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PBL SEM 4 > bowel cancer I and II > Flashcards

bowel cancer I and II Flashcards

1
Q

what are the majority of colorectal cancers?

A

sporadic = no family history

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2
Q

what is FAP?

A
  • familial adenomatous polyposis = 1%
  • 100s of polyps line luminal surface of the colon - at low but predictable frequency, develop into carcinoma
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3
Q

what is HNPCCC?

A
  • hereditary non-polyposis colon cancer
  • aka lynch syndrome - predisposed to other cancers
  • incl. ovary, SI, urinary tract, skin and brain
  • very few polyps but progression is fast, 2-3 years instead of 10
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4
Q

what are the hallmarks of cancer?

A
  • self-sufficiency in growth signals
  • insensitivity to anti-growth signals
  • avoiding immune destruction
  • tumour promoting inflammation
  • tissue invasion and metastasis
  • limitless replicative potential
  • sustained angiogenesis (to provide nutrients and O2)
  • genomic instability
  • deregulated metabolism
  • evading apoptosis
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5
Q

mutations in what genes in particular cause cancer?

A

oncogenes and tumour suppressor genes

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6
Q

what is the genome?

A

all the genetic material of an organisms

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7
Q

what are genes like in humans?

A
  • diploid
  • 46 chromosomes as 23 pairs
  • 22 autosomes and 2 sex chromosomes
  • genes are not evenly distributed along chromosome
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8
Q

describe the cell cycle

A
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9
Q

how do genes get to tissues?

A

genome —> transcriptome —> proteome —> cell function —> tissue architecture

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10
Q

how do mutations cause malignancy?

A

mutations in genes copied into transcriptome then proteome — cell function and tissue architecture affected — tissue homeostasis disrupted — over proliferation — hyperplasia — malignancy

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11
Q

why does cancer risk stately intially rare but increase with age?

A

mutations have to arise in the same cell

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12
Q

what are mutations followed by?

A

successive waves of clonal expansion — gives rise to intra tumour heterogeneity

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13
Q

what does the initiating mutation allow and lead to?

A

allows that cell to grow and proliferative faster than neighbouring cells — leads to 1st wave of clonal expansion — one of these cells then gains a 2nd mutation with a proliferative advantage — 2nd wave of clonal expansion

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14
Q

what are oncogenes?

A

genes that have dominant effects when they’re introduced into cells that can cause cancer

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15
Q

what oncogenes are involved in colon cancer?

A

B-catenin and KRAS

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16
Q

retinoblastoma is caused by what?

A

mutations in a gene on chromosome 13 (Rb gene)

familial - inherit 1 mutated copy of this gene. mutation is recessive

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17
Q

what is Rb?

A

a tumour suppressor gene - its normal function is to suppress tumour formation

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18
Q

Rb in retinoblastoma

A

familial retinoblastoma - mutant Rb allele
only need one hit to get 2 mutant Rb gene copies

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19
Q

bilateral vs unilateral retinoblastoma

A

familial — bilateral and more likely to have other tumours. born with one Rb mutant allele

sporadic — normally in 1 eye and less likely to have other tumours

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20
Q

what tumour suppressor genes are involved in collin cancer?

A

APC and p53

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21
Q

describe signalling pathways from ligands to altered gene expression

A
  • ligands eg. GFs + hormones
  • receptors - ligands bind to receptors on cell surface
  • signalling cascade - binding activates intracellular signal transduction pathways
  • transcription factors - change array of genes expressed in the cell
  • altered gene expression - alter cellular function
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22
Q

describe Ras

A
  • oncogenes
  • act as a swtich
  • can be maintained in an active or inactive state
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23
Q

oncogenic mutations lock Ras in what form?

A

the active form

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24
Q

what is Ras bound to in the inactive state?

A

GDP

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25
Q

what happens when GDP bound to Ras is exchanged for a fresh molecule of GTP?

A
  • stimulates downstream pathways
  • Ras’ on GTPase activity converts it to its inactive form with GDP
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26
Q

describe what happens when Ras is mutated

A
  • single mutation of Ras eg. G12V (glycine at position 12 is mutated to valene) locks Ras in its active form
  • therefore downstream signals on even in absence of upstream signals
  • cells become self-sufficient — proliferation still happens in absence of stimulation
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27
Q

what is Ras maintained in on state by?

A

GFs and proliferative signals from outside the cell

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28
Q

why is ras an oncogene?

A

because a mutation in only 1 copy of the gene is sufficient to push a cell one step down the road to becoming cancerous

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29
Q

in what % of colon/all cancers is Ras mutated?

