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EXMD504 > 9. Invasion and Metastasis > Flashcards

9. Invasion and Metastasis Flashcards

1
Q

what proportion of mortality is caused by metastasis?

A

90%

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2
Q

what is the major site of metastasis for colon cancer?

A

liver

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3
Q

do all circulating cancer cells form metastasis? why?

A

only some will form metastases because there are many steps that must occur

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3
Q

6 major steps in metastasis

A
  1. invasion and infiltration of surrounding normal host tissue
  2. release of neoplastic cells
  3. survival in circulation
  4. arrest in capillary beds of distant organs
  5. penetration of lymphatic or blood vessel walls
  6. growth of disseminated tumour cells
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4
Q

5 main changes for metastasis

A
  1. cell detachment
  2. invasion of stroma
  3. intravasation
  4. migration
  5. extravasation
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5
Q

5 things that occur for cell detachment

A
  1. cells acquire spindle shape for migration
  2. increased matrix-degrading proteinases
  3. increased growth factors in original and metastatic site
  4. decreased adhesion molecules
  5. decreased proteinase inhibitors
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6
Q

2 requirements for cells as they migrate

A
  1. resist immune cells in circulation
  2. anchor themselves via increased endothelial cell adhesion molecules
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7
Q

3 molecules upregulated for extravasation

A
  1. selectin ligands
  2. integrins
  3. matrix-degrading proteinases
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8
Q

what 2 things increase for metastases?

A
  1. increased cell-cell adhesion molecules
  2. increased growth factors
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9
Q

what ultimately determines the fate of metastasis?

A

microenvironment of primary and distant site

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10
Q

6 in vivo experimental models

A
  1. surgical biopsies
  2. histopathology, “omics”, RNAseq
  3. animal tumour models
  4. transgenic/KO/knockin mice
  5. patient-derived xenograft
  6. circulating tumour cells
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11
Q

what do histopathology, “omics”, and RNAseq tell us?

A

shows what primary tumour cells acquire/suppress to be able to grow at secondary site

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12
Q

4 types of animal tumour models

A
  1. induction by chemicals, oncogenic viruses
  2. transplantation
  3. spontaneous metastasis
  4. experimental metastasis
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13
Q

what is spontaneous metastasis in animal model?

A

put kidney tumour cells directly into kidney to see path of metastasis

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14
Q

what is experimental metastasis in animal model?

A

put kidney tumour cells in organ of later stages

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15
Q

describe patient-derived xenograft

A

immediately put patient cells in animal to keep tumour cells as close to origin as possible

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16
Q

how do we get circulating tumour cells?

A

aka liquid biopsy –> isolate cells in circulation that have shed from tumour

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17
Q

5 in vitro experimental models

A
  1. cell lines
  2. reconstituted tissue
  3. ECM models
  4. genetically altered cells
  5. PDX, organoids, slices
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18
Q

what happens at the primary site at beginning of invasion? (4)

A
  1. hyperplasia
  2. loss of polarity
  3. loss of tissue organization
  4. intact basement membrane
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19
Q

what happens during microinvasion?

A

proteolytic enzymes (MMP2, MMP9) break the basement membrane and cells begin migration

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20
Q

what does EMT stand for?

A

Epithelial –> Mesenchymal Transition

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21
Q

what does EMT allow for?

A

allows for cells to be motile

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22
Q

3 things that happen to cells during EMT?

A
  1. Lose organization
  2. Cell-cell contacts are disrupted
  3. Cells become immortalized
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23
Q

5 indications of EMT

A
  1. E-cadherin DOWNregulated
  2. Epithelial integrins DOWNregulated
  3. N-cadherin UPregulated
  4. Vimentin UPregulated
  5. Fibronectin UPregulated
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24
Q

what is the role of E-cadherin?

A

part of junctional complex holding epithelial cells together

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25
Q

what is the role of epithelial integrins?

A

receptor for basement membrane proteins

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26
Q

what is vimentin?

