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MBB164 > Bird (Molecular basis of disease: Cancer) > Flashcards

Bird (Molecular basis of disease: Cancer) Flashcards

1
Q

What is cancer?

A
  • group of diseases characterised by uncontrolled growth and spread of abnormal cells
  • if spread not controlled can result in death
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2
Q

Why is uncontrolled growth of cells unusual?

A
  • most cells don’t divide and only do when stimulated to
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3
Q

What is metastasis?

A
  • 2º spread

- original cells break off and form new tumours

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4
Q

What is the incidence of cancer?

A
  • 1 in 3 get it
  • 1 in 5 die
  • increases w/ age in humans (but cancers that are more common in children)
  • skin most prevalent in younger people
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5
Q

What is the typical tissue structure?

A
  • layer of epithelium separated from supporting mesenchyme by basement membrane
  • support tissue (or stroma) made up of connective tissue and fibroblasts, may be supported on layer of muscle or bone depending on organ
  • in some tissues (eg. skin, intestine) epithelium several cells thick
  • may form tubes (eg. kidney, lungs)
  • solid cords (eg. liver)
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6
Q

What is the 1st stage of cancer?

A
  • carcinoma in situ
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7
Q

What happens if carcinoma in situ detected?

A
  • recovery likely, before metastasis dev

- screening effective tool in preventing cancer by detecting early and removing it

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8
Q

What causes cancer?

A
  • successive mutations
  • usually in somatic cells, small no. germline, passed onto offspring increasing cancer risk
  • usually 5-8 mutations
  • each mutation creates cell increasingly well adapted for autonomous growth
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9
Q

What is the probability of a cell becoming cancerous, and why?

A
  • probability of 1 cell simultaneously acquiring mutations v small
  • can only get all mutations if initiated cell clonally expands
  • 2nd mutation at critical locus gives growth advantage and 2nd clonal expansion occurs
  • process repeats
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10
Q

Why is it surprising cancer isn’t more common?

A
  • DNA v volatile inside cell
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11
Q

What is the traditional view on cancer developing?

A
  • tumour cells heterogenous, but most cells can proliferate extensively and form new tumours
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12
Q

What is the more recent view on cancer developing?

not much evidence but gaining popularity

A
  • tumour cells heterogenous and only cancer stem cell subset has ability to proliferate extensively and form new tumours
  • self renew and prod differentiated daughter cells like normal stem cells
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13
Q

What are the characteristics of benign tumours?

A
  • don’t metastasise
  • grow locally
  • may cause problems by pressure (brain) or obstruction (colon)
  • histologically and cytologically resemble tissue of origin
  • may prod wart like outgrowths containing all cell types, packed closely to form solid nodule
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14
Q

Where are benign tumours found?

A
  • dev in any tissues

- cover or line tissues of skin, intestine, bladder etc.

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15
Q

What are the characteristics of in situ tumours?

A
  • usually dev in epithelium
  • usually small
  • altered histological appearance (show morphological characteristics of tumour cells to greater or lesser degree
  • don’t invade basement membrane and supporting mesenchyme
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16
Q

How do cells of in situ tumours differ from normal cells?

A
  • loss of normal cell arrangement
  • variation in cell size and shape
  • increase in nucleus size
  • presence of abnormal chromosomes
  • increased mitotic activity
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17
Q

What are the characteristics of tumours of small intestine?

A
  • rare
  • despite high cell turnover rate in villus
  • high proliferative rates not necessarily linked to high incidence of tumour formation
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18
Q

What are the characteristics of malignant tumours?

A
  • specific capacity to invade and destroy underlying mesenchyme
  • metastasise
  • stimulate angiogenesis, dev of blood supply, but new blood vessels easily damaged and may increase metastasis and prod more 2º tumours
  • difficult to treat once metastasised
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19
Q

How can 1º tumours be treated?

A
  • surgery or localised chemo/radiotherapy
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20
Q

What are the 6 hallmarks of cancer?

A
  • self insufficiency ingrowth signals
  • insensitivity to antigrowth signals
  • apoptosis evasion
  • limitless replicative pot (must be over 60-70)
  • sustained angiogenesis
  • tissue invasion and metastasis
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21
Q

How is self insufficiency in growth signals achieved?

