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[MBD] NoNa > Mechanisms of Oncogenesis > Flashcards

Mechanisms of Oncogenesis Flashcards

1
Q

What are some risk factors of cancer?

A 
Smoking
Obesity and weight 
Alcohol
Workplace 
Sun and UV
Physical activity 
Hormones
Infections and HPV 
Inherited genes 
Air pollution and radon 
Diet and healthy eating
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2
Q

Define cancer

Hallmarks/Characteristics of Cancer

A

Cancer = A group of disease characterised by specific hallmarks:

  • Abnormal cell proliferation
  • Tumour formation
  • Invasion of neighbouring normal tissue
  • Metastasis to form new tumours at distant sites
  • Ability to supply themselves w nutrients
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3
Q

What are some different types of cancers classification according to origin?

A
  • Cancer in epithelial cells (85%) = Carcinomas
  • Cancers from mesoderm cells (bone/muscle) = Sarcomas
  • Cancers in glandular tissue = Adenocarcinomas
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4
Q

What are the Hallmarks of cancer ?

A
  • Deregulating cellular energetics
  • Sustaining proliferative signalling
  • Evading growth suppressors
  • Avoiding immune destruction
  • Enable replicative immortality
  • Tumour-promoting inflammation
  • Activating invasion and metastasis
  • Inducing angiogenesis
  • Genome instability and mutation
  • Resisting cell death
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5
Q

What are some characteristics of the cancer DNA ?

A

DNA from tumour cell has been shown to contain mutated DNA - point mutations/deletions - due to carcinogen exposure

Mutations accumulate over time (a multi-step process underlies carcinogenesis)

Evades DNA repair mechanisms, apoptosis to remove damaged cells, immune system

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6
Q

What are the 2 diff types of cell that mutations can occur in in cancer?

A
  1. Egg/Sperm Cell mutations - Germ line mutation = These are inheritable mutations and can increase risk of developing cancer
  2. Somatic cell mutation - non-inheritable, but can be passed on to daughter cells in cell division
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7
Q

Outline Somatic cell mutations and what they can cause

A

Somatic cell has alteration in DNA , cell division - Clonal cells.

All cells in a primary tumour arise from a single cell - Initiation of tumorigenesis (development of cancer) is clonal.

Continued accumulation of mutations

10^14 cells in body

Tumour cells can evolve - subclonal selection allowing a growth advantage + heterogeneity of cells in a tumour.

Depends on: Tumour cells interact with surrounding tumour cells + the tumour microenvironment (e.g. immune cells)

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8
Q

Describe the process through which a normal cell can become a tumour cell - Proliferation

A

Proliferation in response to diff signals - GFs, hormones, IL, cytokines
+ Counterbalancing processes - DNA damage = cell cycle arrest, apoptosis
The control of cell division within a tissue is important in self renewing when proliferation must balance cell loss.

There are signals which induce proliferation e.g.
Growth factors :EGF, PDGF
Cytokines: Growth hormones, interleukins
Hormones: Oestrogen

Process is controlled however and balanced with Apoptosis

Programmed cell death as a result of irreparable damage

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9
Q

What is the typical cell life cycle ?

A

Normal cells

Proliferation (growth + division)

Differentiation

Perform function

Apoptosis
(Programmed cell death)

-Mutations in the genes regulating these processes = imbalanced cell growth/cell death = continual division = ⬆ cell number = clinical tumour

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10
Q

What problems can arise in the cell life cycle?

A

Regulation of the cell life cycle processes is vital and if mutations are acquired in the genes that regulate this, it means :

Cells are not balanced between cell division/ cell death

Cells continue dividing = ↑ cell number = tumour

Carcinogenesis

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11
Q

What are the genes which regulate the processes relating to cell growth? What can go wrong with them?

A

Oncogenes + tumour suppressor genes regulate cell growth processes.

