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Cellulaire Oncologie > AMC-HC 3 + 4: Multi-step & Maintainance > Flashcards

AMC-HC 3 + 4: Multi-step & Maintainance Flashcards

dag 2

1
Q

How long does it take for most cancers to develop? (rough estimation)

A

Years/decades

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2
Q

Because of the late onset of cancer, curing it averagely has a minor effect on ….

A

life expectancy

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3
Q

Risk of death to cancer

A

Incedence = age^4-7
> 5-8 independent events must occur for cancer to form

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4
Q

Transformation to some degree does always occur. True or False?

A

True, at a later age

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5
Q

It is possible for different tumor progression stages to …

A

Coexist in the same tissue

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6
Q

Which treatment most effectively reduces risk of disease with cancer?

A

Surgical removal of early-stage lesions (if detected early-stage)

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7
Q

Increasing neoplastic phenotypes correlate with ….

A

Increasing number of altered genetic loci

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8
Q

Tumour stimulating genetic alterations

A

Proto-oncogene activation and tumor-suppressor gene inactivation

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9
Q

The number of inactivated tumor suppressor genes </> (?) number of activated oncogenes in human tumor cell genome

A

>

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10
Q

Loss of heterozygosity (LOH)

A

Loss of one of the both alleles of a gene which can expose a faulty allele if it was masked (or the second allele was already broken) > losing the functionality of both alleles.
Only if the person was already heterozygous for the e.g. tumor suppressor gene (after a first hit)

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11
Q

Cancer cells often underwent multiple gene …

A

LOH

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12
Q

Chromosome translocation is a … for cancer

A

inducer

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13
Q

Why does a single mutation in a gene or loss or gain of function of the gene generically not lead to carcinogenesis?

A

The entire pathway of proliferation/growth/checkpoint is not effected (inactivated or overexpressed). Often, multiple gene routes can lead to a similar outcome (reaction pathways)

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14
Q

Why does tumor progression resemble evolution?

A

-Survival of the fittest
-Competition between cancer cells for limited resources
-The best adaptes cancercells survive and proliferate > advantageous traits.
-Clonal evolution > clonal expansion of the strongest cells after independent mutations

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15
Q

How does genome instability increase with tumor progression?

A

The mutation rates increase with tumor progression

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16
Q

Why do different subclones exist within the same tumor?

A

The selection can’t keep up with genetic diversification

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17
Q

How are distinct subclones able to coexist and help each other?

A

Costimulation with growth factors which they secrete (paracrine signaling and autocrine signaling)

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18
Q

Plasticity

A

the adaptability of an organism to changes in its environment or differences between its various habitats.

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19
Q

Which plasticity adds another layer of complexity to tumor progression?

A

Epigenetic plasticity

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20
Q

Transformation requires at least … mutant genes

A

2
> several thousand mutated ras oncogenes are created every day
> truly normal primary cells are resistant to single-hit transformations

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21
Q

Why are human fibroblast cells diffucult to transform?

A

Passaged human cells become senescent (non-proliferative)

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22
Q

Peto’s Paradox: The connection

A

Within one species, cancer risk and body size are positively correlated (more cell proliferation)

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23
Q

Peto’s Paradox: the counterpoint

A

Larger organisms have bigger and slowly dividing cells with a lower energy turnover which reduces the risk of cancer initiation.
> there are large differences between species

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24
Q

Mitogen

A

Enhances mitosis

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25
Q

Mutagen

A

Enhances mutations

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26
Q

Non-mutagenic or toxic agents which promote tumorigenesis

A

-Tabacco smoke > genotoxic chemicals > initiating agent
-Alcohol: weak mutagen but very toxic to epithelial cells > cells die > repair needed > causes proliferation and enhances risk of tumorigenesis

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27
Q

Mitogenic agents which promote tumorigenesis

A

-Steroid hormones promote cell growth > estrogen and progesterone stimulate proliferation of cells in reproductive tissue in menstrual cycle

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28
Q

The more mentrual cycles a female undergoes, the higher …

A

the risk of breast cancer (inducing cell proliferation)

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29
Q

Which kind of drugs reduce cancer risk?