A
  • by prod own growth factors or receptors in increasing no.s to increase stimulus
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22
Q

How does sustained angiogenesis occur?

A
  • need O2 and nutrient supply to stop inhibition of growth

- late event

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23
Q

How does tissue invasion and metastasis occur?

A
  • escape and colonise other areas

- only likely to dev once tumour mass of sufficient size

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24
Q

In what order are 6 hallmarks developed?

A
  • no particular order or seq

- w/ each acquisition tumour state becomes more pronounced and more aggressive

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25
Q

What is normal cell proliferation in dev and adult life, and why?

A
  • proliferation and cell death carefully regulated to ensure proper growth to adulthood and maintenance of adult state
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26
Q

What proliferation is there in adult tissues?

A
  • cell birth and death rates determine adult body size
  • some adult tissues show constant and continued cell proliferation as constant tissue renewal strategy
  • cells of many adult tissues don’t normally divide except during healing processes
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27
Q

What happens when mutations occur in neurons and muscle cell and why?

A
  • generally don’t induce tumour formation
  • as highly differentiated and rarely divide
  • so cancers rare in adults
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28
Q

Can cancers occur in tissues made up differentiated cells?

A
  • they can and do

- eg. skin and gastro-intestinal tract

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29
Q

What is the series events that occur after DNA damage to form a tumour?

A
  • transient mutation
  • if not repaired becomes permanent mutation
  • cell division leads to tumour
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30
Q

What causes DNA damage?

A
  • exogenous agents, eg. ionising radiation, UV radiation, chemical carcinogens, viruses
  • endogenous events, eg. errors in DNA rep, intrinsic instability, attack by free radicals
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31
Q

What does whether a permanent mutation leads to formation of tumour depend on?

A
  • depends on which gene (or collection of genes) accum mutation
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32
Q

Which genes must accum mutation for tumour to develop and why?

A
  • genes controlling cell proliferation or apoptosis

- to allow cells to evade normal controls reg tissue growth

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33
Q

What does 3% of human genome code for and why does this make tumour formation unlikely?

A
  • protein and regulatory seq assoc w/ them
  • so mutation v unlikely to be in coding seq
  • even if it is must be in particular subset to bring about transformation to malignant state
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34
Q

What are 2 broad classes of genes involved in onset of cancer?

A
  • proto-oncogenes –> excessively active in growth promotion

- tumour suppressor genes –> normally restrain cell growth, damage allows inapprop growth

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35
Q

What do many of the genes in both classes involved in cancer onset code for proteins involved in?

A
  • entry into and passage through cell cycle
  • apoptosis
  • DNA repair
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36
Q

What types of mutation are commonly encountered in cancers?

A
  • point
  • frame shift
  • mutation to stop codon
  • amplification
  • overexpression
  • inapprop expression
  • loss of gene
  • fusion w/ another gene (chromosomal break and rearrangement)
  • epigenetic mods (hypermethylation of cytosine in CpG islands)
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37
Q

Which mutations affect protein structure and how?

A
  • frame shift and mutation to stop codon

- truncate protein or scramble seq

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38
Q

What effect do amplification, overexpression and inapprop expression mutations have?

A
  • normal protein prod, but too much or at wrong time
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39
Q

Which mutations mean no protein prod?

A
  • loss of gene

- epigenetic mod (gene silencing)

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40
Q

What effect does fusion w/ another gene have?

A
  • chimeric protein w/ alt function
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41
Q

How is understanding of chemical events leading to cancer important?

A
  • events causative in cancer dev, so prevention would be effective preventative measure
  • several genetic diseases predisposing cancer involve mutations in gene which normally function to protect DNA from mutational events
  • understanding events has direct clinical relevance
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42
Q

What are major causes of cancer?

A
  • diet agents and lifestyle, approx 70% in Western world
  • tobacco products, approx 30%
  • dietary deficiencies in fruit and veg
  • exposure to various chemical or physical agents in env
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43
Q

Can cancer occur w/o obvious exposure to env carcinogens?

A
  • yes
  • may occur in organs for which no env or genetic causes identified
  • appears spontaneous DNA damage can occur and give rise to carcinogenic mutations
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44
Q

What are examples of spontaneous DNA damage that can occur?