A

cytoskeletal protein unique to mesenchymal cells

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27
Q

what is the role of fibronectin?

A

migration track for cells

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28
Q

why do cells become spindle-shaped?

A

lets them migrate along fibronectin matrix

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29
Q

4 cellular adhesion molecules

A
  1. E-cadherin
  2. Ig superfamily with Ig domain (N-CAM)
  3. Mucin-like CAM
  4. Integrins
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30
Q

role of mucin-like CAM

A

binds selectins

normally expressed on blood vessels and immune cells

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31
Q

why does a metastasizing tumor cell express selectin?

A

so it can bind mucin-like CAM on blood vessels to allow for migration

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32
Q

what do integrins bind (3)

A
  1. ECM
  2. N-CAMs
  3. cadherins
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33
Q

3 roles of integrins

A
  1. adhesion
  2. polarity
  3. migration
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34
Q

what 2 CAMs have homophilic interactions?

A
  1. E-cadherin
  2. N-CAM
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35
Q

what 2 CAMs have heterophilic interactions?

A
  1. Mucin-like CAM
  2. Integrins
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36
Q

describe E-cadherin as a hallmark of EMT

A

DECREASED E-cadherin is a hallmark of EMT

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37
Q

assay showing decreased E-cadherin in EMT

A

induce EMT with Akt expression (Akt downstream of growth factor receptors)

before Akt (aka before EMT): E-cadherin is at cell boundary for cell-cell attachment

after Akt (aka after EMT): E-cadherin diffused thru cytoplasm so no cell-cell attachment

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38
Q

5 types of cadherins and locations

A
  1. Neural (neurons, muscle, endothelial cells)
  2. Epithelial
  3. Placental
  4. Retinal
  5. Endothelial
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39
Q

6 functions of cadherins

A
  1. mediate Ca2+ HOMOTYPIC cell-cell adhesion
  2. mediate cell sorting during embryogenesis
  3. form cellular junctions to form tissues so cells recognize each other
  4. establish cell polarity
  5. inhibit apoptosis
  6. activate/inhibit growth factor receptors
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40
Q

how do cadherins allow cells to recognize each other?

A

ex. cells expressing E-selectin will seek out other cells expressing E-selectin

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41
Q

how do cadherins change cell shape? (4 steps)

A
  1. extracellular domain binds p120
  2. p120 is stabilized at the membrane
  3. beta-catenin and alpha-catenin are recruited
  4. alpha-catenin binds actin to allow stretching of cells to give specific cell shape
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42
Q

cadherins act as a bridge btwn:

A

cadherins act as a bridge btwn cytoskeleton and extracellular environment

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43
Q

describe beta-catenin and its downstream function

A

pre-assembled in ER and acts as transcription factor for Wnt signaling –> important for development and embryogenesis

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44
Q

what do HAV-containing peptides do?

A

disrupt adhesion and trigger cell migration

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45
Q

describe cadherins and cancer

A

A. well-differentiated, poorly invasive adenomas have HIGH E-cadherin

B. invasive carcinomas have LOW E-cadherins

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46
Q

what causes reduced E-cadherin levels in invasive carcinomas? (4)

A
  1. transcriptional repression/inactivation
  2. DNA methylation
  3. mutations
  4. post-translational modification
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47
Q

what makes E-cadherin de-regulated?

A

phosphorylation of E-cadherin, beta-catenin, p120 by RTK

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48
Q

3 things that reduced E-cadherin leads to?

A
  1. increased cell motility
  2. increases invasion
  3. triggers beta-catenin/lymphoid enhancer binding factor (LEF1) regulated transcription
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49
Q

2 opposite roles of beta-catenin

A
  1. keeps cells attached via cadherin complex
  2. if E-cadherin decreases, beta-catenin is released and goes to nucleus to act as TF and cause EMT
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50
Q

how do integrins bind ECM?