A

mutated in 45-50% of colon cancers and 20-30% of all cancers

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30
Q
A
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31
Q

B-catenin vs APC

A

B-catenin is an oncogene, APC is a tumour suppressor gene

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32
Q

what is Wnt?

A

a secreted factor that promotes proliferation by binding to its receptor

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33
Q

unbound state of Wnt?

A

downstream signalling is off

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34
Q

what are components of the Wnt complex?

A
  • GSK-3B = protein kinase
  • Apc
  • B-catenin
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35
Q

what happens when the Wnt complex is intact?

A

GSK-3B phosphorylates B-catenin and this targets B-catenin for degradation

36
Q

what are B-catenin levels like in unstimualted cells?

A

very low

37
Q

what happens when Wnt signals engage with the receptor?

A
  • it disrupts the complex — now GSK-3B is inactive so B-catenin does not get phosphorylate and hence doesn’t get degraded, so B-catenin levels build up in the cell
  • B-catenin can then move into the nuclues where it drives the expressions of genes required for proliferation
38
Q

what do target genes in Wnt signalling include?

A

cyclin D and Myc

39
Q

in what stage of the cell cycle is a cell born?

A

G1

40
Q

which part of the cell cycle is the period during which cells are responsive to mitogenic GFs and to TGF-B?

A

G1 up until the R point

41
Q

what happens when a cell passes the R (restriction) point of the cell cycle?

A

passes the point of no return — cell is committed to complete the entire process. doesnt matter if you withdraw stimulatory sigmas beyond R

42
Q

in what phase does DNA duplicate?

A

S phase

43
Q

what happens in G2?

A

cell prepares for mitosis

44
Q

progression through the cell cycle is driven by a family of protein kinases called what? what are these kinases dependent on?

A

cyclin-dependent kinases —> depend on the binding of a cyclin partner to be active

45
Q

CDKs vs cyclin levels throughout cell cycle

A

the levels of the CDK enzymes stay relatively constant

levels of activating cyclin partners changers — it is the rise and fall of the cyclins that is crucial to regulating cell cycle progression

46
Q

what are the CDK/cyclin complexes at each point of the cell cycle?

A
  • cyclin D / CDK4/6 — drives cell throguh G1
  • cyclin E / CDK2 — triggers entry into S phase
  • cyclin A / CDK2 — drives cell through S phase
  • cyclin A / CDK1 — drives cell into G2
  • cyclin B / CDK1 — drives cell into mitosis
47
Q

what are CKIs?

A

= cyclin-dependent kinase inhibitors

  • small molecules which bind to cyclin-CDK complexes and inhibit them
48
Q

what is p21 an example of?

A

CKI

49
Q

what does exposure to GFs and proliferative signals trigger?

A

activation of the downstream pathways (inc Ras and B-catenin pathways) — which in turn stimulate gene expression and in particular stimulate the production of cyclin D1

50
Q

what happens when cyclin D1 binds to CDK4?

A

forms an active protein kinase

this active complex can then phosphorylate its substrates and in particular can phosphorylate a protein called Rb

51
Q

what happens when Rb is phosphorylated?

A

it lets go of it’s binding partner called E2F. E2F is a transcription factor and once it is liberated it can stimulate the expression of genes including cyclin E — leads to cyclin E protein production — then binds to CDK2 to form active complex — complex also phosphorylates Rb (+ve feedback generating more E2F and cyclin E) and it also phosphorylates origins of replication to trigger S phase

52
Q

why is Rb a tumour suppressor?

A

if there is no Rb in the cell, then E2F will always be liberated and active, so cyclin E will always be synthesised driving entry into S phase

Rb is a break on the cell cycle - if it removed you get uncontrolled proliferation

if one copy of Rb gene is mutated, rendering it inactive, the other copy is still functional. but once the 2nd copy of Rb gets hit, the break is lost as no Rb function in cell

53
Q

what is p53?

A

a transcription factor
tumour suppressor

checkpoint of cell cycle

54
Q

why are p53 levels normally low?

A

it is degrade by the ubiquitin proteasome pathway

55
Q

p53 and colon cancer?

A

p53 gene is mutated in about half of all colon cancers

56
Q

what things can damage p53?

A
  • lack of nucleotides
  • UV and ionising radiation
  • oncogene signalling
  • hypoxia
  • blockage of transcription
57
Q

what can p53 lead to after damage?

A
  • cell cycle arrest
  • DNA repair
  • block of angiogenesis
  • apoptosis

apoptosis best option if damage is too extensive to be repaired

58
Q

what gene is a key target of p53?

A

p21 gene — CKI that an block the activity of numerous CDKs

59
Q

how does p53 affect p21 in response to damage?

