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EXMD 504 > Terrible class > Flashcards

Terrible class Flashcards

1
Q

what is the cause of 90% cancer related mortality

A

metastasis

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2
Q

what are the 5 major steps in metastasis

A

-invasion and infiltration of surrounding normal host tissue
-release of neoplastic cells
-survival in the circulation
-arrest in the capillary beds of distant organs
-penetration of the lymphatic or blood vessel walls followed by growth of the disseminated tumor cells

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3
Q

true or false: only a small % of circulating cancer cells will form metastases

A

true

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4
Q

primary to secondary tumor site test

A

-cell detachment
-invasion of stroma
-intravasation
-migration
-extravasation
-establishment of metastases (in secondary organ site)

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5
Q

what happens in cell detachment

A

-emt
-matrix degrading proteinase (augment)
-growth factors and receptors (egfr, igf1r and tgf) go up
-adhesion molecules go down
-proteinase inhibitor go down

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6
Q

what happens in migration

A

-endothelial cell and adhesion molecules go up

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7
Q

what happens in extravasation

A

-selectin ligans change
-integrins and matrix degrading proteinasa

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8
Q

what happens in establishment of metastases

A

-interaction with local micro environment
-cell-cell adhesion molecules go up
-autocrine and paracrine growth regulatory factors (igf1, igf1r) go up

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9
Q

in vivo models

A

-analysis of surgical biopsies
-histopathology, genome, transcriptome, proteome
-animal tumor models (induction, transplantation, spontaneous and experimental metastasis)
-transgenic mice
-human tumor xenographs
-circulating tumor cells aka liquid biopsiesi

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10
Q

in vitro models

A

-cell lines
-reconstitutes tissues like vessels
-extracellular matrix models
-genetically altered cells
-PDX/organoids/slices

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11
Q

how to know that the poly metastasized

A

-the basal membrane is degraded
microinvasion of tumor

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12
Q

true or false: there can be hyperplasia without metastasis

A

true

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13
Q

what is the key to aquisition of a motile phenotype

A

epithelial to mesenchymal transition

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14
Q

what is downregulated during loss od apico basal polarity

A

e-cadherins and epithelial integrins

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15
Q

what is up regulated during gain of mesenchymal proteins

A

-n cadherins
-mesenchymal integrins
-vimentin

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16
Q

before transition what happened

A

-cell adhesion by adherens/tight junction
-apical basal polarity
-non migratory
-express epithelial markers like ecadherins

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17
Q

after emt what happened

A

-spindle shaped morphology
-loss of cell junctions
-change in cell polarity
-cleavage and invasion of basal lamina
-migration along fibronectin matrix
-express mesenchymal markers like n cadherin

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18
Q

what does fibronectin do

A

migration tracks

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19
Q

which ligans make homophilic interactions

A

-e cadherins and ig-superfamily
-cams aka N cams and type III fibronectin repeats

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20
Q

which ligans make heterophilic interactions

A

-mucins like CAMs and P selectins
-integrins and fibronectin

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21
Q

what is the binding sites of e cadherins

A

ca2+ binding sites

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22
Q

what does E selectin do

A

expressed on endothelial cells mediated tumor cell attachment in blood vessels

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23
Q

what is the hallmark of EMT

A

reduced E cadherins expression

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24
Q

where are N cadherins

A

-neural
-neurons, muscle, endothelial cells

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25
Q

where are e caherins

A

-epithelial cells/tissues

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26
Q

where are P cadherins

A

-placenta

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27
Q

where are r cadherins

A

retina

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28
Q

where are ve cadherins

A

-vascular endothelial cells

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29
Q

what are the roles of cadherins

A

-mediate calcium dependant homotypic cell-cell adhesion
-during embryogenesis mediate cell sorting
-formation of intercellular junctions like adheren, gap, tight, desmosomes
-establish cell polarity
-inhibit apoptosis
-activate or inhibit growth factor receptors like tyrosine kinases

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30
Q

what is a catetin

A

a bridge to actin cytoskeleton

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31
Q

what is eplin

A

epithelial protein lost in neoplasia links a catetin and actin

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32
Q

what does p120 do

A

a src kinase substrate, stabilizes e cadherin and links it to the other signaling systems

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33
Q

what is b catenin

A

a transcription factor in wnt signaling

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34
Q

what does HAV containing peptides do

A

-bind to eachother
-can disrupt adhesion and trigger cell migration

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35
Q

well differenciated, poorly invasive adenomas express what?

A

high E cadherin levels

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36
Q

invasive carcinomas express what?

A

have reduced e cad levels

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37
Q

invasive carcinomas have reduced e cad levels why?

