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Cellular Pathology > Mechanism of Oncogenesis > Flashcards

Mechanism of Oncogenesis Flashcards

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1
Q

Describe the incidence of cancer in the UK

A

Incidence - Every two minutes someone in the UK is diagnosed with cancer
359,960 new cases of cancer in the UK in 2015, that’s 990 cases diagnosed every day

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2
Q

Outline the mortality rate of cancer in the UK

A

Mortality - Every four minutes someone in the UK dies from cancer

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3
Q

What is the cancer risk of the UK population?

A

1 in 2 people in the UK born after 1960 will be diagnosed with some form of cancer during their lifetime

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4
Q

What are the chances of cancer survival in the UK?

A

Cancer survival - Half (50%) of people diagnosed with cancer in England and Wales survive their disease for ten years or more (2010-11)

Cancer survival is improving and has doubled in the last 40 years in the UK

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5
Q

How can cancer be prevented?

A

4 in 10 (42%) of cancer cases in the UK each year are linked to lifestyle

These are cases that can be prevented largely through lifestyle changes

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6
Q

What are the lifestyle factors contributing to cancer onset?

A
  • smoking
  • obesity + weight
  • hormones
  • sun + UV
  • Workplace causes
  • alcohol
  • physical activity
  • infections + HPV
  • diet
  • inheritance
  • air pollution and radion
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7
Q

Describe the age range in prevalence of cancer

A

Adults aged 50-74 account for more than half (53%)
of all new cancer cases, and elderly people aged 75+
account for more than a third (36%), with slightly
more cases in males than females in both age groups.

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8
Q

Why are there more 50-74 y/o in the population with cancer than any other age range?

A

There are more people aged 50-74 than aged 75+
in the population overall, hence the number of
cancer cases is higher in 50-74s, but incidence
rates are higher in 75+s.

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9
Q

What is cancer?

A

Cancer is the name for a group of diseases

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10
Q

What are the group of diseases responsible for cancer?

A

Cancer is a group of diseases characterised by:

  • Abnormal cell proliferation
  • Tumour formation
  • Invasion of neighbouring normal tissue
  • Metastasis to form new tumours at distant sites
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11
Q

How many types of cancer are there?

A

Over 200 different types of cancer have been classified, often according to their origin

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12
Q

Where are the common occurrences of cancer?

A

Approximately 85% of cancer occur in epithelial cells-carcinomas

Cancers derived from mesoderm cells (bone and muscle) are sarcomas

Cancers found in glandular tissue are called adenocarcinomas

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13
Q

What are the hallmarks of cancer defined by Hanahan and Weinberg?

A
  1. sustaining proliferative signalling
  2. evading growth suppressors
  3. avoiding immune destruction
  4. enabling replicative immortality
  5. tumour-promoting inflammation
  6. activating invasion + metastasis
  7. inducing angiogenesis
  8. genome instability + mutation
  9. resisting cell death
  10. deregulating cellular energetics
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14
Q

What is the consequence of carcinogens?

A

Carcinogens cause alterations to the DNA - Mutations

DNA from tumours has been shown to contain many alterations from point mutations to deletions

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15
Q

How does carcinogenesis occur?

A

The accumulation of mutations over time represents the multi-step process that underlies carcinogenesis

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16
Q

When does carcinogenesis occur?

A

This accumulation occurs only after the cells defence mechanism of DNA repair have been evaded

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17
Q

When is apoptosis induced during cancer?

A

In cases of severe damage cell apoptosis is induced

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18
Q

What mechanisms are available in the body to fight cancer?

A

Many mechanisms exist for blocking carcinogenesis but over burdening the system increases the possibility that cells will escape surveillance

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19
Q

Why does age play a major factor in cancer development?

A

The 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

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20
Q

How do germ line mutations lead to cancer?

A

Alterations in egg/sperm DNA (point mutations / deletions)

inheritable; make up ~5% of all cancers

Majority of cell mutations affect somatic cells instead

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21
Q

Explain how somatic mutations cause cancer?

A

> non-inheritable mutation

All cells in a primary tumour arise from a single cell, initiation of the development of cancer is clonal

Dependent on interaction with other tumour cells and the tumour microenvironment

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22
Q

Why are somatic mutations such a common cause of cancer?