A

via glycoproteins

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51
Q

2 types of glycoproteins

A
  1. fibronectins
  2. laminins
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52
Q

what is the ECM? its role?

A

web of proteins and carbohydrates at cell surface –> connect the cell exterior to cytoskeletal fibres on interior

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53
Q

how are integrins expressed?

A

always expressed as a complex, each with unique ligand specificity

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54
Q

what are beta3, 5, 6, and 8 integrin subunits for?

A

endothelial cell receptors that mediate angiogenesis

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55
Q

what does alpha5beta1 bind?

what does alpha2beta1 bind?

what does alpha6beta4 bind?

A

alpha5beta1 –> fibronectin

alpha2beta1 –> collagen

alpha6beta4 –> laminin

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56
Q

what is the first step of integrin signaling called?

A

INSIDE-OUT signaling

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57
Q

describe INSIDE-OUT signaling for integrin signaling (activation)

A
  1. integrin starts out inactive –> folded over PM and binds ECM proteins with low affinity
  2. chemokines and growth factors activate integrin –> elongated and 2 cytoplasmic domains separate to form pocket for ECM to bind with high affinity
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58
Q

what does activation of integrin require?

59
Q

function of talin

A

recruited due to GPCR into integrin beta-subunit and begins process for elongation and separation

60
Q

describe OUTSIDE-IN signaling (3 steps)

A
  1. once ECM binds activated integrin, there is clustering and creation of focal adhesions
  2. signaling proteins, tyrosine kinases, focal adhesion kinases recruited
  3. signaling begins!
61
Q

relationship btwn integrins and actin

A

integrins communicate with actin polymerase to change cell shape

62
Q

3 steps of integrin + actin relationship

A
  1. inactive talin activated by GPCR or RTK
  2. talin forms dimer which binds and activates integrins
  3. integrins mediate actin polymerization
63
Q

role of RTK?

A

mediate EMT and involved in diff stages of metastasis

64
Q

role of VEGFR1 and VEGFR3

A

VEGFR1 = driver of angiogenesis

VEGFR3 = driver of lymph angiogenesis

65
Q

unique thing about INSR/IGF1R

A

Only RTK family that is expressed on surface as DIMER –> when ligand binds, there is conformational change in cytoplasmic domain where 1 kinase domain can phosphorylate tyrosine in the other subunit

66
Q

6 steps of RTK

A
  1. Growth factor binds
  2. Receptor dimerizes
  3. Receptor auto-phosphorylates
  4. Adapter proteins and GEF protein bind
  5. Ras-GTP activates protein kinase cascade
  6. TFs become phosphorylated to alter gene expression
67
Q

4 results of mutations in RTK

A
  1. Autocrine loop
  2. Amplification
  3. Constitutive activation
  4. Genomic rearrangement (constitutively dimerized)
68
Q

what does EGFR activate? (2)

how does it relate to integrin?

A
  1. Akt for cell survival and metabolism
  2. Erk for cell proliferation

more potent than integrin

69
Q

when does EMT occur?

A

during normal development and cancer

70
Q

2 key regulators of EMT program

A

Snail1 and Snail2

71
Q

4 roles of Snail signaling

A
  1. Link Wnt, TGFbeta, notch signaling
  2. Upregulate MMP proteinases
  3. Upregulate Lef-1 partner of beta-catenin
  4. Block E-cadherin transcription
72
Q

what upregulates Snail signaling?

73
Q

What does beta-catenin do once Snail signaling causes E-cadherin to decrease?