A
  • breakage of bonds between purines and deoxyribose, leading to random base insertions
  • deamination of cytosine to uridine
  • deamination of methylcytosine to thymidine
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45
Q

What is the most common spontaneous DNA damage and how frequently does it occur?

A
  • deamination of cytosine to uridine

- 20x/cell/day

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46
Q

Why do few of spontaneous DNA damages usually accum?

A
  • repaired by action of DNA repair enzymes
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47
Q

Why do DNA mutations occur?

A
  • result of DNA rep

- inherent instability of DNA molecule

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48
Q

Is DNA stable, why?

A
  • yes when isolated from cells

- no w/in cells, breakage of bond connecting purines to deoxyribose 10^4 events/cell/day

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49
Q

What other factor can cause DNA damage?

A
  • chemical attack by products of oxidative metabolism
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50
Q

What are the characteristics of chemical carcinogens?

(DNA damage by endogenous agents)

A
  • large chemical diversity
  • may have great chemical stability
  • stable chemical carcinogens known to undergo metabolic activation by enzymes normally involved in detox, and form highly reactive compounds which particularly react to guanine
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51
Q

How is guanine often affected by chemical carcinogens?

A
  • converted to methylguanine
  • mistaken for adenine when DNA rep
  • paired w/ T in copied strand
  • meaning eventually G-C replaced by A-T (point mutation)
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52
Q

What is the earliest discovered chemical carcinogen and what discoveries did this lead to?

A
  • tumour induction in workers exposed to coal tar
  • identification of polycystic aromatic hydrocarbons in coal tar
  • discovery they acted as skin carcinogens in lab animals
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53
Q

What was identified as a carcinogen in rubber and chemical industry and what did it cause?

A
  • 2-naphthylamine

- bladder cancer

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54
Q

What are the characteristics of physical carcinogens? (DNA damage by endogenous agents)

A
  • ionising radiation

- UV radiation

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55
Q

How can ionising radiation result in direct and indirect damage? (Physical carcinogens)

A
  • direct = ss and ds DNA breaks

- indirect (radiolysis of water) = damage from free radicals

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56
Q

How does UV radiation result in DNA damage? (Physical carcinogens)

A
  • insufficient energy to prod ions
  • absorbed by bases and induces chem reactions between 2 thymidines in helix
  • forms covalent cross link
  • disrupts normal bping
  • obstacle to DNA pol
  • mutations arise if not repaired
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57
Q

Where do 90% skin cancers occur?

A
  • sun exposed areas
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58
Q

What is xeroderma pigmentosum and what can it lead to?

A
  • acute sensitivity to UV
  • if not recognised leads to high incidence of skin cancer
  • defects in gene for repair of DNA damage
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59
Q

Which genes repair damaged DNA?

A
  • p53 evolved to survey DNA for damage and to repair it

- other genes repair errors introd during rep

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60
Q

How are thymidine dimers repaired?

A
  • removal of whole stretch of DNA

- resynthesis using opp strand as template

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61
Q

How are 0-6 methylguanine errors repaired?

A
  • directly removed by breaking phosphate backbone
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62
Q

Can ss and ds breaks be repaired?

A
  • ss directly repaired

- ds not easily repairable

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63
Q

How does p53 repair damage?

A
  • delays DNA rep until repair completed

- apoptosis if damage too severe

64
Q

Can p53 be mutated?

A
  • mutated in over 50% of all human cancers

- mutations in 1 allele result in cancer susceptible state called Li-Fraumeni syndrome

65
Q

What are growth signals generated by?

A
  • diffusible growth factors
  • extracellular matrix components
  • cell to cell adhesion molecules
66
Q

What are some examples of diffusible growth factors?

A
  • EGF = epidermal growth factor
  • FGF = fibroblast growth factor
  • TGFα = transforming growth factor α
  • PDGF = platelet derived growth factor
67
Q

Do cells req growth signals to grow?

A
  • normal cells don’t proliferate w/o signals

- many oncogenes of cancer cells subvert normal growth signalling in various ways

68
Q

What is always the end result of cancer cells subverting normal growth signals?

A
  • cont mitogenic stimulation

- centering on cyclin D in cell cycle

69
Q

What to mechanisms of subverting growth signals differ between?

A
  • between cancers and w/in specific tumour type by chance
70
Q

What are 3 ways cancer cells can become growth signal autonomous?