A

Only one of the 10^14 cells in body need to be transformed to create a tumour
Continued accumulation of mutations

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23
Q

Why is cancer hard to cure?

A

Tumour cells can ‘evolve’- sub clonal selection allowing a growth advantage and explain and heterogeneity of cells in a tumour

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24
Q

When are normal cells converted to cancerous tumour cells?

A

If the balance between the process by which cells proliferate and apoptosis occurs is lost normal healthy cells can convert into tumour cells

It is a delicate balance.

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25
How do cells proliferate?
Cells respond to growth factors and signals allowing proliferation
26
How does apoptosis occur?
Damage and irreversible DNA damage acts as a balance enabling cell loss via apoptosis
27
Which processes regulate cell number?
Growth, Apoptosis and Differentiation
28
What is the cell growth and apoptosis pathway regulated by?
This pathway is regulated by a number of different genes: - Oncogenes - Tumour suppressor genes Acquiring a mutation in one of those genes will cause a loss in regulation
29
What is the consequence in mutations of cell number regulation pathways?
Mutation usually causes an increase in cell no. to the point where you have a clinically detectable tumour
30
What are proto-oncogenes?
Normal genes that can be activated to be oncogenic
31
What is an oncogene?
An oncogene is a proto-oncogene that has been mutated in a way that leads to signals that cause uncontrolled growth- i.e., cancer. → This is like pushing down on the gas pedal
32
What is the role of tumour suppressor genes?
Tumour suppressor genes inhibit both growth and tumour formation They act as braking signals during phase G1 of the cell cycle, to stop or slow the cell cycle before S phase.
33
What is the effect of mutations in tumour suppressor genes?
If tumour-suppressor genes are mutated, the normal brake mechanism will be disabled, resulting in uncontrolled growth, i.e. cancer
34
What are the 3 assumptions of multistage carcinogenesis?
Malignant transformation of a single cell is sufficient to give rise to a tumour Any cell in a tissue is as 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
35
What are the 5 molecular mechanisms of cancer?
1. Mutational 2. Genome Instability 3. Non-genotoxic 4. Darwinian 5. Tissue organisation
36
Describe the formation of cancer formation
Cancer is a multi-step process that includes initiation, promotion and progression.
37
What is the effect of chemical carcinogens on the multistage process of cancer?
Chemical carcinogens can alter any of these process to induce their carcinogenic effects
38
What evidence supports the idea cancer is due to DNA damage?
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.
39
What is the major consequence of chemical carcinogens?
In the majority of instances chemical carcinogens can induce this DNA damage and act in a genotoxic manner. > specific chemicals can induce cancer
40
What are the different classes of carcinogens?
- chemicals - physical - heritable - viral - environmental
41
What are the different types of chemical carcinogens?
10 groups: - polycyclic aromatic - hydrocarbons - aromatic amines - azo dyes - nitrosamines - carbamates - halogenated compounds - alkylating agents
42
Give examples of physical carcinogens
Asbestos, Radiation - ionizing & UV
43
What is the effect of heritable carcinogens?
Patients have a predisposition to cancer
44
Name some viral carcinogens
Hepatitis B, Epstein Barr
45
How do chemical carcinogens lead to cancer?
Four of the major groups polycyclic aromatic hydrocarbons, aromatic amines, nitrosamines and alkylating agents exert their effects by adding functional groups to DNA bases called DNA adducts
46
Give an example of a DNA adduct caused added due to chemical carcinogens
One example is coal tar, which contains benzo[a]pyrene, a polycyclic hydrocarbon Benzo[a]pyrene is commonly found in cigarette smoke (together with 81 other carcinogens)
47
Outline how Benzo[a]pyrene can become carcinogenic
On its own it's a procarcinogen, and becomes a carcinogen when taken in and in contact with microsomal enzymes (Benzo[a]pyrene epoxide) changes G to T
48
What is the purpose of the Ames test?
A test to determine the mutagenic activity of chemicals by observing whether they cause mutations in sample bacteria
49
Outline how an Ames test is carried out
