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EXMD504 > 3. Oncogenes and Tumor Suppressors > Flashcards

3. Oncogenes and Tumor Suppressors Flashcards

1
Q

4 characteristics of neoplasia

A
  1. dysregulated cellular differentiation
  2. irreversible aberrant proliferation and size
  3. IMMORTAL –> can proliferate but not differentiate
  4. selective growth advantage
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2
Q

what is a selective growth advantage?

A

more cells produced than die

(ratio btwn birth and death of cells >1)

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3
Q

what is dysplasia?

A

pre-neoplastic tissue with abnormal properties (size, shape) and irregular dividing

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4
Q

how does the placenta compare to cancer?

A

placenta has same hallmarks as cancer but can even grow faster!!

most work studying angiogenesis in cancer uses placenta

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5
Q

what did researchers find in 1902 about cancer? why?

A

that cancer is genetic disease –> some chromosomes stimulate cell division while others inhibit it

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6
Q

what did researchers find in 1911 about cancer?

A

chicken grew spontaneous sarcoma –> ground up sarcoma and injected into young chickens –> sarcoma grew again

therefore this cell-free extract is oncogenic

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7
Q

what did Huebner and Todaro do in 1969?

A

made the word ONCOGENE

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8
Q

what did Martin do in 1970?

A

found that v-src drives sarcoma

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9
Q

what did President Nixon do in 1971?

A

declared war on cancer via National Cancer Act –> allowed for high-level funding of cancer

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10
Q

what did Stehelin, Bishop, Varmus find in 1976?

A

found v-src in un-infected cells so oncogenes must be in our genome as proto-oncogene then become activated and cancerous

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11
Q

what is oncogene?

A

gene that increases selective growth advantage of cancer in a cell

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12
Q

what is proto-oncogene?

A

normal gene that can become oncogene due to mutations or increased expression

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13
Q

what is tumour suppressor?

A

gene that increases selective growth advantage of cancer when INACTIVATED by mutation

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14
Q

what is amplification mutation?

A

making many copies

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14
Q

what is rearrangement mutation?

A

mutation that juxtaposes nucleotides that are normally separated

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14
Q

what are the 4 types of mutations that drive cancer?

A
  1. amplification
  2. Indel
  3. rearrangement
  4. SBS
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14
Q

what is indel mutation?

A

small insertion or deletion of a few nucleotides

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15
Q

what is SBS mutation?

A

single-nucleotide substitution

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16
Q

what is a driver gene mutation?

A

directly/indirectly gives selective growth advantage to cell

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17
Q

what is a passenger mutation?

A

mutation with no effect on selective growth advantage of cell –> accidental

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18
Q

do all cancers have the same number and types of mutations?

A

no, diff cancers have diff numbers and types of mutations

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19
Q

what gene follows a loss of heterozygosity model?

A

Rb1 tumour suppressor

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20
Q

describe the loss of heterozygosity model and the 2 types

A

gene must be “hit” on both alleles

SOMATIC: 2 somatic mutations = cancer

GERMLINE: 1 inherited germline mutation + 1 somatic mutation = cancer

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21
Q

why do both alleles need to be lost in loss of heterozygosity model?

A

if only 1 allele, the remaining allele will compensate and not get cancer –> only become predisposed to cancer

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22
Q

which 2 genes follow the haploinsufficiency model?

A

p53 and PTEN

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23
Q

what is the haploinsufficiency model?

A

a small loss of gene/1 allele lost = CANCER!

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24
Q

does haploinsufficiency model need to be germline or somatic mutation?

A

doesn’t matter

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25
Q

describe haploinsufficiency model for P53?

A

small loss of gene/1 allele missing = CANCER!

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26
Q

describe haploinsufficiency model for PTEN

A

it has OBLIGATE haploinsufficiency
- some loss of gene = CANCER
- total loss of gene is bad for cancer bc cell’s defense mechanisms will be more efficient

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27
Q

where do oncogenes work in the cell?

A

anywhere that gives them a selective growth advantage

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28
Q

what is RAS?

A

GTPase proto-oncogene that is highly mutated to be more in the GTP/active state to promote cancer

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29
Q

how is RAS inactivated?

A

NF1 tumour suppressor to make RasGDP

30
Q

how is RAS activated?

A

SOS1 oncogene to make RasGTP

31
Q

describe RAS signaling normally

A

normally cells proliferate by growth factors

  1. growth factors bind to receptor tyrosine kinase
  2. tyrosine gets phosphorylated to activate receptor
  3. RAS can activate proliferation, survival, etc.
32
Q

describe RAS signaling in cancer cells

A

doesn’t require growth factors bc RAS mutated to be in active state

33
Q

are there more tumour suppressors or oncogenes?

A

ONCOGENES

34
Q

What are the 2 domains of p53 and the function of each?

A
  1. DNA binding domain –> bind target genes
  2. oligomerization domain –> so it can become an active tetramer
35
Q

what did p53 evolve from?

A

p63/p73 ancestor gene

36
Q

what determines whether p53 induces apoptosis or survival?

A

type and intensity of signal

37
Q

what happens when there is basal p53?

