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Molecular Basis Of Disease > Mechanisms Of Oncogenesis > Flashcards

Mechanisms Of Oncogenesis Flashcards

1
Q

What is cancer and state the 4 major characterisations?

A

Cancer is the name for a group of diseases characterised by:
- Abnormal cell proliferation
- Tumour formation
- Invasion of neighbouring normal tissue
- Metastasis to form new tumours at distant sites
- Metastasis = the development of secondary malignant growths at a distance from a primary site of cancer

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2
Q

State the origin of these type of cancers: carcinomas, sarcomas and adenocarcinomas?

A
  • Carcinomas: Epithelial cells (85% of all cancers)
  • Sarcomas: Mesoderm cells - bone and muscle
  • Adenocarcinomas: Glandular tissue
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3
Q

State atleast 6 hallmarks of cancer

A
  • Sustaining proliferation signalling
  • Evading growth suppressors
  • deregulating cellular energetics
  • Resisting cell death
  • Genome instability mutation
  • Inducing angiogenesis
  • Activating invasion and metastasis
  • Tumour promoting inflammation
  • Enabling replicative immortality
  • Avoiding immune destruction
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4
Q

State the 2 emerging hallmarks out of these?

A
  • Avoiding immune destruction
  • Reprogramming energy metabolism
  • Remember cancer doesn’t have to show all of these hallmarks, just the majority of them
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5
Q

State the evidence to show that cancer is a disease of the genome at cellular level? (PART 1)

A
  • DNA from tumours has been shown to contain many alterations from point mutations to deletions
  • The accumulation of mutations over time in DNA represents the multi-step process that underlies carcinogenesis (initation of cancer formation)
  • This accumulation occurs only after the cells defence mechanism of DNA repair have been evaded
  • In cases of severe damage, cell apoptosis is induced
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6
Q

State the evidence to show that cancer is a disease of the genome at cellular level? (PART 2)

A
  • Many mechanisms exist for blocking carcinogenesis but over burdening the system increases the possibility that cells will escape surveillance
  • 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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7
Q

What would occur if an alteration to DNA in egg/sperm cell occured?

A
  • Egg/sperm cell -> Alteration in DNA (point mutations/deletions) -> Germline mutations -> either -> inheritable mutation or -> Egg/Sperm cell offspring’s
  • Increased risk of developing cancer, Rarely involved in causing cancer immediately
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8
Q

Describe the source of the origin of tumour cells

A
  • Somatic mutations constitute almost all mutations in tumour cells
  • All cells in a primary tumour arise from a single cell, initiation of the development of cancer is clonal
  • Only one of the 10 14 cells in body need to be transformed to create a tumour
  • Created via Continued accumulation of mutations
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9
Q

How can tumour cells evolve?

A
  • Tumour cells can ‘evolve’ through sub clonal selection allowing a growth advantage and explains heterogeneity (diversity) of cells in a tumour
  • Dependent on interaction with other tumour cells and the tumour microenvironment
  • VD
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10
Q

Carcinogenesis (formation of tumour cells
Describe the 3 possible paths for a normal cell after being made

A
  • Could become tumour cells
  • Could become proliferative and then go into either apoptosis or signals
  • Proliferation and control: Control of cell division within a tissue is particularly important in rapidly self renewing tissues when proliferation must balance cell loss
  • Apoptosis: Programmed cell death as a result of irreparable damage
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11
Q

State the signals required when appropriate

A
  • Signals: Messages,
  • Growth factors: EGF, PDGF
  • Cytokines: Growth hormones, interleukins
  • Hormones: Oestrogen
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12
Q

What are the 3 processes that regulate cell number?

A
  • Proliferation
  • Apoptosis
  • Differentiation regulate cell numbers
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13
Q

illustrate how carcinogenesis can arise from these?

A

VD

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14
Q

What is the difference between oncogenes and tumour suppressor?

A
  • Normal genes regulate growth
  • Normal genes that can be activated to be oncogenic are called proto-oncogenes
  • 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
  • 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
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15
Q

Describe what would happen if tumour suppressor mutated?

A

If tumour-suppressor genes are mutated, the normal brake mechanism will be disabled, resulting in uncontrolled growth, i.e. cancer

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16
Q

State the 3 assumptions for multistage carcinogenesis?