A
  • modulation of growth factor provision
  • modulation of growth factor receptor activity
  • modulation of intracellular signalling pathways
71
Q

What occurs during modulation of growth factor provision?

A
  • normally heterotypic signalling
  • but many cancers acquire capacity for autocrine growth stimulation
  • eg. glioblastomas, prod PDGF
  • eg. sarcomas, prod TGFα
72
Q

What is heterotypic signalling?

A
  • growth factors made by 1 cell type and released to stimulate growth in different cell types
  • in most normal tissues
73
Q

What is autocrine growth stimulation?

A
  • prod growth factor itself can respond to

- so doesn’t req growth factor prod by other cells w/in tissue

74
Q

What occurs during modulation of growth factor receptor activity?

A
  • growth factor binds to receptor in membrane
  • receptor becomes active as Tyr kinase and autophosphorylates Tyr residues
  • some proteins can then dock w/ active receptor and become activated
  • some proteins act as substrates for receptor kinase and become Tyr phosphorylated
  • these proteins usually protein kinases (Tyr or Ser kinases) and phosphorylate other proteins
  • overexpression of receptor may allow cell to become hyper-responsive to normal low growth factor levels that wouldn’t normally induce growth response
  • excessive overexpression of growth factor receptors may also result in ligand independent signalling
  • receptors may also become structurally altered and become ligand independent as a result
75
Q

What are some examples of growth factor receptors that can become unregulated in certain tumours?

A
  • EGF-R (EGF receptor) and Erb (heregulin receptor) unreg in stomach, brain and breast tumours
  • HERZ overexpressed in stomach and breast tumours
76
Q

What occurs during modulation of intracellular signalling pathways?

A
  • transmit signals gen at cell surface by growth factor-receptor interaction (subject to mod in many cancer cells)
  • often involves 50S-Ras-Raf-MAPK cascade
  • many tumours have mutated Ras protein, meaning mitogenic signals transmitted w/o any upstream activation of pathway
  • suggested signalling pathways dereg in all tumours (hard to prove and not certain)
  • direct interaction of Ras protein w/ survival promoting pI3 kinase enables growth signals to simultaneously gen survival signals (protecting cells from apoptosis)
77
Q

What is the 50S-Ras-Raf-MAPK cascade known to interact w/?

A
  • several other growth promoting pathways
78
Q

What % of human tumours have a mutated Ras protein?

A
  • approx 25% overall
  • 90% pancreas
  • 50% colon
  • 30% lung
79
Q

What is an oncogene?

A
  • gene w/ pot to cause cancer
80
Q

What family of proteins is Ras part of?

A
  • GTP binding proteins that function as signal transducers
81
Q

How does Ras function?

A
  • GTP binds causing conformational change
  • allows Ras to interact w/ other downstream signalling molecule
  • Ras hydrolyses GTP –> GDP, released and Ras returns to inactive state
82
Q

How does mutated Ras differ from normal Ras?

A
  • decreased GTPase activity
  • GTP not released
  • constantly activated
83
Q

What must happen to maintain normal tissue mass?

A
  • response to growth signals when approp

- response to antiproliferative signals to stop growing

84
Q

What do growth signals and antiproliferative signals both depend on?

A
  • soluble growth inhibitors

- immobilised inhibitors bound to extracellular matrix and on surface of nearby cells

85
Q

How are growth signals and antiproliferative signals generated?

A
  • generated by inhibitors binding to cell surface receptors which then activate intracellular signalling circuits
86
Q

What are 2 distinct mechanisms of blocking proliferation in normal tissues?

A
  • cells become quiescent (inactive)

- cells differentiate (so can’t re-enter cell cycle)

87
Q

How does cells becoming quiescent block proliferation in normal tissues?

A
  • push actively dividing cells out of cell cycle into G0
  • normally reversible
  • may go back to G1 if approp growth stimuli
88
Q

How does cells differentiation block proliferation in normal tissues?

A
  • push cells into highly differentiated state, eg fully differentiated muscle fibres or nerve cells
  • lose ability for future cell division
  • often assoc w/ change in cell morphology, physically limiting cells pot to divide
89
Q

What is TGFβ and how does it work?