A

for cell maintenance, mitochondrial function, etc.

38
Q

what happens when there is LOW stress and DNA damage?

A

TRANSIENT arrest, repair and autophagy –> cell recovers and survives

39
Q

what happens when there is HIGH stress and DNA damage?

A

senescence, apoptosis, necrosis –> cell death

40
Q

is p53 always present in human tumours? how?

A

always present, just mutated or inactivated so it cannot function properly

41
Q

what are the 3 types of p53 mutations?

A
  1. gain of function
  2. dominant negative
  3. loss of function
42
Q

what happens with a gain of function mutation of mutant p53?

A

MUTANT p53 is active to allow cell proliferation, survival, and metastasis

43
Q

what happens with a dominant negative mutation of mutant p53?

A

blocks WT p53 from binding to prevent tetramer formation

44
Q

what happens with a loss of function mutation of mutant p53?

A

mutant p53 is inactivated, allowing apoptosis/DNA repair/growth suppression

45
Q

what is the highest risk factor for getting cancer?

A

age

46
Q

why is age the highest risk factor for getting cancer?

A

multiple oncogenic events build up throughout life to develop cancer –> 1 is not enough

47
Q

describe the demonstration of oncogene collaboration using 2 types of fibroblasts (4 steps) and what this showed us

A
  1. looked at immortal fibroblasts and normal embryo fibroblasts
  2. add tumour DNA to immortalized cells –> cells were transformed and became malignant
  3. add Myc/Ras alone to normal fibroblasts –> cells were not transformed, no cancer
  4. add Myc/Ras together to normal fibroblasts –> cells were transformed and became malignant

shows that minimally need activation of 2 oncogenes

48
Q

what is the role of Myc?

A

signals cells to enter the cell cycle and prolfierate

49
Q

what happens when you have fibroblast with Myc and serum?

A

proliferation and survival –> survival bc serum has growth factors

50
Q

what happens when you have fibroblast with Myc and no serum?

A

proliferation, then apoptosis

51
Q

what happens when you have fibroblast with Myc and Ras?

A

proliferation and apoptosis is blocked, survival!! even in absence of growth factors

52
Q

based on above experiments, describe oncogene collaboration between Myc and Ras?

A

Myc induces proliferation and Ras inhibits apoptosis –> cells can grow without dying

53
Q

what happens when oncogenes are activated?

A

tumour suppressors are also activated to counteract oncogenes

54
Q

what tumour suppressor do Myc and Ras activate? what does this lead to?

A

Activate ARF –> blocks MDM to stabilize p53, allowing apoptosis

55
Q

what is ARF?

A

from alternate reading frame of INK4a locus that encodes p16

56
Q

what is senescence?

A

“to grow old”
state of irreversible growth arrest –> never re-enters cell cycle and deteriorates with age

57
Q

how does senescence prevent cancer?

A

prevents excessive/aberrant cell proliferation

58
Q

what 3 things trigger senescence?

A
  1. telomere shortening
  2. reduced ARF locus
  3. DNA damage
59
Q

do you want to prevent or induce senescence to prevent aging?

A

PREVENT bc senescent cells are what make you look old

60
Q

do you want to prevent or induce senescence to prevent cancer?

A

INDUCE

61
Q

how does Ras induce senescence?

A

Ras activates ARF which blocks MDM2 to stabilize p53 –> senescence

62
Q

what is the Hayflick limit?

A

replicating limit –> number of times a cell population will divide until cell division stops

63
Q

are all tumour cells senescent?

A

most are, but a few escape and cause carcinoma

64
Q

what is oncogene addiction?

A

when oncogenes drive cancer, cell becomes addicted and critically dependent on the oncogene

65
Q

how can we use oncogene addiction to find targeted therapy?

A

inhibit this specific function = cell death

66
Q

3 models for oncogene addiction

A
  1. genetic streamlining
  2. oncogenic shock
  3. synthetic lethal
67
Q

what is genetic streamlining?

A

cells streamline 1 pathway and inhibit other pathways –> if the remaining pathway is inhibited, cell dies

68
Q

what is oncogenic shock?

A

pro-survival pathway dominates pro-apoptosis pathway but blocking this = apoptosis

69
Q

what is synthetic lethal?

A

loss of 1 pathway allows for survival but loss of both = apoptosis

70
Q

what is an example of targeted therapy?

A

kinase inhibitors

71
Q

what are kinase inhibitors used for? how do they work?

A

To treat chronic myeloid leukemia with Philadelphia chromosome mutation –> selectively kills cancer cells

72
Q

what are the 2 ways to develop resistance to targeted therapy?

A
  1. vertical resistance
  2. horizontal resistance
73
Q

what is vertical resistance?

A

cells activate something downstream in pathway being blocked

74
Q

what is horizontal resistance?

A

drug works on intended pathways but cell activates alternate pathway that is not targeted

75
Q

what is the challenge with treating cancer?

A

cancer is big and heterogenous –> even if you know initiating mutation, there are many clones and oncogene addictions

76
Q

since a tumour is heterogenous, can you use many drugs to target the different parts?

A

can lead to many side effects

EXMD504 (12 decks)

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