Ames test uses salmonella (strain of bacteria that requires histidine) mixed with liver extract and plated on a plate with minimal histidine - this produces no growth as in absence of histidine Introducing a carcinogen will produce colonies if the compound is mutagenic
50
How do physical carcinogens lead to cancer?
Unlike chemical carcinogens physical carcinogens act by imparting energy into the biological material (not changing DNA)
51
What is the most common physical cancerous agent?
Several types of radiation can act as carcinogens
52
How does UV radiation lead to skin cancer?
1. skin exposed to ionising / UV radiation 2. Causes DNA breaks and pyrimidine dimers form (DNA damage) 3. Failed repair 4. Translocation mutations occur
53
What are heritable carcinogens?
syndromes predisposing to cancer
54
What is the major heritable carcinogen?
DNA damage is a risk factor for cancer development | Accounts for 5% of all cancers
55
Describe the effect of germline mutations in cancer
An inherited germline mutation, has an increased risk of developing certain tumours but are rarely involved in causing cancer immediately
56
Are heritable cancers due to a single or multiple gene mutations?
In most known hereditary malignant syndromes the elevated cancer risk is due to a mutation of a single gene (monogenic hereditary diseases)
57
What is a common factor among cancerous genes?
The affected genes concerned usually have a controlling function on the cell cycle or the repair of DNA damage
58
How does failed DNA repair increase cancer risk?
A deficiency in DNA repair would cause more DNA damages to accumulate, and increase the risk for cancer
59
Which DNA repair defects cause syndromes predisposing to cancer?
DNA Repair Defects - Ataxia telangiectasia - Bloom’s syndrome - Fanconi’s anaemia - Li-Fraumeni syndrome - Lynch type II - xeroderma pigmentosum
60
What chromosomal abnormalities lead to syndromes predisposing to cancer?
Chromosomal Abnormalities - Down’s syndrome - Kleinefelter’s Syndrome
61
What is ataxia telangiectasia?
A neuromotor dysfunction, dilation of blood vessels, telangiectasia = spider veins
62
How does a DNA defect cause ataxia telangiectasia?
Mutation in ATM gene, codes for a serine/threonine kinase that is recruited and activated by dsDNA breaks leading to cell cycle arrest, DNA repair and apoptosis -cell cycle arrest
63
Which cancers are predisposed by ataxia telangiectasia?
Cancer predisposition: lymphoma, leukaemia and breast cancer
64
What is Bloom's syndrome?
short stature, rarely exceed 5 feet tall, skin rash that develops after exposure to the sun
65
Describe the DNA defect that causes Bloom's syndrome
Mutation in BLM gene that provides instructions for coding a member of the RecQ helicase family that help maintain the structure and integrity of DNA
66
What are the cancers predisposed by blooms syndrome?
skin cancer. basal cell carcinoma and squamous cell carcinoma.
67
What is Lynch type?
Mutations in DNA mismatch repair (MMR) genes, notably MLH1, MSH2, MSH6 and PMS2.
68
Describe the signs of Lynch type?
LS doesn't cause any symptoms. Sometimes the first sign that a person has LS is when the symptoms of bowel and womb cancer develop.
69
What cancer can Lynch type lead to?
Cancer predisposition: colorectal cancer
70
What diseases are viruses responsible for?
Viruses capable of causing a wide range of human disease from smallpox to common cold
71
When are viruses most dangerous?
Most harm caused when viruses multiply inside the infected cell, kill the cell and release progeny to further infect other cells
72
When do cells become very proliferative?
Most viruses are very proliferative when they infect a cell, exhibiting a lytic cycle: express all the genes found in their genome They aim to produce lots of viral capsids that can be released for further infection
73
How do viruses become cancerous?
In rare circumstances, viruses switch from lytic to latent cycle, which is a restrictive pattern of gene expression and some viruses can become tumorigenic; allow transformation of cells
74
What are the 3 required properties of tumorigenic viruses?
1. Stable association with cells 2. Must not kill cells 3. Must evade immune surveillance of infected cells
75
How do tumorigenic viruses form stable associations with cells?
- chromosomal integration | - episomes
76
How do tumorigenic vuiruses avoid killing cells?
Via: - non-permissive host (virus cannot replicate) - suppression of viral lytic cycle - viral release by budding
77
How do tumorigenic viruses evade immune surveillance of infected cells?
- immune suppression | - viral antigens not expressed at cell surface