A

transcriptional repression/inactivation dna methylation , mutations or post transcriptional events

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38
Q

e cadherins levels and the stability of e cad catenin complex can be de regulated through what?

A

phosphorylation of e cad, b catenin or p120 catenin by activated receptor tysosine kinases

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39
Q

e cad can negatively regulate what?

A

rtk

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40
Q

a reduction in e cad levels increase what????

A

cell motility, invasion and triggers b catenin/lymphoid enhancer binding factor: lef1 regulated transcription

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41
Q

what are the 3 classes of molecules in the ecm

A

-structural proteins (collagens and elastins)
-protein polysaccharide complexes to embed the structural proteins (proteoglycans)
-adhesive glycoproteins to attach cells to matrix (fibronectins and laminins)

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42
Q

what is the ecm

A

-web of proteins and carbohydrates at cell surface
-outside plasma membrane
-connected to cytoskeletal fibers and transmembrane proteins

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43
Q

18 a subunits and 8b subunit of integrins associate to form what….

A

multiple non-covalently bound heterodimeric transmembrane receptors

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44
Q

which endotelial cells receptors mediate angiogenesis

A

fibronectin
vitronectib
osteopontin
tenascin

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45
Q

integrin signaling cascade steps

A

-step 1: inside out signaling: an unbending and elongation of the dimer
-step 2: outside in signaling : separation of the 2 cytoplasmic abilities

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46
Q

true or false: integrins associate with receptor tyrosine kinases to amplify survival and growth signals

A

true
ex: avb3 with IR, vegfr and pdgfr and a5b1 with egfr

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47
Q

integrin signaling involves ….. with other regulatory signaling pathways

A

crosstalk
-there is focal adhesion

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48
Q

which kinases can mediate emt anbd are involved in different stages of metastasis

A

receptor tyrosine kinase

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49
Q

which rtks are already a dimer

A

insr
igf1r
irr

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50
Q

ras cascade

A

-growth factor binding
-receptor dimerization
-receptor autophosphorylation
-binding of adaptor protein and gef protein at membrane
-activated ras aka ras gtp activated a protein kinase cascade
-phosphorylated transcription factors ebter the nucleus to change gene expression

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51
Q

main roles of activation of rtks in human tumors

A

-autocrine loop
-amplification
-constitutive activation by point mutation
-genomic rearrangemnet- constituvely dimerized fusion protein

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52
Q

what is emt

A

-epithelial mesenchymal transition is an essential process during devlopment and is replicated in early stages of malignant progression

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53
Q

what are snail 1 and 2

A

-slugs are key regulators of the emt program linking wnt, tgfb and notch signalling

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54
Q

what does snail upregulate

A

-fibronectin
mmp
lef 1

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55
Q

what does snail down regulate

A

e cadherin

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56
Q

20x increse in snail 1 in patients with what

A

metastatic relative to non metastatic hcc

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57
Q

true or false: nfkb is an inflammatory mediator that downregulates snail

A

false it up regulates it

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58
Q

what is gsk 3b

A

glycogen synthase 3b is a destabilizer of b catenin (narking it for proteosomal degradation), smad, notch 1 and snail which is at the crossroad if severak signaling pathways

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59
Q

what does sinc finger e box binding homeobox proteins zeb1/2

A

represses e cad and increase mmp expression

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60
Q

tgfb signalling is a major inducer of what

A

emt

61
Q

true or false: tgfb1 is a transcriptional repressor of e cad

A

true

62
Q

mouse mammary epithelial cells undergo emt in response to what and how can it be blocked

A

tgfb1 can be blocked by n cad shrna

63
Q

GSK-3 b - guardian of epithelial phenotype through its negative regulatory effect on
…..

A

b-catenin, SMAD, Notch1
and Snail

64
Q

GSK-3
b phosphorylation by AKT releases t…….

A

his inhibition, stabilizing these TF and targeting them to the nucleus for transcriptional activation of EMT drivers

65
Q

Signaling pathways that activate AKT (RTK, integrins)
or SMAD (TGF b) can initiate ….

A

EMT

66
Q

true or false: tgfb only induces emt

A

false, it also regulates the tumor microenvironment

67
Q

E-N Cadherin switching occurs in many cancers, is probably a …..

A

late event and can influence many cellular activities

68
Q

effects of e-n cadherin switching

A

-increased detachment (loss of sorting)
-increased motility
-increased survival

69
Q

Circulating soluble N-cadherin has been observed in the serum of cancer patients and shown to stimulate …..

A

angiogenesis and the migration of endothelial cells by associating with fibroblast growth factor receptor (FGFR)

70
Q

what does e cadherin INHIBIT

A

-igf, egf and fgf receotir signaling

71
Q

WHAT DOES N CADHERIN upregulate

A

expression induced by tgfb and b catenin

72
Q

Non metastatic carcinoma cell (MCF-7) become metastatic upon
….