A
  • 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
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17
Q

State the 5 models of carcinogenesis and the main feature?

A
  • Chemical carcinogens
  • Genome instability
  • Non-genotoxic
  • Darwinian
  • Tissue organisation
  • Key thing to know that all these models overlap (non-exclusive) and must happen for carcinogenesis to occur (formation of tumour).
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18
Q

How are chemical carcinogens involved in the multi-step process of cancer?

A
  • Cancer is multi step process that includes initiation, promotion and progression
  • Chemical carcinogens can alter any of these process to induce their carcinogenic effects - DNA damage in a genotoxic (toxic) manner majority of times
  • 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
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19
Q

What are carcinogens?

A

Cancer causing substances

20
Q

State the 4 major classes of carcinogens
State examples for each

A
  • Chemical: Aromatic amines, Azo dyes, Nitrosamines, Aromatic hydrocarbons, Carbamates
  • Physical: Radiation, ionising or UV, Asbestos
  • Heritable: Predisposition - Increased likehood of disease
  • Viral: Hepatitis B + Epstein Barr
  • Many environmental hazards are risk factors for cancer, but genetics plays a part too
21
Q

Which of the 4 groups of chemical carcinogens exert their effect by DNA adducts?

A
  • DNA adducts = Segment of DNA bound to functional groups of carcinogen
  • Effects exerted by adding functional groups to DNA bases
  • Four of the major groups polycyclic aromatic hydrocarbons, aromatic amines, nitrosamines and alkylating agents
22
Q

Explain how coal tar acts as a carcinogen

A
  • Coal tar, which contains benzo[a]pyrene (BP), a polycyclic hydrocarbon
  • Benzo [a]pyrene is commonly found in cigarette smoke (together with 81 other carcinogens)!
  • BP can easily enter into cells
23
Q

State the name of the test and how it works for determining the mutagenic activity of chemicals?

A
  • Ames test: Observes whether chemicals cause mutations in sample bacteria
  • Rat liver extract -> One sample mixed with possible mutagen, other isn’t -> plate (media with minimal histidine) -> Incubate
  • If a large number of colonies present then bacteria must’ve mutated to grow without histidine
  • Revertants: Organisms which have changed back to normal from mutant form, occurs via mutation
24
Q

What is the major principle by which physical carcinogens exert their effect?

A
  • They act by imparting energy into the biological material
  • Energy -> changes in bonding of molecules -> Biological effects
25
Q

State the primary physical agent carcinogens with examples of how the lead to their effect?

A
  • Radiation is the primary agent carcinogen
  • lonizing radiation (X-rays, nuclear radiation)
  • UV radiation
  • These causes damage -> DNA breaks, pyrimidine dimers -> Failed repair -> Translocations, mutations
26
Q

State how inherited germline mutations effect differs to the cause of hereditary malignant syndrome? LAQ

A
  • Heritable carcinogens - accounts for 5% of all cancers
  • An inherited germline mutation, has an increased risk of developing certain tumours but are 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
  • A deficiency in DNA repair would cause more DNA damages to accumulate, and increase the risk for cancer
27
Q

Syndromes predisposing to cancer LAQ
State 6 examples of syndromes which predispose to cancer as a result of DNA repair defects?

A
  • ataxia telangiectasia
  • Bloom’s syndrome
  • Fanconi’s anaemia
  • Li-Fraumeni syndrome
  • Lynch type II
  • Xeroderma pigmentosu
28
Q

State 2 examples of syndromes which predispose to cancer as a result of chromosomal abnormalities?

A
  • Down’s syndrome
  • Klinefelter’s syndrome
29
Q

State the symptoms, cause (with gene) and cancer predisposition of ataxia telangiectasia (LAQ)

A
  • Symptoms: neuromotor dysfunction, dilation of blood vessels, telangiectasia = spider veins
  • Cause: Mutation in ATM gene, codes for a serine/threonine kinase that is recruited and activated by DNA breaks leading to cell cycle arrest, DNA repair and apoptosis -cell cycle arrest
  • Cancer predisposition: lymphoma, leukaemia and breast cancer
30
Q

State the symptoms, cause (with gene) and cancer predisposition of Bloom’s syndrome?