A

Anti-inflammation drugs

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30
Q

Why is cell proliferation essential for tumor progression?

A

For increasing the number of mutations which the cells are carrying.

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31
Q

Why does cell proliferation (cell divisions) lead to new mutations?

A

DNA replications can lead to new mutations

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32
Q

Important: A carcinogen is not always a …

A

Mutagen, it can also be a mitogenic agent which doesn’t damage the DNA, but induces mitosis.

33
Q

Complete carcinogens

A

Initiate and promote tumorigenesis

34
Q

How do the cells of the gastrointestinal lining minimalise the accumulation of mutations?

A

Paneth cells at the bottom of the crypt. rapidly dividing stem cells between the Paneth cells. In the zone of proliferation until pushed out of the crypt into the zone of differentiation and they are moved to the top of the villus and released into the lumen of the small intestine to be removed by poop. > discarded from the body.

35
Q

Do the stem cells in the bottom of the crypts divide a lot?

A

No, after asymmetrical division, one daughter cell becomes a Transit-amplifying cell which divides a lot (pushing the cells before it to the villus). When in the zone of differentiation, only two cell divisions are needed to get a highly differentiated cell (which is dicarded very fast)

36
Q

How are the stem cells in the bottom of the crypt protected against mutations?

A

-Not replicating a lot
-Being localized in the bottom of the crypt, away from the hazardous intestine lumen.
- Asymmetric stem cell division: only one daughter cell stays a stem cell, the other differentiates and is pushed out

37
Q

Risk with the intestinal stem cells

A

When there is a shortage of stem cells, the transit-amplifying cells (which underwent a lot of divisions) are able to de-differentiate and switch to a stem cell
> risk of a stem cell with higher rate of transformation

38
Q

Cytotoxic agents

A

Kill (stem) cells

39
Q

Correlation cancer risk and stem cells

A

Number of stem cell division in a given tissue is positively correlated to lifetime risk of cancer in that tissue

40
Q

Protective mechanisms of stem cells

A

-Apoptosis: intestinal stem cells with DNA lesions will undergo apoptosis and not attempt repair
-Drug pumps: stem cell pumps out certain drugs more effectively than differentiated cells (because of high expression of Mdr1 (multi-drug resistance 1)
> pumping out the dangerous stuff

41
Q

Cancer stem cells and apoptosis

A

Cancer stem cells have a reduced potential for apoptosis and a increased DNA repair capacity.

42
Q

Proofreading

A

-By DNA polymerase
-3’ -> 5’ exonuclease activity when errors occur
-Low error rate of polymerases

43
Q

Mismatch repair

A

-Not part of DNA polymerase, but repairs are done during replication
-MMR enzymes monitors recently synthesized DNA and recognize altered DNA structures like loops or nicks
-The enzymes make a nick downstream and excise a strand fragment, DNA polymerases and ligases repair the gap

44
Q

Which enzymes are involved in MMR

A

-DNA damage detection enzymes
-nucleases
-polymerases
-ligases

45
Q

Does the mechanism of proofreading and mismatch repair prevent any mutations from arising?

A

No: the mechanism still allows evolutionary mutations, but the risk of carcinogenesis is decreased.

46
Q

Endogenous processes for mutagenesis

A

Depurination, depyrimidation, deanimation of bases

47
Q

Causes of endogenous mutagenesis

A

-Oxidation by reactive oxygen species (ROS) with metabolic by-products
> induce single and double stranded
> apurinic and apyrimidinix sites (abasic sites)
-Base mispairing during replication

48
Q

Exogenous agents as a source for mutagenesis

A

-Ionizing radiation
-UV-light
-Alkylating agents
-Cellular processes
-Alcohol
> infrequent

49
Q

Ionizing radiation like X-rays as exogenous agent

A

Can hit DNA directly but mostly strips the electrons from watermolecules > creating ROS > creating SSBs (single strand breaks) and DSBs

50
Q

UV-light as exogenous agent

A

Is ubiquitous
-covalent bonds between adjacent pyrimidine bases create pyrimidine dimers