Oncogenes = Normal genes that regulate cell growth. Can be activated to be oncogenic are called proto-oncogenes

An oncogene is a pro-oncogene that has been mutated in a way which leads to signals that cause uncontrollable growth = accelerates cell growth

Mutation 1: Accelerated cell division

Tumour suppressor genes inhibit cell growth + tumour formation.
Braking signals during G1 phase of cell cycle to stop/slow the cell cycle before the S phase.
Mutated tumour suppressor genes = disables the normal brake mechanism = cancer

Mutation 1 = Susceptible to cancer
Mutation 2 = Leads to cancer

Acquire 2 mutations within tumour suppressor gene = cut off brakes in car = can’t stop car.
In tumorigenesis, mutations in both genes speed up cell growth

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12
Q

What are 3 assumptions which are made when it comes to cancer ?

A
  1. Malignant transformation of a single cell is sufficient to give rise to a tumour
  2. Any cell in a tissue is as likely to be transformed as any other cell of the same type
  3. Once a malignant cell is generated, the mean time to tumour detection is generally constant
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13
Q

What are the 5 models of carcinogenesis ?

A

Model 1 - Mutational - Chemical carcinogens
Model 2 - Genome instability - knudson’s 2-hit hypothesis
Model 3 - Non-genotoxic - cancer modulators.
Model 4 - Darwinian - how tumours evolve
Model 5 - Tissue organisation - tissue environment, tissue structure

These models overlap = non-exclusive, not distinct
Models for cells to become tumorigenic

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14
Q

Outline Model 1 - Chemical carcinogens and how it can cause cancer

A

Cancer is a multi step process which includes :
1 - Initiation
2 - Promotion
3 - Progression

Chemical carcinogens can alter any of these 3 processes to induce carcinogenic effects
Alter DNA structure
Damage not repaired = damage accumulates

The presence of multiple mutations in critical genes is a distinctive feature of cancer cells and supports that cancer arises through the accumulation of irreversible DNA damage.

Chemical carcinogens can induce DNA damage and act in a genotoxic (damage to genetic information within a cell ) manner

e.g. benzene, arsenic, asbestos

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15
Q

What are the 4 groups of Carcinogens?

Provide examples for each

A
  1. Chemical - organic compounds
    polycyclic aromatic hydrocarbons ,aromatic amines,azo dyes,nitrosamines,carbamates,halogenated compounds ,alkylating agents
  2. Physical
    Radiation - Ioninsing /Ultraviolet
    Asbestos
  3. Heritable
    Genetic Predisposition to cancer
  4. Viral
    Hepatitis B
    Epstein Barr
    -viruses associated with tumours
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16
Q

What are chemical carcinogens ?

A 
4 of the major groups are:
-Polycyclic aromatic hydrocarbons
-Aromatic amines
-Nitrosamines
-Alkylating agents
Exert their effects by adding functional groups to DNA bases called DNA adducts

Example - Coal Tar Benzo(a)pyrene = a polycyclic hydrocarbon
Found in cigarrete smoke
procarcinogen -> carcinogen (in body by microsomal enzymes, G->T transversion)

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17
Q

What are pro-carcinogens ?

A

Pro-carcinogens = any substance which is converted into carcinogens through metabolism (microsomal enzymes)

18
Q

How do we know if a chemical is actually a carcinogen ?

A

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

A rat liver extract is taken and combined with a salmonella strain which only grows in Histidine.
Plate mixture and grow in an agar plate which lacks histidine.

Overnight incubation, There should be very little colonies.
However following addition of the chemical, if the bacteria does grow many colonies, this suggests that change in bacteria = grow in absence of histidine = the chemical is carcinogenic

19
Q

How do chemical carcinogens exert their effects?

A

Chemical carcinogens exert their effects by adding functional groups to DNA bases called DNA adducts

20
Q

How do physical carcinogens exert their effects?

A

Physical carcinogens alter the bonding of molecules by imparting energy into the biological material

21
Q

What are physical carcinogens ?

A

These impart energy into the biological material, altering the bonding of molecules

2 types - UV radiation, Ionizing radiation

DNA damage causes DNA breaks + pyrimidine dimers.
Failed DNA damage repair following this = translocations, mutations

22
Q

Why does sunscreen protect against UV radiation?

