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BIOM 3500 - Midterm 3: The Cell Cycle > Lecture 21 - Cancer > Flashcards

Lecture 21 - Cancer Flashcards

1
Q

What is a tumour?

A

A group of over-poliferating cells

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2
Q

What is a key characteristic of benign tumours?

A

They’re not able to invade neighbouring tissues and therefore are not cancerous

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3
Q

What is cancer?

A

A malignant tumour which can invade nearby tissues

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4
Q

What is a metastatic tumour?

A

Cancer that spreads to secondary sites - via travel of cancer cells through lymph or blood system

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5
Q

Cancer classifications: Carcinomas

A
  • Arise from epithelial cells
  • Most common and most dangerous cancers in humans
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6
Q

Cancer classifications: Sarcomas

A

Arise from connective tissue or muscle

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7
Q

Cancer classifications: Leukemias and lymphomas

A

Arise from white blood cells

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8
Q

What can general cancer classifications be further characterized by?

A

Specific cell type affected
- E.g., melanoma, small-cell lung carcinoma

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9
Q

What are the original theories on the origins of cancer?

A
  • Chemicals and other agents that damage DNA (mutagens) as causes of cancer
  • Viruses as causes of cancer
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10
Q

Gene mutations as causes of cancer: 1775

A

First study linking chemical exposure to cancer
- Observation that chimney sweeps have high incidences of cancer

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11
Q

Gene mutations as causes of cancer: 1918

A

First experimental evidence that chemical agents can cause cancer in animals
- Tar exposure leads to increased cancer incidence (in rabbits)

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12
Q

Gene mutations as causes of cancer: 1920s

A

Humans that work with radiation have high incidence of cancer

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13
Q

Gene mutations as causes of cancer: 1930s

A

Chemicals and radiation result in mutations in DNA
- Carcinogens = mutagens

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14
Q

Gene mutations as causes of cancer: 1960s

A

In vitro transformation of normal cells to cancer cells using chemical mutagens

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15
Q

What happens to normal cells grown in culture from a monolayer?

A
  • Cells that lose contact with plate surface undergo apoptosis - anchorage dependence
  • Cells divide about 30 times before replication-induced senescence or they stop dividing after reaching a uniform monolayer - contact inhibition
  • Cells require added serum to survive and grow
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16
Q

What happens when normal cells are turned into cancer cells in vitro by adding chemicals and radiation?

A
  • Loss of anchorage dependence
  • Loss of contact inhibition
  • Ability to divide indefinitely - immortality
  • Reduced requirement for added serum
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17
Q

What was the first characterized tumour virus?

A

Rous sarcoma virus - RSV

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18
Q

What did characterized RSV lead to?

A

The model that cancer is caused by infectious agents

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19
Q

What kind of virus is RSV?

A

Retrovirus

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20
Q

In the 1960s, what was discovered about RSV?

A

Leads to
- Loss of anchorage dependence
- Loss of contact dependence
- Ability to divide indefinitely - immortality
- Reduced requirement for added serum

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21
Q

Viruses as causes of cancer: 1910

A

RSV virus causes chicken sarcoma

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22
Q

Viruses as causes of cancer: 1960s

A

Purified RSV can cause cell transformation in vitro

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23
Q

Viruses as causes of cancer: 1960s

A

Several unrelated viruses found to also cause cancer

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24
Q

Viruses as causes of cancer: 1968

A

Tumour virus DNA integrates into host chromosomal DNA

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25
Q

Viruses as causes of cancer: 1974

A

RSV transformation ability linked to a single viral gene - later named src

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26
Q

At what rate does murine leukemia virus (MLV) cause cancer compared to RSV?

A

MLV causes slow onset of cancer whereas RSV causes cancer quickly

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27
Q

What does the RSV src gene do?

A

Confers transformation ability to cells

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28
Q

What was identified in tumour-causing viruses in the 1970s?

A

Oncogenes

29
Q

In the late 70s to mid 80s, what was searched for and not found?

A

“Viral origins of cancer”
- Proponents search for viruses in human tumours

30
Q

What small percentage of human cancers appear to have viral origins?

A

Cervical cancer and some sarcomas

31
Q

After chemical mutagens were identified to cause cancer (60s to 80s), what was not clear?

