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MBD > Mechanisms of oncogenesis > Flashcards

Mechanisms of oncogenesis Flashcards

1
Q

What is the incidence of cancer? and mortality statistics

A

Ever 2 mins someone in the UK is diagnosed, 359,960 new cases of cancer in UK 2015

Mortality: every 4 minutes someone in UK dies of cancer

Survival: half of people diagnosed survive 10 years or more

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2
Q

How can cancer be prevented/reduced risk?

A

Smoking

Obesity and weight, small changes you can stick with help to lose weight

Hormones changes in our hormone levels can affect the risk of cancer

Sun and UV, UV light from sun and sunbeds cause skin cancer

Physical activity, around 3400 cases can be prevented by keeping active

Diet and healthy eating, eating healthy balanced diet reduces risk of cancer

Inherited genes, some inherited faulty genes increase your risk of cancer

Infections and HPV, some infections increase risk of cancer

Air pollution and radon, although exposure ti air pollution can be linked to cancer, the UK risk is low

Work place causes of cancer

Alcohol increases risk of cancer

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3
Q

What is cancer?

A

Group of diseases characterised by

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

85% of cancers occur in eptihelial cells - carcinomas

cancers in mesoderm cells (bone and muscle) - sarcomas

cancers found in glandular tissues - adenocarcinomas

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4
Q

What are the hallmarks of cancer?

A

Evading growth suppressors

Avoiding immune destruction

Enabling replicative immortality

Tumour promoting inflammation - 2011

Activating invasion and metastasis

Inducing angiogenesis

Genome instability and mutation - 2011

Resisting cell death

Deregulating cellular energetics

Sustaining proliferative signalling

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5
Q

Why is cancer more prevalent as lifespan increases?

A

Accumulation of mutations over time represents the multi-step process that underlies carcinogenesis.

accumulation occurs after cells defence mechanism of DNA repair has been evaded

the longer we live, the more time there is for DNA to accumulate mutation sthat may lead to cancer

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6
Q

What two types of cells do mutations affect?

A

In egg or sperm = germ line mutations

  • Can be passed onto offspring
  • increased risk of developing cancer

In somatic cells

  • non-heritable
  • but can be passed onto daughter cells by cell division
  • constitute almost all mutations in tumour cells
  • only one of cells in body need to be transformed to create tumour
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7
Q

What signals does cells proliferate in response to?

What counter balances this?

A

1.

  • Messages
  • Growth factors EGF and PDGF
  • Cytokines, growth hormone
  • Interleukins
  • Hormones
  1. Apoptosis, programmed cell death as a result of irreparable damage.
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8
Q

Why do you need to regulate cell prolieration and death?

A

Regulation needed as mutations in DNA that alter function of normal genes involved in growth, apoptosis and differentiation affects balance of cell proliferation and apoptosis.

Can lead to tumour e.g mutations in genes regulating processes, cells continue to divide

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9
Q

What is an oncogene?

A

Normal genes regulate growth, these can be activated to be oncogenic - proto-oncogenes

Oncogene is a proto-oncogene that has been mutated in a way that leads to signals that cause uncontrolled growth ie. cancer

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10
Q

What are tumour suppressor genes?

A

Tumour suppressor genes inhibit both growth and tumour formation.

Act as braking signals during G1 of cell cycle to stop/slow cell cycle before S phase.

If tumour suppressor genes are mutated, normal brake mechanism is disabled, resulting in uncontrolled growth ie. cancer

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11
Q

What are the 3 assumptions about 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 mean time to tumour detection is generally constant

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12
Q

What is model 1 mechanism for cancer?

A

Model 1, Chemical carcinogens

Cancer is multi-step process, includes initiation, promotion and progression

Carcinogens can alter any of these processes to include carcinogenic effects

chemical carcinogens can induce DNA damage and act in a genotoxic manner.

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13
Q

What are the classes of carcinogens and examples of each of them?

A

Chemical: 10 groups:

  • Polycyclic aromatic hydrocarbons
  • Aromatic amines
  • Azo dyes
  • Nitrosamines
  • Carbamates
  • Halogenated compounds
  • Alkylating agents

Physical

  • Radiation – ionising, ultraviolet
  • Asbestos

Heritable

  • Predisposition

Viral

  • Hepatitis B
  • Epstein Barr
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14
Q

How do polycyclic aromatic hydrocarbons, aromatic amines, nitrosamines and alkylating agents exert their effects?

A

Adding functional groups to DNA bases, called DNA adducts.

e.g benzo[a]pyrene, polycyclic hydrocarbon, on its own isn’t carcinogenic but gets converted from pro-carcinogen to carcinogen via microsomal enzymes, causes G to T transversions

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15
Q

Wat is the Ames test? How is it conducted?

A

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

Take bacteria, e.g rat liver extract mushed up with salmonella strain that only grows in presence of histidine

Plate mixture on an agar plate lacking histidine

Overnight incubation

Should have very few colonies on the plate, only due to natural reversion you may get some

If you add chemical in question to it

plate it and you get lots of colonies suggests there has been change in bacteria and they can now grow in the absence of histidine

Confirms compound is carcinogenic

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16
Q

How do physical carcinogens work?