A

UV radiation only penetrates skin-deep, so sunscreen protects.

23
Q

What are heritable carcinogens and what effects do they have ?

A

Genetic predisposition to cancer -
DNA damage is a risk factor for cancer development

Can be mutation in a single gene - DNA damage repair mechanism = allows mutations to accumulate = ⬆ risk of cancer

An inherited germline mutation has an increased risk of developing certain tumours but are rarely involved in causing cancer immediately .

In most hereditary malignancy syndromes , the elevated cancer risk is due to a mutation of a single gene = monogenic hereditary diseases

The affected genes usually have a controlling function on the cell cycle or the repair of DNA damage.

A deficiency in DNA repair would cause more DNA damage to accumulate and increase the risk of cancer

24
Q

Examples of syndromes causing DNA repair defects - predispose to cancer

A 
Ataxia telangiectasia 
Bloom's syndrome
Fanconi's anaemia
Li-Fraumeni syndrome 
Lynch type 2
Xeroderma pigmentosum
25
Q

Examples of chromosomal abnormalities - predispose to cancer

A

Down’s syndrome

Klinefelter syndrome

26
Q

What is Ataxia telangiectasia and how can it lead to Cancer?

A

This is a neuromotor dysfunction causing vasodilation
Telangiectasia = spider veins

Mutation in ATM gene which codes for serine/threonine kinase (Phosphorylation of CHECK 1, CHECK 2, activation of p53, DNA repair/cellcyclearrestapoptosis) that is recruited and activated by dsDNA breaks leading to cell cycle arrest , DNA repair and apoptosis.
Mutation = this doesn’t happen = predisposed to cancer

Cancer predisposition : Leukaemia and breast cancer

27
Q

Outline Bloom Syndrome and how it may lead to cancer

A

Short stature, <5 feet tall, skin rash develops following sun exposure.

Mutation in the BLM gene that provides instructions for coding a member of the RecQ helicase family that help maintain the structure and integrity of DNA
Mutation in this BLM gene = cancer

Cancer predisposition: Skin cancer, Basal cell carcinoma, Squamous cell carcinoma

28
Q

Outline Lynch Syndrome and how it can lead to cancer

A

LS doesn’t cause any symptoms
First sign that person has LS: Symptoms of bowel + womb cancer.

LS is due to Mutations in DNA mismatch repair (MMR) genes - MLH1, MSH2, MSH6 and PMS2

Cancer predisposition : Colorectal cancer, bowel cancer, womb cancer

29
Q

Identify how infectious agents can be carcinogens

A

Viruses capable of causing a wide range of human disease - small pox, common cold.

Viruses cause harm when multiply inside the infected cell, kill the cell (lysis) and release progeny (descendant) to further infect other cells
Most genome is expressed during this phase

During latent phase of infection , restricticted pattern of gene expression (e.g. viral oncogenes). -Viruses associated with cancer. express genes that cause cell to transform into tumour cell = tumorigenesis

30
Q

What properties does a tumourigenic virus have?

A

Must have stable association with cells:
-Chromosomal integration
Episome

Must not kill cells :
Non-permissive host (virus cannot replicate )
Suppresion of viral lytic cycle
Viral release by budding

Must evade immune surveillance of infected cells:
During latent phase very few genes are expressed - nonimmunogenic genes = survive by avoid detection by immune system
Immune suppression
Viral antigens not expressed at cell surface

31
Q

Describe viral carcinogenesis

A

Viral gene products act as transcription factors

Virus carries mutated cellular gene (oncogene)

Viral integration into the cellular genome disrupts cellular genes

Viral gene products inactivate cell cycle regulatory proteins

Viral infection results in immunodeficiency

32
Q

What viruses are associated with human cancer?

A 
DNA viruses:
Epstein-Barr Virus 
Papilloma viruses
Hepatitis B and C 
Burkitts's lymphoma
Nasopharyngeal carcinoma 
Cervical carcinoma 
Warts 
Hepatoma

RNA retroviruses :
HTLV-I
Adult T-cell leukaemia
Lymphoma

33
Q

Outline Model 2 - Genome Instability

A

Knudson’s 2-hit hypothesis

Studied tumour suppressors - Rb.