A

The understanding of how mutations could cause cancer

32
Q

Unification of the viral and genetic origin of cancer theories: 1978

A

Varmus and Bishop identified a gene that is very similar to the viral src gene - in the genome of the infected chicken
- Even uninfected chickens have this gene
- Even animals that cannot be infected by RSV have a src gene

33
Q

What experiment was carried out once it was discovered that the src related gene was also found in uninfected, non-transformed cells from other vertebrates including humans

A

A gene was transformed from RSV in a gene that originated in the host (chicken) and got incorporated into the virus at some point to give the virus a selective advantage and allow it to be retained in the viral genome

34
Q

What did the src-related gene help with determining in terms of the cause of cancer?

A

Cancer is caused by the overexpression of specific genes that originated from our own genome (proto-oncogenes), that are carried in viruses (viral oncogenes)

35
Q

How may slower-acting tumour viruses act?

A

By inserting near and causing high-level expression of host oncogenes which would only occur by chance after many rounds of cell infection

36
Q

What was suggested for how chemical mutagens cause cancer?

A

Idea that it’s caused by converting proto-oncogenes into oncogenes

37
Q

What transfection was done in determining gene mutations as the main cause of cancer?

A

1) Mix genomic DNA with calcium phosphate
2) Add to cells
3) DNA goes into cell and can be maintained for several generations as a extrachromosomal DNA (transient transfection), or incorporated into chromosomes (stable transfection)
4) If DNA includes a gene, it will be expressed

38
Q

Gene mutations as main cause of cancer: 1972

A

Development of transfection technique to introduce DNA into cells
- DNA can integrate into host cell genome and genes can be expressed

39
Q

Gene mutations as main cause of cancer: 1981

A

Use transfection method to identify the genes that are altered by mutagen to cause cancer

40
Q

How were human and mouse cells used in an experiment to determine that gene mutations are the main cause of cancer?

A
  • Transfect normal mouse cells with DNA from a human tumour
  • 1 of the transfected cells is transformed into a cancer cell
  • These transformed cells can be injected into a healthy mouse –> tumour formation
41
Q

Gene mutations as main cause of cancer: 1982

A

Robert Weinberg
- Genomic DNA library from these transfected mouse cells
- Identify a clone that contains human DNA (contains human-specific Alu sequence)
- This clone contains Ras gene (mutation ras-V12 in carcinoma ras gene which makes the protein constitutively active)

42
Q

What can oncogenes be present in when amplified?

A

Up to hundreds of copies in cancer cells

43
Q

How are oncogenes activated in cancer?

A

1) Viral copy of oncogene expressed at high levels by viral enhancers
2) Virus integration near a proto-oncogene leading to high-level expression of the neighbouring gene by viral enhancers
- Chemical mutagens - translocation - oncogene translocates near the enhancer for a highly expressed gene
- Chemical mutagens - point mutation - leading to constitutively activated form of the protein
- Chemical mutagens - gene amplification

44
Q

What is the purpose of cell fusion experiments?

A

Fusing a cancer cell with a normal cell to see if the cancer was caused by oncogenes
- The fusion cell should appear cancerous but in many cases appear normal

45
Q

What did the results of fusion experiments indicate?

A
  • Argued that something present in normal cells can rescue the fusion cell
  • Perhaps normal cells have genes that protect them from getting tumours (and these genes are inactivated in cancer cells)
46
Q

Retinoblastoma - Knudson’s two-hit hypothesis. Normal, health individual

A

Occasional cell inactivates one of its two good Rb genes
- No tumour

47
Q

Retinoblastoma - Knudson’s two-hit hypothesis. Hereditary retinoblastoma

A

Inherited mutant Rd gene; occasional cell inactivates its only good Rb gene copy; excessive proliferation leading to retinoblastoma
- Most people with inherited mutation develop multiple tumours in both eyes

48
Q

Retinoblastoma - Knudson’s two-hit hypothesis. Honheredirary retinoblastoma

A

Occasional cell inactivated one of its two good Rb genes; the second copy of Rb is rarely inactivated in the same line of cells; excessive cell proliferation leading to retinoblastoma
- Only about 1 in 30,000 normal people develop one tumour in one eye

49
Q

How can loss of heterozygosity occur?