A

N-cadherin overexpression

73
Q

N-cadherin silencing in pancreatic carcinoma cells renders them…..

A

non-invasive and non-metastatic

74
Q

Transgenic expression of N-cadherin does not cause …..

A

tumorigenesis and does not alter tumor onset in mammary carcinoma models (Polyoma middle T or Neu) although it could accelerate metastasis

75
Q

Cadherin switch is a late event, not oncogenic but promotes…..

A

invasion and metastasis.

76
Q

what are the different modes of tumor migration

A

-MESENCHYMAL
-mesenchimal multicellular
-solid strand
-outward pushing tumor

77
Q

steps of individual cell migration

A

-pseudopod protrusion adhesion and traction force generation
-focalized proteolysis
-actomyosin contraction
-rearend retraction s

78
Q

steps of collective cell migration

A

-same steps as individual
0multicellular group ecm remodeling along interface macrotract

79
Q

invasion into surrounding tissue requires that:

A

-tumor cells traverse several tissue compartments comprised of cells seperated bu the ecm
-destructive enzymes are secreted that can locally degrade the ecm
-tissue architecture breaks down, enabling the tumor to expand, invade neighboring blood vessels and spread to distant sites

80
Q

true or false: invasion is a requirement at all stages of the metastatic process

A

true

81
Q

what are the classes of proteinases

A

serine
cysteine
aspartic
metallo

82
Q

what are exampkes of metallo proteinases

A

collagenese and stromelysin

83
Q

true or false: mmps are sinc and calcium dependent enzymes

A

true

84
Q

who are the normal physiologic mediators of matrix degradation

A

mmps

85
Q

true or false: mmps share a high degreee of structure homology but differ in substrate specificity

A

true

86
Q

what are the sub classes of mmpa

A

collagenases
-gelatinases
-stromelysins
-mt-mmps and other

87
Q

true or false: mmps play a hige role in invasion and metastasis

A

true

88
Q

how many genes encode for mmts

A

23 in humans

89
Q

what is special in mmp 2 and 9

A

rhey have fibronectin type 2 repeats
they are gelatin binding

90
Q

what do mmp 2 and 9 do when you ko them

A

metastasis and angionesis reduced in KO mice

91
Q

where are located mt mmps

A

transmembrane

92
Q

what are the minimal domains of mmps

A

mmp 7 and 26

93
Q

what is mmp1

A

it is a standard domain

94
Q

The MMPs are tightly regulated at multiple levels

A

 Gene expression
 Activation
 Inhibition
 Proteolytic cascades and feedback mechanisms (MMP can cleave plasminogen) to ensure tightly regulated tissue processing

95
Q

what mechanism regulate mmps

A

the cysteine switch
-it has a pro domain that sirts on top of the catalytic domain rendering the enzyme inactive
-becomes active when the pro domain is displaced

96
Q

MMP-2 KO mice :

A

Blockade of experimentally induced pancreatic
carcinogenesis; suppression of angiogenesis and tumor growth ;
delayed mammary gland differentiation; mild growth retardation.

97
Q

MMP-9 KO mice :

A

Blockade of experimentally induced skin
carcinogenesis; suppression of experimentally induced pancreatic
carcinogenesis; decreased experimental metastasis

98
Q

MMP-11 KO mice:

A

Suppression of experimentally induced mammary carcinogenesis; decreased tumor cell survival and growth

99
Q

MMP-14 KO mice:

A

Reduced collagen turnover; defective angiogenesis

100
Q

MT4-MMP in breast cancer cells involved
in …..

A

vessel dissociation and intravasation
increasing metastasis.

101
Q

what is the invadopodia

A

are actin-rich protrusions of the plasma membrane that are associated with degradation of the extracellular matrix. They play a crucial role in cancer cell invasion and metastasis

102
Q

what is adam

A

disintegrin and metalloproteinase – mostly
transmembrane

103
Q

WHAT IS ADAMT

A

disintegrin and metalloproteinase with thrombospondin motifs -secreted

104
Q

what is the cr region on the adams

A

hypervariable region, site of molecular reactions

105
Q

what are the dis and egf regions

A

integrin binding substrate specificity

106
Q

what do the adms participate in

A

ecm proteolysis and engance cancer cell growth

107
Q

21 known human ADAMS Can mediate…..