A

By imparting energy into biological material, altering bonding of molecules.

e.g radiation causes DNA breaks and pyrimidine dimers, but can be repaired.

but if you have mutations in DNA damage repair mechanisms there is failure to repair, leading onto more changes - translocations and mutations

17
Q

What syndromes predispose to cancer?

A

Cancer repair defects

  • Ataxia telangiectasia
  • Bloom’s syndrome
  • Fanconi’s anaemia
  • Li-Fraumeni syndrome
  • Lynch type II
  • Xeroderma pigmentosum

Chromosomal abnormalities

  • Down’s syndrome
  • Klinefelter’s syndrome
18
Q

What is ataxia telangiesctasia? What cancers does it predispose to?

A

Neuromotor dysfunction, dilation of blood vessels, telangiectasia = spider veins

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

Cancer predisposition: lymphoma, leukaemia and breast cancer

19
Q

What is bloom’s syndrome?

A

Short stature, rarely exceed 5 feet tall, skin rash that develops after exposure to the sun

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

Cancer predisposition: skin cancer, basal cell carcinoma and squamous cell carcinoma

20
Q

What is lynch type?

A

Doesn’t cause symptoms, first sign a person has LS is when symptoms of bowels and womb cancer develop

mutations in DNA mismatch (MMR) genes, notably MLH1, MSH2, MSH6 and PMS2

cancer predispostion: colorectal cancer

21
Q

What properties do tumorigenic viruses require?

A

Stable associated with cells

  • Chromosomal integration
  • Episome

Must not kill cells, hence often that viruses hijack machinery in host cell for its benefit

  • Non-permissive host (virus cannot replicate)
  • Suppression of vital lytic cycle
  • Viral release by budding

Must evade immune surveillance of infected cells

  • Immune suppression, shouldn’t be picked up by immune system. Hence you find in latent phase allow virus to survive within host being undetected by immune system
  • Viral antigens not expressed at cell surface
22
Q

Examples of viruses associated with human cancer

A

DNA viruses

  • Epstein-Barr virus (doesn’t give symptoms) – Burkitt’s lymphoma, nasopharyngeal carcinoma
  • Papilloma viruses – cervical carcinoma, warts
  • Hepatitis B and C – hepatoma

RNA retroviruses

  • HTLV-I  -adult T-cell leukaemia, lymphoma
23
Q

Explain model 2, genome instability

A

Knudson performed statistical analysis on cases of retinoblastoma of two types, inheritedand sporadic type

Suggested that multiple hits were required to cause cancer

e.g if the first mutated allele was inherited, the second mutation would lead to cancer.

In sporadic forms of the tumour both mutations had to take place and hence sporadic form tumour developed later in life than inherited

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

24
Q

Explain model 3, non genotoxic

A

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

Several important modulators of cancer risk (diet, obesity, hormones and insulin resistance)

don’t act through structural change in DNA but through functional changes including epigenetic events

Group of carcinogens that induce cancer via non-genotoxic mechanisms.

Non-genotoxic carcinogens have been shown to act as:

  • Tumour promoters (1,4-dichlorobenzene)
  • Endocrine-modifiers (17B-estradiol)
  • Receptor-mediators (2,3,7,8-tetrachlorodibenzo-p-dioxin)
  • Immunosuppressants (cyclosporine) or
  • Induces of tissue-specific toxicity and inflammatory responses (metals such as arsenic and beryllium)

Although little is known about this group of carcinogens, it is known that in high proportion of them, multiple pathways need to be altered for cancer induction

25
Q

Explain model 4, Darwinian

A

Carcinogenesis by mutation and selection model of clonal expansion

the role of the environment in selecting cells that have some accquired advantage

cells acquire mutations due to carcinogens

cells will have mutations in mechanisms driving cell growth

leads to transformation

single tumour cell continually evolving

eventually end up with more tumour cells

can also apply selection e.g patients undergoing chemotherapy, patients end up resistant to treatment due to selecting cells that can outgrow chemotherapy

26
Q

Explain model 5, tissue organisation

SMT theory

A

Tissues are groups of cells with similar function: epithelial, connective muscle and nervous

Somatic mutation theory SMT

  • Cancer is derived from single somatic cell that has successively accumulated multiple DNA mutations
  • mutations damage genes which control cell proliferation and cell cycle
  • thus according to SMT neoplastic lesions are the result of DNA-level events
27
Q

Explain tissue organisation field theory TOFT (model 5)

A

Carcinogenesis is primarily a problem of tissue organisation

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

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

28
Q

How does the immune system respond to cancer?

A
  • Protect from virus-induced tumours
  • Eliminate pathogens
  • Identify and eliminate tumour cells

Immune surveillance.

29
Q

What is cancer immunoediting?

A

Despite immune surveillance tumours can still arise.

Normal cells exposed to carcinogens and transformed, have tumour antigens on surface, immune system picks these up.

Elimination

  • immune system eradicates developing tumours but is not 100% and some cells may enter equilibrium

Equilibrium

  • When incomplete removal is present tumour cells remain dormant and enter equilibrium. immune system exerts 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 (longest of the phases, around 20 years)

Escape

  • expanding tumour populations become clinically detectable, here you have cancer progression
30
Q
A

MBD (21 decks)

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