A
  • anti-growth factor
  • upregulates expression of inhibitors of cell cycle (eg. p15, p21, p27)
  • these are inhibitors of cyclin/CDK complexes which need to be activated for cell cycle to function
  • in some cell types, suppresses expression of c-myc gene, which regulates G1 cell cycle machinery
90
Q

What ways have tumours dev to block TGFβ acting?

A
  • expression of TGFβ receptor down regulated
  • receptor mutated to inactive or less active form
  • intracellular signally disrupted by mutation of Smad4 protein
  • mutation of Rb
91
Q

How does mutation of Smad4 protein block TGFβ acting?

A
  • disrupts intracellular signalling
  • by elimination of p15
  • or decrease in responsiveness of CDK4 cell cycle kinase to inhibition by p15
92
Q

Why is Rb important?

A
  • Rb important in control which acts at restriction point in G1 phase of cell cycle
  • many antiproliferative signals operate through Rb
  • important in non dividing cells as forms complex w/ E2F family of transcrip factors, preventing E2F acting, so preventing expression of genes involved in G1 to S transition
93
Q

How does mutation of Rb block TGFβ acting?

A
  • in DNA-virus induced tumours, Rb inactivated by being complexed w/ protein made by virus
94
Q

What other aspect of insensitivity to antigrowth signals probably acts through Rb?

A
  • can turn off expression of cell adhesion molecules that transmit antigrowth signals
95
Q

How does c-myc function in normal cells?

A
  • c-myc codes for transcrip factor Myc
  • in actively dividing cells, active transcrip form of Myc complexed w/ Max
  • Myc/Max complex = growth
  • Mad/Max = differentiation
96
Q

What is the mechanism for avoiding differentiation - involving c-myc oncogene?

A
  • overexpression of c-myc (lots of Myc)
  • favouring Myc/Max formation
  • decreasing Mad/MAx formation
  • maintains cells growth and blocks differentiation
97
Q

What are the major steps in avoiding apoptosis?

A
  • chromatin condenses and cyto shrinks
  • nucleus fragmented, DNA “laddering”, blebbing and cell fragmentation
  • phagocytosis of apoptotic bodies
98
Q

What happens during apoptosis?

A
  • cellular membranes disrupted
  • cytoplasmic and nuclear skeletons degraded
  • chromosomes broken down
  • nucleus fragmented
  • all w/in 30-120 mins
  • dismembered cell engulfed by neighbouring cells
  • usually completely eliminated wi/in 1 day
99
Q

Can all cells apoptose?

A
  • most have capacity to apoptose if directed to
100
Q

Where are apoptosis initiating signals generated?

A
  • from inside and outside cell
101
Q

How are apoptosis initiating signals from outside cell transmitted?

A
  • transmitted through receptors that bind death inducing factors (inc FAS ligand and TNFα)
  • signals may be offset by signals gen by survival factors, eg. IGF1
102
Q

How can apoptosis be triggered by cells gen intracellularly?

A
  • unrepairable DNA damage
  • signalling imbalance due to oncogene action
  • lack of sufficient survival signal
  • hypoxia
  • loss of cell-cell contact or cell-ECM contact
103
Q

The multitude of signalling opps means what for tissues?

A
  • keeps normal cells in contact w/ neighbours

- regulates individual cell growth, survival or death in way approp for whole tissue

104
Q

Why is cytochrome c important to apoptosis?

A
  • potent apoptosis catalyst

- key process involves its release from mito

105
Q

How are proteins of Bcl-2 family involved in apoptosis?

A
  • in apoptotic cascade
  • some pro-apoptotic and some anti-apoptotic
  • regulate cytochrome c release
106
Q

How is apoptosis a defence against tumour progression?

A
  • if hormones removed, hormone dependent tumours undergo massive apoptosis
  • suggests increase in cell growth and apoptosis occurred at same time
  • apoptosis may be switched on by oncogene overexpression
  • elimination of cells w/ activated oncogene expression 1º way that mutant cells continuously removed from tissues
107
Q

What mutation is found in 50% lymphomas?

A
  • mutation in c-myc and bcl-2

- further evidence for myc-bcl-2 interaction

108
Q

In low conc serum, c-myc expressing cells show what level of apoptosis?

A
  • high apoptosis
109
Q

What could increased apoptosis be abolished by?

