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SEM 4:Cellular Pathology > Mechanisms of Oncogenesis > Flashcards

Mechanisms of Oncogenesis Flashcards

1
Q

What is cancer?

A

A disease of loss of control of cell signaling pathways

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2
Q

What are the characteristics of cancer?

A
  • Abnormal cell proliferation
  • Tumor formation
  • Invasion of neighbouring normal tissue -> angiogenesis
  • Metastasis to form new tumours at distant sites
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3
Q

Carcinomas

A

Cancer occuring in epithelial cells = 85%

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4
Q

Sarcomas

A

Cancers derived from mesoderm cells - bone and muscle

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5
Q

Adenocarcinomas

A

Cancers found in glandular tissues

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6
Q

How do tumours provide themselves with nutrients?

A

Via angiogenesis - allows them to spread from the primary site to a secondary site.

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7
Q

What are the six hallmarks of most cancers?

A
  • Sustaining proliferative signaling
  • Evading growth suppressors
  • Avoiding immune destruction
  • Enabling replicative immortality
  • Tumor-promoting inflammation
  • Activating invasion and metastasis
  • Inducing angiogenesis
  • Genome instability and mutation
  • Resisting cell death
  • Deregulating cancer energetics
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8
Q

What are the two emerging hallmarks?

A

Avoiding immune destruction and reprogramming energy metabolism

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9
Q

What is the hallmark wheel show?

A

It shows everything a cell has to undergo to become a cancer cell.

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10
Q

Action of carcinogens

A

Cause alterations to the DNA - mutations in the genome

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11
Q

How do mutations cause cancer?

A
  • Tumour DNA has a lot of alterations from point mutations to deletions.
  • Over time, they accumulate representing the multi-step process that underlies carcinogenesis.
  • Accumulation only occurs after the cells defence mechanism of DNA repair has been evaded.
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12
Q

Why do some cells escape surveillance?

A

Some cells can escape surveillance because the system to block carcinogenesis is overburdened so increases the possibility of cells escaping.

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13
Q

Why is cancer more prevalent as lifespan increases?

A
  • The longer we live, the more time there is for DNA to accumulate mutations that may lead to cancer.
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14
Q

What are the mechanisms to reverse cancer?

A
  • Immune system by immune surveillance
  • Apoptosis
  • DNA repair
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15
Q

How can cancer be developed through germline mutations?

A

Obtaining a mutation in the DNA of the egg/sperm means that it is passed in the germline. This means that the offspring will inherit the mutation and increase the risk of developing cancer. However, this is rarely causes cancer immediately.

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16
Q

How are cancers developed through the somatic line?

A
  • Somatic mutations are obtained through alterations in the DNA in somatic cells.
  • During cell division, cancer will develop clonally. This is an example of a non-inheritable mutation.
  • There is a continued accumulation of mutations.
  • The tumor cells can ‘evolve’ - subclonal selection allowing a growth advantage.
  • This explains the heterogeneity of cells in a tumor.
  • It is dependent on the interaction with other tumor cells and the tumor microenvironment.
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17
Q

How does somatic cancer explain the differences in cancer genetics?

A

Two patients with same cancer will have different tumour genetics because of the difference in mutations accumulated.

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18
Q

Why does proliferation need to balance cell loss?

A

Control of cell division within a tissue is particularly important in rapidly self-renewing tissues when proliferation must balance cell loss.

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19
Q

What is the normal cell pathway?

A

Normal cells -> proliferate -> differentiate -> perform their function -> then undergo apoptosis. This process is in balance and under tight control.

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20
Q

What affects the balance of the normal cell pathway?

A

Mutations in DNA that alter the function of normal genes involved in growth, apoptosis, and differentiation can affect this balance.

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21
Q

What happens if there is an increased division at the proliferation stage and function stage?

A

Then the total cell number increases and this can cause carcinogenesis.

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22
Q

What are the two main genes that control cell growth?

A

(Proto)-oncogenes and tumour suppressor genes

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23
Q

What is an oncogene?

A

They are mutated proto-oncogenes that leads to signals that cause uncontrolled growth i.e. cancer.

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24
Q

What is a tumour suppressor gene?

A

It inhibits both growth and tumour formation. They are the brake signals in G1 phase to slow the cycle before S phase to check if any abnormalities.

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25
Q

What happens if there is a mutation in the tumour-suppressor gene?