2 types - Familial Rb, Sporadic Rb
Sporadic Rb = develop tumour later in life, compared to familial Rb.

Need to acquire 2 hits for Rb alleles in order to develop that disease

34
Q

Outline Model 3 - Non genotoxic

A

Non-genotoxic is characterised by an emphasis on non-genotoxic effects

Important modulators of cancer risk (diet, obesity , hormones and insulin resistance ) do not alter DNA structure but act through functional changes (epigenetics)

Carcinogens that induce cancer via non-genotoxic mechanisms:

  • tumour promoters
  • endocrine modifiers
  • receptor mediators
  • Immunosuppressants
  • Inducers of tissue-specific toxicity and inflammatory responses - e.g. arsenic, beryllium (overlap, Model1)

High frequency of mutations occur to genome - continuous DNA damage + repair.
Tumour suppressors

35
Q

Outline Model 4 - Darwinian

A

(NATURAL SELECTION)
Carcinogenesis by Mutation and Selection model of clonal expansion

The role of the environment in selecting cells that have some acquired advantage

Sequential accumulation of mutations due to exposure to carcinogens

Tumour cells will be selected for ability to grow/invade

Artificial Selection, resistance to therapy.
Chemotherapy = selecting for tumour cells that can overcome this selection pressure.

Some mutations may be deleterious for tumour.

Initial growth from a single tumour cell is clonal (identical cells) but as cell progresses, continual accumulation of mutations, cells acquire diff. mutations = evolving = natural selection for cells with growth advantage

36
Q

What are tissues

A

Tissues = Groups of cells with similar function:

Epithelial tissue, connective tissue, nervous tissue, cardiac tissue, smooth muscle tissue

37
Q

What is the Somatic Mutation Theory (SMT)?

A

A Single catastrophic event that triggers carcinogenesis

Cancer is derived from a single somatic cell that has successively accumulated multiple DNA mutations

These mutations damage genes which control cell proliferation and cell cycle - DNA damage repair, cell cycle, apoptosis

According to SMT , neoplastic lesions are the results of DNA -level events

38
Q

What is the Tissue Organisation Field Theory ?

A

Carcinogenesis is a problem of general deterioration of the tissue microenvironment due to extracellular causes

Carcinogenesis is primarily a problem of tissue organisation

Carcinogenic agents destroy the normal tissue architecture thus disrupting cell-to-cell signalling and compromising genomic integrity

The DNA mutations are random and are the effect not the cause of the tissue level events

39
Q

How does the immune system respond to cancer ?

A

The immune system will :

  1. Protect from virus induced tumours
  2. Eliminate pathogens
  3. Identify and eliminate tumour cells

Immune surveillance

Despite this, tumours can still arise - Cancer immunoediting

Group of cells (tissue, model 5) are exposed to carcinogens (model 1), radiation, viral infection, inherited genetic predisposition, chemical carcinogens = some cells transform. cell surface has tumour antigens for immune system to detect tumour antigens.
Despite this, tumours still arise = cancer immunoediting

40
Q

Outline the three E’s and Cancer immunoediting

A

Elimination (immune surveillance):
Immune system eliminates developing tumour cells within tissues by detecting by tumour antigens on tumour cell surface

Equilibrium (cancer persistence):
When incomplete removal is present, tumour cells remain dormant and enter equilibrium. The immune system exerts a potent, relentless pressure that contains the tumour. During this phase, tumour cells mutate (model 4, Darwinian) or give rise to genetic variants that survive, grow and enter the next phase = select for cells that overcome the selection pressure, outgrow suppression = escape = cancer progression

Escape
The expanding tumour populations becomes clinically detectable

41
Q

Which genes drive tumorigenesis?

What are the counterbalancing proteins?

A

Oncogenes

Tumour suppressors

42
Q

Cancer can be described as a disease of ……

A

ageing

Risk of cancer increases w age
Live longer = accumulate changes, mutations etc.

[MBD] NoNa (28 decks)

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