A
  • addition of survival factors, eg. IGF1, to medium
  • overexpression of Bcl-2 or Bcl-XL
  • disruption of FAS pathway
110
Q

What has been demonstrated about apoptosis evasion in transgenic mice?

A
  • inactivation of Rb prod slow growing microscopic tumours w/ high rate apoptosis
  • inactivation of p53 in same cells prod rapidly growing tumours
111
Q

What can some lung and colon cancers do to evade apoptosis?

A
  • prod decoy non-signalling receptor for FAS ligand
112
Q

Do normal cells have limitless replicative pot?

A
  • no, limited capacity for repeated divisions

- stop after certain no. doublings

113
Q

How can tumour cells avoid cell growth stopping in cultured human fibroblasts?

A
  • disabling p53 and Rb tumour suppressor proteins
  • continue dividing until enter 2nd state termed crisis
  • but small no. (appox 1 in 10^7) continue to divide w/o limit –> immortalisation
114
Q

Why do tumour cells need to become immortalised?

A
  • normal cells have capacity for 60-70 doublings
  • should enable clones of tumour cells to expand to no.s vastly exceeding no. cells in body
  • but during tumour dev, widespread apoptosis alongside cell division
  • no. cell in tumour greatly under represents no. divisions req
  • so generational limit of normal somatic cells may be barrier to cancer dev
115
Q

What are human telomeres?

A
  • simple seq of DNA repeats found at chromosome ends

- contain 2500 copies TTAGG

116
Q

How does loss of telomeres lead to apoptosis?

A
  • at each cell division 50-100bp of telomeric DNA lost from ends of every chromosome
  • DNA pol unable to completely replicate 3’ ends during each S phase
  • progressive shortening w/ each division
  • eventually lose ability to protect ends of chromosomes
  • end to end chromosomal fusion and apoptosis
117
Q

What telomerase activity is there in malignant cells?

A
  • telomere maintenance in most malignant cells
  • most show upregulated expression of telomerase
  • maintaining telomere length critical to state of immortality
118
Q

What does telomerase do?

A
  • adds hexanucleotide repeats onto ends of telomeric DNA
  • keeping telomeres at length above critical threshold
  • allowing unlimited multiplication of descendant cells
119
Q

How is proximity of normal cells to blood vessels achieved?

A
  • cells in tissue need to be w/in 100μm of capillary
  • during organ dev
  • once tissue formed, growth of new blood vessels, angiogenesis transitory and carefully reg
120
Q

Why do cells need close proximity to blood vessels?

A
  • oxygen and nutrient supply
  • for cell function and supply
  • for cancer cells, also gives route to rest of body
121
Q

What is angiogenesis?

A
  • growth of new blood vessels
122
Q

Do cancer cells have angiogenic capacity?

A
  • initially lack it, limiting initial expansion

- usually dev it in order to get to clinically detectable size

123
Q

What signals do cancer cells of approx 2mm emit?

A
  • to recruit surrounding connective tissue and vascular cells to tumour and induce them to grow into blood vessels
124
Q

What are the most common positive angiogenic signals?

A
  • vascular endothelial growth factor (VEGF)

- acidic and basic fibroblast growth factors (FGF1 and FGF2)

125
Q

How do positive angiogenic signals act?

A
  • through transmembrane Tyr kinase receptors on capillary endothelial cells
126
Q

What are the most common negative angiogenic signals?

A
  • thrombospondin-1, binds to transmembrane receptor (CD36) on endothelial cells
127
Q

When is the ability to induce and sustain angiogenesis acquired and activated?

A
  • acquired in discrete steps during tumour dev

- activated in mid-stage lesions, prior to appearance of full-blown tumours

128
Q

How do tumours activate angiogenesis?

A
  • changing balance of inducers and inhibitors
  • many increase expression of VEGF and/or FGFs
  • some downregulate expression of inhibitors, eg. thrombospondin-1
129
Q

How do tumour cells increase expression of growth factors to activate angiogenesis?

A
  • activation of ras oncogene may upregulate VEGF expression
130
Q

How do tumour cells downregulate inhibitor expression to activate angiogenesis?

A
  • positively reg by p51
  • loss of p53 function (occurs in most human tumours) decreases levels
  • releasing endothelial cells from inhibition
131
Q

How are cells of normal tissues held in place?