A

in response to damage, p53 induces the synthesis of p21. p21 can then inhibit the CDKs putting a block on the cell cycle. that block provides sufficient time for cell to repair that damage before the block is liberated and the cell cycle continues.

60
Q

what is sometimes called the guardian of the genome?

A

p53

61
Q

what is the important DNA damage repair pathway involved in colon cancer?

A

mismatch repair — important in HNPCC

62
Q

what things provide continuous repair to the genome?

A
  • BER = base excision repair
  • NER = nucleotide excision repair
  • proofreading
  • NHEJ = non-homozygous end joining
  • HR = homolygous recombination
63
Q
A
64
Q

what are located at the base of the colonic crypts?

A

Lgr5+ stem cells

65
Q

are villi in the SI or LI?

A

SI

66
Q

describe tissue homeostasis in the intestines

A

stem cells down at bottom of crypt. 1 daughter cell stays behind to maintain stem cell compartment, other migrates up and out until eventually it is shed off at top of lumen (villus in SI, luminal surface in LI).

this tissue is highly proliferative. tissue homeostasis is maintained by balancing proliferation at bottom with loss at the top.

67
Q
A
68
Q

a highly proliferative crypt eventually grows out of sheet to form a. what?

A

polyp

69
Q

what is Apc?

A

adenomatous polyposis coli — mutated in 80-90% of sporadic CRC

it is an important tumour suppressor gene

70
Q

what is Apc? link to colon cancer?

A

= adenomatous polyposis coli
- tumour suppressor gene
- mutated in 80-90% of sporadic CRC
- people with FAP inherit one mutated copy (normally germline truncation at amino acid 1061 or 1309). still 2nd copy as we are diploid so we still have Apc function. if 2nd is lost there is no functional copy of Apc — cell takes step towards being a cancerous cell

71
Q

80-90% CRCs have ___ mutation. 10-20% have _____ mutations

A
  • Apc
  • B-catenin
72
Q

deregulation of ______ is an obligate and early step in CRC

A

APC/B-catenin

73
Q

what happens if there is a single point mutation in B-catenin that stops it being phosphorylated?

A

not degraded and switches on cyclin D synthesis even in absence of Wnt signalling

Wnt : complex disrupted, B-catenin not phosphorylated and therefore not degraded, remains stable, protein levels accumulate, then moves into nucleus and drives proliferation by up regulating cyclin D

74
Q

in the crypt what secrete Wnt signals?

A

the surrounding stromal cells

75
Q

describe Wnt signalling in the crypt?

A

Wnt signals engage with the stem cells. B-catenin is switched on and proliferation is stimulated. stem cells then migrate up and out of crypts, and because they are in close proximity to the wnt signals,. they keep proliferating. once they get too far up the side they are too far away from the source of the Wnt signals so the Wnt signalling pathway is turned off - B-catenin degraded, proliferative signal removed, cells stop dividing, they differentiate and disappear out of the top.

76
Q

what happens when a stem cell loses APC function?

A

, it is no longer reliant on Wnt signals for proliferation, so as it moves up it can still proliferate even in the absence of Wnt signals (APC mutants dont care as tehy move up beyond the zone of Wnt signalling). cells dont differentiate - they keep proliferating and dont finish migrating, forming a highly proliferative zone

77
Q

all colon cancers either have a mutation in ___ or ____

A

APC or B-catenin

78
Q

what is an obligate step in becoming a colon cancer?

A

deregulation of Wnt signalling

79
Q

mutation rate in FAP vs HNPCC

A

much higher in HNPCC

80
Q

what causes the genomic instability seen in HNPCC?

A

mismatch repair defect

81
Q

name 2 DNA repair genes

A

MutSa and MutLa

82
Q

what happens if there is a mutation in the genes that encode DNA repair proteins?

A

the damage cant be repaired so the mutation rate goes up

mismatch repair

83
Q

what is silenced by methylation in around 15% of sporadic CRCs?

A

MLH1 promoter

84
Q

mutations in what cause HNPCC?

A

MSH2 and MLH1

85
Q

describe MSH2 and MLH1 and their role in colon cancer when they’re mutated

A
  • they are effectively tumour suppressor genes
  • mutation of MSH2 or methylation of MLH1 does not itself cause cancer (they are not normal TSG), but rather losing MSH2 or MLH1 function, the mutation rate goes up and that accelerates the accumualtion of mutations in traditional TSG + oncogenes
86
Q

in 90% of CRC that have a mismatch repair defect, what receptor is mutated?

A

TGF-B

87
Q

describe TGF-B

A

growth inhibitory - anti-proliferation pathway

PBL SEM 4 (50 decks)

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