mutations.
- Those mutations damage the genes which control cell proliferation and cell cycle.
- Thus, according to SMT, neoplastic lesions are the results of DNA-level events.

  1. Tissue Organization Field Theory (TOFT):
    Carcinogenesis as general deterioration of the tissue microenvironment due to extracellular causes.
    - Carcinogenesis is primarily a problem of tissue organization.
    - Carcinogenic agents destroy the normal tissue architecture thus disrupting cell-to-cell signaling and compromising genomic integrity.
    - The DNA mutations are random and the effect, not the cause, of the tissue-level events. โ€œ
50
Q

What is the Immune Response in Cancer?

A

โ€œ1. Protect from Virus-induced Tumours.

  1. Eliminate Pathogens.
  2. Identify and Eliminate Tumour Cells. โ€œ
51
Q

What is Cancer Immunoediting?

A

โ€œThe Three Eโ€™s:

  1. Elimination
    - The immune system is able to eradicate developing tumours.
  2. Equilibrium:
    - When incomplete removal is present tumour cells remain dormant and enter equilibrium.
    - The immune system exerts a potent and relentless pressure that contains the tumour.
    - During this phase some of the tumour may mutate or give rise to genetic variants that survive, grow and enter the next phase (around 20 years).
  3. Escape:
    - The expanding tumour population becomes clinically detectable.โ€
52
Q

Describe the development of a Cancer and how it escapes the Immune System:

A

โ€œ1. Normal cell undergoes a change.

  1. Normal cell expresses tumour antigens.
  2. Through cancer immune surveillance the immune system eliminates those cells.
  3. One or two of the tumours can escape the surveillance and move to the next phase called cancer persistence.
  4. The tumour then acquires further changes which means itโ€™s able to survive the immune system and overrides the suppression.
  5. The escape phase is where there is cancer progression.โ€

๐˜พ๐™š๐™ก๐™ก๐™ช๐™ก๐™–๐™ง ๐™‹๐™–๐™ฉ๐™๐™ค๐™ก๐™ค๐™œ๐™ฎ ๐Ÿงซ COPY COPY (13 decks)

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