A

when there’s reduced E-cadherin, beta catenin will activate transcription

74
Q

role of GSK3B

A

Guardian of beta-catenin stability –> keeps beta-catenin levels low by phosphorylating it and targeting it for degradation

75
Q

how do RTK and integrins affect GSK3B

A

Activate Akt by phosphorylation to inactivate GSK3B

76
Q

2 results of inactivated GSK3B

A
  1. Prevents beta-catenin degradation –> allows it to accumulate for increased transcription
  2. activates Snail1/2
77
Q

overall, 2 ways beta-catenin increase transcription for EMT

A
  1. Reduced E-cadherin = increased beta-catenin
  2. RTK and integrins inactivate GSK3B
78
Q

3 ways that TGFbeta induces EMT

A
  1. GSK3B
  2. SMAD2/3
  3. aPKC

^all upregulate Snail to repress E-cadherin

79
Q

what happens to cells treated with TGFbeta

A

cells become mesenchymal-like –> induces stress fibers and stretching

80
Q

in addition to EMT, what is an effect of TGFbeta?

A

regulates tumour microenvironment –> macrophage polarization, blocking T cell response to tumour

81
Q

what is cadherin switching? what induces it (2)?

A

switches from E to N cadherin –> induced by TGFbeta and beta-catenin

82
Q

where is N-cadherin normally expressed? how does this help the migrating cells?

A

N-cadherin is normally expressed on endothelium and nerve cells

epithelial cells lose ability to recognize each other so now they can bind endothelial and nerve cells at N-cadherin for migration

83
Q

in addition to physically helping migrating cells move, 2 other functions of cadherin switching

A
  1. N-cadherin stabilizes growth factor receptors
  2. N-cadherin competes with E-cadherin for p120 so beta-catenin can be released into cytoplasm
84
Q

N-cadherin and growth factor receptors (3)

A
  1. Stabilizes FGFR to drive cell proliferation and migration
  2. Stabilizes PDGFR to drive cell motility
  3. E-cadherin normally inhibits IGF, EGF, and FGF but N-cadherin releases this inhibition
85
Q

3 overall results of cadherin switching?

A
  1. increased detachment
  2. increased motility
  3. increased survival
86
Q

3 pieces of evidence for cadherin switching

A
  1. N-cadherin and other non-typical cadherins found in many tumours
  2. Non-metastatic carcinoma cell can become metastatic upon N-cadherin overexpression
  3. Carcinoma cells become non-invasive and non-metastatic upon N-cadherin silencing
87
Q

how do we know that cadherin switching is a LATE event?

A

Transgenic expression of N-cadherin does not induce tumourigenesis and does not alter tumour onset –> therefore not oncogenic, but helps once cancer has developed

88
Q

3 models of tumour migration

A
  1. Mesenchymal –> migrate in mesenchymal way as single or multi cell
  2. Solid strand –> migrate as cluster of cells
  3. Outward pushing tumour –> push thru as solid mass to break down tissue
89
Q

4 parts of single cell migration

A
  1. rear-end retraction
  2. actomyosin contraction
  3. proteolysis at leading edge
  4. pseudopod production, adhesion, traction force, proteolysis to break ECM
90
Q

collective cell migration

A

LEADING EDGE (aka microtrack) –> some cells make a channel to pull the rest of the cells along

Macrotrack –> the rest of the cells induce ECM remodeling along interface

91
Q

3 requirements of invasion

A
  1. tumour cells go thru many tissue compartments made of cells that are separated by ECM
  2. secretion of destructive enzymes that can locally degrade ECM
  3. tissue architecture breaks down so tumour can expand, invade blood vessels, and spread to distant sites
92
Q

what stages of metastasis require invasion?

93
Q

5 stages of metastasis that require invasion

A
  1. development of invasive potential
  2. expansive growth + basement membrane invasion
  3. angiogenesis, intravasation, transport thru body
  4. arrest and extravasation at secondary site
  5. invasion of secondary tissue for micro/macrometastasis
94
Q

what are MMPs regulated by? (2)

A

beta catenin and SNAIL

95
Q

what 2 ions do MMPs rely on?

96
Q

normal physiologic function of MMPs?

A

for matrix degradation when there is turnover of tissue where basement membrane must be broken

97
Q

4 main subclasses of MMPs

A
  1. collagenases
  2. gelatinases
  3. stromelysins
  4. MT-MMPs
98
Q

regulation of MMPs during metastasis

A

normally, MMPs have on/off signals for regulation but this system is broken during metastasis

99
Q

are most MMPs secreted?