A

The normal brake mechanism will be disabled, resulting in uncontrolled growth i.e. cancer.

26
Q

What are the 3 assumptions of multistage carcinogenesis?

A
  1. Malignant transformation of a single cell is sufficient to give rise to a tumor.
  2. Any cell in a tissue is as likely to be transformed as any other of the same type.
  3. Once a malignant cell is generated the meantime to tumour detection is generally constant.
27
Q

What are the 3 steps in cancer?

A
  • Initiation
  • Promotion
  • Progression
28
Q

What are the effects of chemical carcinogens?

A
  • Directly alter the structure of DNA
  • The unrepaired change will lead to the development of a tumor-induced by chemical carcinogens and acts in a genotoxic manner.
29
Q

Give an example of chemicals that can induce cancer.

A

Coal tar was found in 1915 to induce cancer of rabbit ears. The rabbits developed skin carcinomas.

30
Q

What are the most common classes of carcinogens?

A

Chemical, Physical, Heritable (Predisposition to cancer), Viral

31
Q

Where do the most carcinogens found and what are the 10 groups?

A

Most are chemical carcinogens - a lot are organic compounds. The ten groups are:

  • Polycyclic aromatic hydrocarbons
  • Aromatic amines
  • Azo dyes
  • Nitrosamines
  • Carbamates
  • Halogenated compounds
  • Alkylating agents
32
Q

Examples of physical carcinogens

A

Radiation - Ionising and ultraviolet

Asbestos

33
Q

Examples of viral carcinogens

A

Hepatitis B and C
Epstein Barr
Papilloma viruses
RNA retrovirus: HTLV-I

34
Q

What are the four major groups of chemical carcinogens?

A

Polycyclic aromatic hydrocarbons, aromatic amines, nitrosamines and alkylating agents

35
Q

How do the four major chemical carcinogen groups work?

A

They exert their effects by adding functional groups to DNA bases called DNA adducts. For example, coal tar which is a polycyclic hydrocarbon in the presence of microsomal enzymes (in cells) is converted into a carcinogen. This involves the transversion of G into T.

36
Q

What is the Ames test?

A

A test to observe the mutagenic ability of chemicals by observing whether they cause mutations in sample bacteria.
E.g. possible mutagen added to an extract and put onto a plate, then incubated to show a higher number of revertants suggesting the mutagen causes mutations in comparison to the control.

37
Q

Difference between chemical and physical carcinogens

A

Physical carcinogens act by imparting energy into the biological material. They do not directly alter the structure of DNA but lead to biological effects.
Energy -> Changes in the bonding of molecules -> biological effects

38
Q

What is the primary physical agent?

A

Radiation

39
Q

How does ionizing and UV radiation cause mutations?

A

Radiation causes damage and the DNA breaks or causes pyrimidine dimers. When there is failed repair, this leads to translocations and mutations.

40
Q

What are heritable carcinogens?

A
  • Occur in the germline
  • Causes cancer family syndrome
  • Usually affects genes that regulate the cell cycle, DNA repair genes, etc
  • The inability to repair cell damage leads to accumulation and increases the risk of cancer.
  • Accounts for 5% of all cancers
41
Q

DNA repair defect syndrome that predisposes to cancer

A
  • Ataxia telangiectasia
  • Bloom’s syndrome
  • Fanconi’s anaemia
  • Li-Fraumeni syndrome
  • Lynch type II
  • Xeroderma pigmentosum
42
Q

Chromosomal abnormality syndromes that predispose to cancer

A
  • Down’s syndrome

- Klinefelter’s syndrome

43
Q

Ataxia telangiectasia

A
  • Mutation in the ATM gene that codes for a serine/threonine kinase that is recruited and activated by dsDNA breaks leading to a cell cycle arrest, DNA repair and apoptosis - cell cycle arrest (p53).

Symptoms:

  • Neuromotor dysfunction
  • Dilation of blood vessels
  • Telangiectasia = spider veins
  • Causes predisposition to certain cancers: lymphoma, leukaemia and breast cancer.
44
Q

Bloom’s syndrome

A
  • Mutation in the BLM gene that provides instructions for coding a member of the RecQ helicase family to help maintain the structure and integrity of DNA. The mismatch repair genes are damaged.