A
  • Symptoms: short stature, rarely exceed 5 feet tall, skin rash that develops after exposure to the sun
  • Cause: 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
  • Cancer predisposition: skin cancer. basal cell carcinoma and squamous cell carcinoma.
31
Q

State the symptoms, cause (with gene) and cancer predisposition of Lynch type? (LAQ)

A
  • Lynch syndrome doesn’t cause any symptoms. Sometimes the first sign that a person has LS is when the symptoms of bowel and womb cancer develop
  • Cause: Mutations in DNA mismatch repair (MMR) genes, notably MLH1, MSH2, MSH6 and PMS2.
  • Cancer predisposition: colorectal cancer
32
Q

When is the most harm caused with viruses?

A
  • They can cause a wide range of human disease
  • Most harm caused when viruses multiply inside the infected cell, kill the cell and release progeny to further infect other cells
33
Q

How do viral cells transform into tumour cells?

A
  • Viruses will disrupt normal expression
  • Favors the expression of limited number of viral genes
  • Malignant transformation of cells - cancer
  • Cell becomes infected with virus -> either causes lysis of the cell or -> leads to transformation of tumour cell
34
Q

State the key properties (3) and their features required of tumourigenic viruses?

A

Stable association with cells
- Chromosome integration
- Episome: A genetic element inside some bacterial cells, especially the DNA of some bacteriophages, that can replicate independently of the host and also in association with a chromosome with which it becomes integrated

35
Q

State the key properties (3) and their features required of tumourigenic viruses? (PART 2)

A

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

36
Q

State the key properties (3) and their features required of tumourigenic viruses? (PART 3)

A

Must evade immune surveillance of infected cells
- Immune suppression
- Viral antigens not expressed at cell surface

37
Q

What cancer is caused by the following DNA viruses? Epstein-Barr virus, Papilloma viruses, Hepatitis B and C

A
  • E-B viruses: Burkitt’s lymphoma, nasopharyngeal carcinoma
  • PV: Cervical carcinoma, warts
  • Hep. B and C: Hepatoma
38
Q

What cancers is caused by the RNA retrovirus - HTLV-I?

A
  • Adult T-cell leukaemia
  • Lymphoma
39
Q

Describe the genome instability model for carcinogenesis? (PART 1)

A

Genome instability -> increased tendency of genome alteration during cell divison -> Cancer arises from damage to multiple genes
- Known as the two hit hypothesis
- Multiple hits (mutations) are required to cause cancer
- So for example 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

40
Q

Describe the genome instability model for carcinogenesis? (PART 2)

A
  • 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.
  • VD
41
Q

Describe the non-genotoxic model for carcinogenesis?

A
  • Non-genotoxic = Not damaging to DNA directly or indirectly
  • 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.
  • A group of carcinogens that induce cancer via non-genotoxic mechanisms from mentioned above
42
Q

Name 5 carcinogens that induce cancer using non-genotoxic mechanisms?

A
  • tumour promoters (1,4-dichlorobenzene),
  • endocrine-modifiers (17ß-estradiol), •
  • receptor-mediators (2,3,7,8-tetrachlorodibenzo-p-dioxin), •
  • immunosuppressants (cyclosporine)
  • inducers of tissue-specific toxicity and inflammatory responses (metals such as arsenic and beryllium)
43
Q

Describe the darwinian model for carcinogenesis?

A
  • Carcinogenesis by Mutation and Selection-Model of Clonal Expansion
  • The role of the environment in selecting cells that have some acquired advantage
  • Clones will become diverse
44
Q

State the name of the 2 approaches behind the forces driving carcinogenesis?

A
  • Somatic mutation theory (SMT)
  • Tissue organisation field theory (TOFT)
45
Q

Describe the somatic mutation theory for the force driving carcinogenesis?

A
  • 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
  • An abnormal mass of tissue that forms when cells grow and divide more than they should or do not die when they should
46
Q

Describe the tissue organisation field theory for the force driving carcinogenesis?

A
  • 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.
  • Carcinogenesis as general deterioration of the tissue microenvironment due to extracellular causes
47
Q

State the immune response to cancer?

A
  1. The immune system will: Protect from virus-induced tumours, Eliminate pathogens, Identify and eliminate tumour cells
  2. Immune surveillance
  3. Despite this tumours can still arise- Concept of cancer immunoediting

Molecular Basis Of Disease (30 decks)

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