A

yes, except MT-MMPs

100
Q

basic structure of MMP

A
  1. signal peptide
  2. pro domain
  3. catalytic domain
101
Q

role of pro domain

A

covers active site to prevent MMP from degrading matrix when not needed

102
Q

what is unique about gelatinases? why?

A

have fibronectin-like domains

integrins bind fibronectin so if there’s integrins in focal adhesion, MMP can bind these sites and concentrate themselves for a lot of proteoly

103
Q

2 examples of gelatinases

A

MMP2 and MMP9

104
Q

what is unique about MT-MMPs?

A

have unique transmembrane domain that allows them to sit on PM and concentrate proteolysis in 1 spot on cell surface

105
Q

4 ways of MMP regulation

A
  1. gene expression
  2. activation
  3. inhibition
  4. proteolytic cascades and feedback mechanisms
106
Q

what is the mechanism for MMP activation called? how does it work (3 steps)?

A

called CYSTEINE-SWITCH

  1. pro domain is cleaved/chemical enters
  2. Zn within active domain has cysteine replaced by water
  3. Active site is no longer sequestered and enzyme can begin breaking down ECM
107
Q

3 roles of MT-MMPs?

A
  1. act as MMPs for proteolysis
  2. on cell surface can cleave pro domain to activate other MMPs
  3. on cell surface can cause shedding of molecules like TNF
108
Q

what are invadopodia?

A

actin-rich protrusions of PM associated with ECM degradation

109
Q

what are found in invadopodia? (2)

A
  1. mediators like RTK
  2. MMPs
110
Q

4 stages of invadopodia formation

A
  1. TRIGGER –> integrin, chemokine, growth factor
  2. forms scaffold that accumulate in site of actin polymerization and induce actin polymerization
  3. MMP14/19 recruited to stabilize scaffold
  4. MMPs activated to degrade matrix in focalized site for invadopodia maturation
111
Q

what do we expect to happen to invasion and invadopodia with KO chemokine receptor?

A

less invasion, less invadopodia

112
Q

why is invadopodia an efficient way to invade?

A

concentrates all degradation power in 1 place

113
Q

ADAMs and ADAMTs
- type of molecule
- transmembrane or secreted?

A

ADAM = disintegrin and MMP (transmembrane)

ADAMT = disintegrin and MMP with thrombospondin motifs (secreted)

114
Q

when are ADAMs and ADAMTs highly expressed?

A

in cancers

115
Q

7 domains of ADAM

A
  1. Pro domain
  2. MMP domain
  3. Disintegrin domain
  4. EGF domain
  5. cysteine-rich domain
  6. transmembrane domain
  7. cytoplasmic domain
116
Q

why are ADAMs and ADAMTs aka sheddases?

A

can cleave PM proteins to secrete ectodomains

117
Q

role of ADAM and ADAMT

A

for ECM proteolysis, EMT, etc

118
Q

3 ADAM substrates

A
  1. degrade E-cadherin
  2. TNFalpha
  3. Notch
119
Q

4 non-specific MMP inhibitors + where are they produced and found?

A
  1. Alpha2-macroglobulin
  2. Alpha1-proteinase inhibitor
  3. Alpha1-chymotrypsin
  4. Alpha2-antiplasmin

produced in liver, circulate in plasma

120
Q

specific MMP inhibitors
- how are they produced?
- NT domain?
- CT domain?
- where do they act?

A

TIMPs 1-4
- produced by tumour or host cells from diff genes
- NT domain = 125 aa
- CT domain = 65 aa
- act regionally/specifically

121
Q

how do TIMPs 1-4 interact with MMPs (2)?