Symptoms:

  • Short stature
  • Rarely exceed 5 feet tall
  • Skin rash is developed after exposure to the sun
  • Causes predisposition to certain cancers: skin cancer, basal cell carcinoma, and squamous cell carcinoma
45
Q

Lynch type

A
  • Mutations in DNA mismatch repair (MMR) genes, notably MLH1, MSH2, MSH6, and PMS2.

Symptoms:

  • LS doesn’t cause any symptoms.
  • Sometimes, the first sign a person with LS has is when the symptoms of bowel and womb cancer develop.

-Causes predisposition to certain cancers: Colorectal cancer

46
Q

How do viruses cause cancer?

A

Rather than viruses entering cells and causing lysis. It can also transform the cell into a tumour cell causing excessive cell division.

47
Q

What are the properties of tumourigenic viruses?

A
  • Stable association with cells:
    • > Chromosomal integration
    • > Episome
  • Must not kill cells:
    • > Non-permissive host (virus cannot replicate)
    • > Suppression of viral lytic cells
    • > Viral release by budding
  • Must evade immune surveillance of infected cells:
    • > Immune suppression
    • > Viral antigens not expressed at cell surface
48
Q

What cancers do the most common viruses cause?

A

Epstein-Barr virus: Burkitt’s lymphoma (infection occurs in the malarial belt), nasopharyngeal carcinoma
Papilloma viruses: Cervical carcinoma, warts
Hepatitis B and C: Hepatoma
HTLV-I: Adult T-cell leukaemia, lymphoma

49
Q

What are the five models of carcinogenesis?

A
  1. Mutational
  2. Genome instability
  3. Non-genotoxic
  4. Darwinian
  5. Tissue organization
50
Q

What is Knudson’s Hypothesis for genome instability cause for cancer?

A
  • Proposed by Carl Nordling in 1953 and then formulated by Knudson in 1971.
  • Developed by Knudson for RB (the basis for two-hit hypothesis)
  • Led to the formulation of the theory of “tumor suppressor genes” and then to the discovery of Rb1, the TSG that causes retinoblastoma when both copies are mutated.
  • He suggested that multiple hits were required to cause cancer. For example, the first mutated allele was inherited, and the second mutation would lead to cancer.
  • In the sporadic forms, both mutations had to take place and hence this could explain the difference of age at diagnosis between sporadic and inherited.
51
Q

What are non-genotoxic compounds?

A

Compounds that affect processes and function. They are characterized by an emphasis on non-genotoxic effects. Modulators of tumourigenesis that don’t alter DNA direct.

52
Q

Examples of factors that are important modulators for cancer and how they act

A

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.

53
Q

How do non-genotoxic carcinogens act?

A
  • Tumour promoters (1,4- dichlorobenzene)
  • Endocrine modifiers (17beta 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)
    High proportion of them in multiple pathways need to be altered for cancer induction.
54
Q

What type of cancers do Darwinian carcinogens cause?

A

Non-static, continually evolving tumors

55
Q

What is the Darwinian model?

A

The idea that cells will acquire changes that lead to transformation. Then tumour cells will be selected for and grow more continuously.

56
Q

How can artificial selection occur?

A

During chemotherapy, patients may become resistant. The cells will expand and grow rather than die.

57
Q

What is the somatic mutation theory (SMT) - Model 1-4?

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.
  • Single catastrophic event triggering carcinogenesis
58
Q

What is the tissue organization field theory (TOFT) - Model 5?

A
  • Carcinogenesis is primarily a problem of tissue organization.
  • Carcinogenic agents destroy the normal tissue architecture thus disrupting cell-to-cell signalling and compromising genomic integrity.
  • The DNA mutations are random and the effect, not the cause, of the tissue-level events.
  • Carcinogenesis as a general deterioration of the tissue microenvironment due to extracellular causes.
  • Exposure to carcinogens will affect cell organisation first.
59
Q

What is immune surveillance?

A

The immune system will:

  • Protect from virus-induced tumours
  • Eliminate pathogens
  • Identify and eliminate tumour cells -> Immune surveillance
  • Despite this tumours can still arise - the concept of cancer immunoediting
60
Q

What is cancer immunoediting?

A

Elimination
- The immune system is able to eradicate developing tumors

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.

Escape
- The expanding tumour populations become clinically detectable

If similar cells, multiple models may apply.

SEM 4:Cellular Pathology (13 decks)

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