78
What are the DNA viruses associated with human cancer?
``` Epstein-Barr virus Burkitt’s lymphoma nasopharyngeal carcinoma papilloma viruses cervical carcinoma warts hepatitis B and C hepatoma ```
79
What are the RNA retroviruses associated with human cancers?
HTLV-I | Adult T-cell leukaemia, lymphoma
80
What is the theory behind genome instability causing cancer?
> Knudson's Hypothesis for Hereditary Cancers based on discovery of Rb1, the TSG that causes retinoblastoma when both copies are mutated
81
How did knudson identify genome instability as a model of cancer?
Knudson performed statistical analysis on cases of retinoblastoma of which there are two types the inherited type and the sporadic type
82
What were the results of knudsons' analysis?
He suggested multiple hits were required to cause cancer If the first mutated allele was inherited the second mutation would lead to cancer In the sporadic forms of the tumour both mutations had to take place and hence this could explain the difference of age at diagnosis
83
What is the non-genotoxic model of cancer?
Non-genotoxic is characterized by an emphasis on non-genotoxic effects
84
How do non-genotoxic effectors lead to cancer?
Several important modulators of cancer risk (diet, obesity, hormones and insulin resistance) do not seem to act through a structural change in DNA but rather through functional changes including epigenetic events
85
What are the effects of non-genotoxic carcinogens?
carcinogens that induce cancer via non-genotoxic mechanisms have been shown to 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)
86
How do non-genotoxic carcinogens cause cancer?
Although little is known about this group of carcinogens it is known that in a high proportion of them, multiple pathways need to be altered for cancer induction
87
Describe the darwinian model of cancer
Carcinogenesis by Mutation and Selection-Model of Clonal Expansion The role of the environment in selecting cells that have some acquired advantage
88
What is the significance of tissue organisation in cancer?
To 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
89
What are tissues?
Groups of cells with similar function are known as tissues: epithelial, connective muscle and nervous
90
What are the 2 theories describing the forces driving carcinogenesis?
Two drastically different approaches to understanding the forces driving carcinogenesis have crystallized through years of research. 1. Somatic mutation theory (SMT) 2. Tissue organization field theory (TOFT)
91
What is the somatic mutation theory?
> Single catastrophic event triggering carcinogenesis
92
What is the Tissue Organisation Field theory?
Carcinogenesis as general deterioration of the tissue microenvironment due to extracellular causes
93
Outline the tissue organisation field theory
1. Carcinogenesis is primarily a problem of tissue organisation 2. carcinogenic agents destroy the normal tissue architecture thus disrupting cell-to-cell signalling and compromising genomic integrity 3. The DNA mutations are random and the effect, not the cause, of the tissue-level events
94
Outline the somatic mutation theory of cancer
1. cancer is derived from a single somatic cell that has successively accumulated multiple DNA mutations 2. those mutations damage the genes which control cell proliferation and cell cycle 3. Thus, according to SMT, neoplastic lesions are the results of DNA-level events
95
How does the immune system respond to cancer?
- Protect from virus-induced tumours - Eliminate pathogens - Identify and eliminate tumour cells ↓ - Immune surveillance ↓ - Despite this tumours can still arise- - Concept of cancer immunoediting
96
What are the 3 'E's' of cacer immunoediting?
Elimination Equilibrium Escape
97
Describe how the immune system tries to eliminate cancer
The immune system is able to eradicate developing tumours
98
What is equilibrium in cancer immunoediting?
When incomplete removal is present tumour cells remain dormant and enter equilibrium
99
Describe what occurs during equilibrium phase of cancer immunoediting
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
100
How long does the equilibrium phase of cancer immunoediting last?
(Longest of the phases, around 20 years)
101
How can cancer risk be reduced?
Some risk factors for cancer are easier to avoid than others But everyone can avoid some of them. There are also positive things that we can all do to reduce the cancer risk. The choice is ours

Cellular Pathology (13 decks)

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