A

INACTIVE MMP –> bind pro domain to block activation

ACTIVE MMP –> blocks catalytic activity

122
Q

why is the tumour microenvironment important for proteolytic cascades? (2)

A
  1. MMPs activate each other
  2. other enzymes, like plasmin, can activate MMPs
123
Q

4 factors that the microenvironment can produce for angiogenesis

A
  1. VEGF-A
  2. VEGF-C
  3. Pro-tumour macrophages
  4. Immune cells, tumour cell, TNFalpha, integrins
124
Q

role of VEGF-A in angiogenesis

A

initiates angiogenesis from existing vessels

125
Q

role of VEGF-C in angiogenesis

A

main trigger of LYMPH angiogenesis

126
Q

example of angiogenesis inhibitor?

A

ECM collagen

127
Q

how do ECM collagens inhibit angiogenesis?

A

Endostatin/Turnstatin/Vastatin/Restin (aka NT of collagens) is cleaved when MMP cleaves collagen and inhibits angiogenesis

therefore, the product of invasion can shut down angiogenesis

128
Q

what is the seed and soil hypothesis?

A

must have compatibility btwn seed (cancer cells) and soil (target organ)

some cancers tend to metastasize to very specific organs but can’t really explain sites of metastasis from the pattern of circulation

129
Q

how can we predict the site of metastais? + assay to discover this

A

GENE SIGNATURES can predict the site of metastasis

took tumour cells and continuously passaged thru lung/brain/bone ==> RNA seq and found that cells for lung/brain/bone each had diff gene expression

130
Q

role of chemokines in tumour cell movement

A

chemokines are unique to diff organs and form gradients towards cancer cells that express chemokine receptors –> guide tumour cells towards target organ

131
Q

6 steps of movement towards target organ w chemokines

A
  1. tumour cells binds E-selectin
  2. ECM degraded by MMP proteolysis
  3. respond to chemokines
  4. break barrier
  5. move towards chemokines in target organ
  6. begin proliferating at new organ
132
Q

describe host-tumour interactions with adhesion

A

adhesion mediated by the fact that tumour cells interact with inflammatory cells and blood cells

133
Q

4 steps of tumour cells metastasizing in liver:

A
  1. cells transverse endothelium and enter liver
  2. attach to vessel via E-selectin
  3. cells enter space of Disse
  4. hepatic stellate cells induce ECM deposition to create tracks for tumour cells to transverse and cause angiogenesis
134
Q

what is a pre-metastatic niche?

A

organs of future metastasis are selectively and actively modified by the primary tumour even BEFORE metastatic spread has occurred –> i.e. tumour induces changes in distant microenvironment

135
Q

what causes PMN formation?

A

results from combined systemic effects of tumour-secreted factors and tumour-shed extracellular vesicles

136
Q

what INITIATES PMN formation? (3)

A
  1. induction of leaky vessels
  2. remodelling of stroma and ECM
  3. systemic effects on immune system
137
Q

describe the extracellular vesicles on cancer cells for PMN

A

extracellular vesicles/exosomes containing mediators will deliver the signal to target organs and determine the PMN + secrete chemokines for recruitment of cells

138
Q

describe cancer dormancy

A

not every cell that enters new organ will form metastasis –> some remain dormant and may develop later

139
Q

what process must occur once the cancer cells enter the new organ?

A

Mesenchymal to epithelial transition (MET)

140
Q

Why does MET occur?

A

in the new organ, tumour doesn’t need to be migratory anymore –> needs to be stationary

141
Q

what occurs in MET?

A

re-expression glues aka collagen that hold cells together so they can expand

142
Q

when is metabolic adaptation required?

A

crucial for tumour cell survival and growth in secondary organ

143
Q

why is metabolic adaptation required?

A

each organ has unique metabolic landscape –> tumour cells must metabolically adapt

144
Q

why can metabolic adaptation explain cancer dormancy

A

tumour cells may be unable to reprogram metabolically and stay dormant

145
Q

why does metastasis cause a therapeutic challenge?

A

metastasis is dynamic –> diff stages in lifespan of metastatic cell may require diff approaches

EXMD504 (12 decks)

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