51
Q

Why does skin cancer occur a lot in Australia

A

Not very well pigmented humans live with a lot of UV radiation which increases the incidence of skin carcinomas

52
Q

Alkylating agents as exogenous agent

A

Lead to a loss of purine or pyrimidine bases

53
Q

Cellular processes as exogenous agent

A

Convertion of procarcinogens to carcinogens > formation of DNA adducts by for example tabacco smoke

54
Q

Alcohol as exogenous agent

A

Can be a mutagen, but not directly. Toxic effect kills cells, thereby inducing proliferation and chance on DNA damage during replication

55
Q

Cell protection of DNA

A

-Physical shielding (like melanine)
-ROS scavangers (vitamin C, bilirubin, urate) > react with ROS
…[]

56
Q

Base excision repair (BER)

A

-Cleave the bond linking the modified base to the deoxyribose sugar
-Mostly repair non-helix distorting lesions

57
Q

Nucleotide-excision repair (NER)

A

-Repair helix-distorting lesions
-Removes the entire nucleotide and repairs the gap
-Transcriptional coupled repair or global coupled repair
…..[]

58
Q

Xinoderma pigmentosum

A

A disease which leads to a 2000-fold increased risk of skin cancer before the age of 20 > even without being in contact with the skin, skin carcinomas will appear

59
Q

Double strand breaks repair

A

-Homologous recombination
-Non-homologous end joining

60
Q

Where are DSBs localized

A

Arise at stalled replication forks and can be induced by ionizing radiation

61
Q

Homologous recombination (HR)

A

-Active in S and G2 phase > second copy of the same chromosome is available and is used as a scaffold to repair the DNA strands at the site of the break
-Involves BRCA1 and BRCA2 mutations
-Used in genome editing

62
Q

Non-homologous end joining (NHEJ)

A

-Takes the two end and ligates them together > loss of bases > deletion and possibly frameshift
-Quick and dirty
-No way to perserve perfect information at the break site

63
Q

Changes in karyotype often occurs in tumor cells. What does this mean?

A

Changes in number and/or structure of chromosomes

64
Q

What are changes in chromosome structure called?

A

Chromosomal aberrations

65
Q

Examples of chromosomal aberrations

A

Deletions, amplifications, translocations

66
Q

What kind of aberrations are detected in many tumor types?

A

recurrent aberrations

67
Q

What can these recurrent aberrations lead to?

A

Loss of heterogeneity (LOH)
> can expose a faulty gene if it was dominated by the healthy allele

68
Q

Chromothripsis

A

Localized, massive chromsome fragmentations, followed by multiple rejoining between resulting fragments

69
Q

Polyploidy

A

Due to errors in mitosis, duplication of the entire chromosome set > haploid, triploid or tetraploid state

70
Q

Aneuploidy

A

Changes in number of individual chromosomes > caused by mitotic errors or errors in DSB repair

71
Q

Chromosome instability

A

A state of susceptibilty to change in chromosome number (in >80% of carcinomas)

72
Q

Are chromosomal instability and chaotic karyotypes required for transformation?

A

No

73
Q

Can chromosome instability lead to full transformation and stimulation of initial mutations?

A

Yes

74
Q

Chromosome instability is cancer dependent. Name the scenarios for solid tumors andf hematopoietic tumors

A

-Solid tumors: characterized by instability
-Hematopoietic tumors: cells often have diploid karyotypes with one or two translocations

75
Q

What is the most common cause of changes in chromosome number?

A

Mitotic missegregation of chromosomes

76
Q

Nondisjunction

A

both sister chromatids in a pair are pulled to one centrosome and end up in the same daughter cell

77
Q

Merotely

A

A single chromatid is pulled by both centrosomes
> often in cancer cells
> result of disfunctional centrosomes

78
Q

Genetic instability in cancer

A

-Dysfunction of repair mechanisms make cancer cells vulnerable
-Allows cancer to accumulate genomic changes which are needed for transformation > accelerated evolution

Cellulaire Oncologie (14 decks)

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