A
  • Genetic changes: nondisjunction, chromosome loss, chromosome duplication, mitotic recombination, gene conversion, deletion, point mutation
  • Epigenetic gene silencing
50
Q

What is epigenetic gene silencing?

A

Somatically inherited chromatin modifications

51
Q

What do Rb and INK4 have in common?

A

Both genes are tumour suppressors necessary for preventing premature entry into S-phase

52
Q

What mutation do those with Li-Fraumeni syndrome have?

A

p53

53
Q

What are most familial cancers caused by?

A

Inheritance of recessive mutant alleles of tumour suppressor genes
- Retinoblastoma - Rb
- Li-Fraumeni syndrome - p53
- neurofibromatosis I - rasGAP
- Familial melanoma - INK4A

54
Q

Why do elephants rarely get cancer?

A

Although elephants live almost as long as humans (up to 70 years) and have 100x more cells than humans, their cancer incidence is 2 to 4x less than humans because their cells are more prone to apoptosis than other cells
- Elephant genome has 20 copies of the p53 gene

55
Q

Is cancer caused by the activation of oncogenes or by the loss of tumour suppressors?

A
  • RSV and transfection experiments show that a single oncogene can cause cancer, however, the resulting tumour also has many other mutations, including loss of tumour suppressor genes
  • Familial cancers result from loss of a single tumour suppressor, however, the resulting tumour also has mutations in other tumour suppressor genes and mutations in oncogenes
56
Q

What does cancer progressino require?

A

Multiple genetic events

57
Q

What do most cancers derive from?

A

Clones
1) A single cell that acquires a somatic mutation that helps promote (benign) tumour formation
2) This cell produces a clone of daughter cells, one of wich acquires a new mutation that further promotes tumour formation

58
Q

Is the loss of a single tumour suppressor or gain of a single oncogenic mutation sufficient to cause cancer?

A

No, multiple somatic mutations must accumulate to produce cancer

59
Q

What are mutations that contribute to the progression of cancer called?

A

Driver mutations

60
Q

What does genomic instability facilitate?

A
  • A rapid acquisition of new mutations - increasing the likeliness of cancer developing
  • Failure to arrest the cell cycle in response to double-stranded DNA breaks
61
Q

No matter what genomic instability occurs, what must happen in all cases?

A

Checkpoint pathways must be inactivated to allow these cells to survive and keep dividing

62
Q

What do DNA breaks activate?

A

A checkpoint that arrests in cell division

63
Q

What causes genome rearrangements?

A

Genome instability

64
Q

What did whole genome sequencing of cancers reveal?

A

Cases where a single chromosome has incurred massive damage, while other chromosomes are largely unaffected
- Evidence suggests that this can occur almost instantly, within a single cell division

65
Q

What does chromothripsis typically result from?

A

One or two chromosomes being isolated in a micronucleus (e.g., failure to segregate at anaphase)
- Cytoplasmic enzymes that damage DNA can get into micronucleus
- Micronucleus lacks DNA repair proteins
- DNA replication is not regulated
- Single chromosome is rapidly pulverized and may instantly lead to alteration of oncogenes and tumour suppressors leading to cancer

66
Q

What kind of genes being lost can lead to increased genome instability?

A

Loss of DNA repair genes
- E.g., BRCA1, ATM

67
Q

What kind of genes being lost allows cells to survive despite genome instability?

A

Loss of DNA damage checkpoint genes
- E.g., ATM, ATR, Chk1, Chk2, p53, pro-apoptotic genes

68
Q

What can the loss of SAC lead do?

A

Microtubule formation and genome instability via chromotripsis

69
Q

What are Hanahan and Weinberg’s hallmarks of cancer?

A

Cancer results from the accumulation of mutations that give the cell the following capabilities:
- Self-sufficient in growth signals and/or insensitivity to anti-growth signals (e.g., ras activation, Rb loss)
- Evading apoptosis (e.g., Bcl2 overexpression, -53 loss)
- Limitless replicative potential (e.g., telomerase overexpression, Chk2 loss)
- Angiogenesis
- Metastasis
- Avoiding immune response
- Genome instability - (e.g., Loss of p53 or ATM)
*The order of acquiring these capabilities is not important but once genome instability is acquired, other mutations arise faster

BIOM 3500 - Midterm 3: The Cell Cycle (7 decks)

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