A
  • by cell adhesion molecules which bind them to neighbouring cells and to ECM by integrins
  • cadherins linked to internal cytoskeleton of cell by catenins
132
Q

What is the exception to the immobilised format of tissue and why?

A
  • WBCs

- can migrate out of blood (and lymphatic system) to enter other tissues

133
Q

What must tumours do in order to metastasise?

A
  • acquire migratory properties usually restricted to WBCs
  • break connections to neighbouring cells and ECM
  • break through collagen and other proteins making up connective tissue that encapsulates organs and tissues
  • inc breaking through basement membrane, separating epithelial cells from underlying mesenchyme
134
Q

A poor prognosis is shown by spread of cancer to where?

A
  • localised spread to lymph nodes
135
Q

Where can tumours spread to?

A
  • depends, certain tumours spread to particular organs

- not to do w/ distance

136
Q

Are cells in 2º tumour the same as in 1º tumour?

A
  • yes

- eg. if breast cancer spreads to lungs, still made up of abnormal breast cells

137
Q

Are mutations in E-cadherin gene common?

A
  • no, relatively rare
  • as often result in poorly differentiated cancer cells w/ interior architecture that no longer resembles original structure
  • decrease in amount more common
138
Q

How do catenins (linking proteins) vary in tumour cells?

A
  • often absent or nonfunctioning
139
Q

How do integrins vary in metastasising cells?

A
  • fewer prod

- different subset that help migration through connective tissue or blood vessel wall

140
Q

What forms usually make up cadherin-catenin complexes?

A
  • usually E-cadherin assoc w/ β-catenin
141
Q

What is the role of β-catenin?

A
  • in adhesion complex

- transcrip factor

142
Q

What do integrins do?

A
  • link cells to proteins such as collagen in surrounding connective tissue
  • span the cell’s membrane, forming connections with connective-tissue proteins outside cell and proteins in the cell’s cytoskeleton
143
Q

What do migratory cells extend into matrix of connective tissue and what is their role?

A
  • cytoplasmic protrusions

- latch onto proteins in matrix w/ help of new integrins and pull themselves through

144
Q

Is the ability to secrete proteases or induce

surrounding cells to, a property of cancer cells?

A
  • yes, 1 of changes that turns normal cells to cancer cells and then to metastatic cancer cells
145
Q

What must happen in order for cell to make protrusions?

A
  • cytoskeleton reconfigured for mobility
146
Q

Are cancer cells motile?

A
  • most derived from cells that are not naturally motile

- so lack necessary skeleton giving motility

147
Q

What shape are normal epithelial cells?

A
  • cylindrical, cuboid, flattened
148
Q

What shape are cancer cells?

A
  • star shaped and elongated

- more closely resemble fibroblasts than epithelial cells

149
Q

When is similar morphology to cancer cells observed in epithelial cells?

A
  • during dev of embryo
150
Q

What is req for tumour to pass through ECM?

A
  • proteases to degrade basal membrane (proteolysis)

- breakdown of ECM proteins

151
Q

What proteases can be used to degrade the basal membrane (allowing tumour to pass through ECM)?

A
  • plasminogen activators (Ser activators), leads to conversion of plasminogen to plasmin
  • Cathepsin B ( Cys proteases)
  • Matrix Metalloproteinases (MMPs), often converted from inactive Pro form by plasmin
152
Q

What are 2 mechanisms for survival of cancer cells in bloodstream?

A
  • travel in clusters, increasing poss at least 1 will survive
  • surround themselves w/ blood cells, eg. platelets, masking them from immune surveillance
153
Q

What are the stages of metastasis?

A
  • cancer cells invade surrounding tissues and vessels
  • transported by circulatory system to distant sites
  • reinvade and grow at new location
154
Q

How do cancer cells interact w/ their 2º location?

A
  • specific interactions between cancer cell surface and endothelial cells lining blood vessels in new host tissue
  • carbs on cell surface bind to specific receptor on endothelial cells, called selectin
  • more bonds mediated by integrins form between cells
155
Q

How do cancer cells recognise diff tissues?

A
  • diff selectins recognise diff carbs on cancer cell surface

- each cancer cell expresses diff set of carbs

156
Q

What are carb-selectin interactions usually used by and why?

A
  • WBCs

- to identify particular tissues to combat infection

MBB164 (7 decks)

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