A

Proteolysis of BM proteins E-Cad degradation Processing of GF, cytokine
precursors

108
Q

ADAM10 and ADAM 17 expression levels
increase in

A

CRC liver metastases ADAM12 –ectodomain shedding of VE-CAD

109
Q

adam10 is alssociated with what

A

e cadherin

110
Q

what is adam17 associated with

A

protnfa, proamphiregulin and notch

111
Q

inhibitors of mmps in the plasma

A

a2-macroglobulin
a1-proteinase inhibitor
a1-chymotrypsin
α2-antiplasmin
-produced in liver, actibe in plasma and non specific

112
Q

what do TIMPS 1-4 do

A

-inhibitors of mmps in plasma
- products of separate genes
 NT domain of 125 a.a. and CT domain of 65 a.a.
each stabilized by s-s bonds
 produced by tumor (or host cells)
 highly specific
 act regionally

113
Q

true or false timp can bind to inactibe forms of mmp

A

it can also bind to the active form of mmp

114
Q

which cell do mmp2 and plasmin bind to

A

on tumor cells

114
Q

he tumor microenvironment is critical and contributes to proteolytic cascades of….

A

MMP-2

115
Q

New blood vessels provide ….

A

a source of nutrients and oxygen and a venue for dissemination

116
Q

the angiogenic switch is necessary for what

A

tumor growth and metastasis

117
Q

what happens in neovascularization

A

-makes rapid tumor growth possible bu supplying ocygen and nutrients and removing waste
-facilitates metastasis

118
Q

angiogenesis can be triggered by what

A

tumor or microenvironmnet derived factors

119
Q

Angiogenesis and lymphangiogenesis are orchestrated through interplay between

A

GF (VEGF), cytokines (TNFa) and integrins

120
Q

ECM collagens are a source of ….

A

angiogenesis-inhibitor
-inhibitors are built in the invasive process

121
Q

linical and experimental evidence
support Paget’s ……hypothesis
…..

A

-“seed and soil”
-Tumor-intrinsic and extrinsic determine the site of metastases.
-basically the type of tissue will determine the type of cancer

122
Q

true or false: gene signatures can predict the site of metastasis and outcome

A

yeah

123
Q

tumor cell movement toward a target organ is mediated by what

A

cytokineswha

124
Q

t what is the role oc cxclr4-6

A

plays a role in tumor cell extravasation crosstalk with tumor associated stroma

125
Q

where is found cxcr4-6 and mcp4

A

multiple organs

126
Q

where is ccl20 found

A

in liver

127
Q

where is ccl21 cound

A

lymph nodes and lung

128
Q

time line of the early steps in organ colonization

A

-interaction with platelets 0-2 min
-interaction with neutrophils 2 min to 7-24h
-interaction with monocytes and macrophages rest of the time

129
Q

Tumor cells form
microthrombi with platelets,
this protects them from….

A

shear stress and NK-mediated
lysis.
-It is also a source of
TGF b and PDGF.
 Microthrombi do not form in
P-selectin−/− mice and these
mice are protected from
metastasis

130
Q

true or false: cells derived from the bone marrow precede tumor cells to the site of metastasis

A

true

131
Q

Cells derived from the bone marrow (green) precede tumour cells (red) to the
lung, the site of metastasis. The bone-marrow cells create…..

A

a proposed ‘pre-metastatic niche’, and the tumour cells join them to form a metastasis.

132
Q

Organs of future metastasis are selectively and actively ….

A

modified by the primary tumor before metastatic spread has occurred

133
Q

Tumors induce the formation of microenvironments in distant organs that are conducive to
…….

A

the survival and outgrowth of tumor cells before their arrival at these sites. These
microenvironments are termed pre-metastatic niches (PMNs).

134
Q

PMN formation is a ……. process resulting from the combined systemic effects
of tumour-secreted factors and tumor-shed extracellular vesicles

A

step wise process

135
Q

PMN formation is initiated with local c….

A

changes such as the induction of vascular
leakiness, remodelling of stroma and extracellular matrix, followed by systemic
effects on the immune system

136
Q

The development of new technologies and approaches to identify PMNs in

A

distant organ sites in patients could revolutionize cancer treatment and lead to pre-emptive treatments to hinder metastasis

137
Q

what delivers the signals to theorgans abouy the cancer cell

A

exosomes

138
Q

Exosomes produced by pancreatic cancer cells induce

A

a pre-metastatic niche in the liver

139
Q

Exosomal integrin expression as a potential predictor of

A

-patient organ-specific metastasis.
-NED- no evidence of disease
-LR- locoregional disease
-POD-predictor of dissemination

140
Q

In the target organ cancer cells (often) undergo…..

A

mesenchymal to epithelial transition (MET)

141
Q

Re-expression of…. is required for establishment of liver metastases

A

type iv collagen

142
Q

Metabolic adaptation is crucial for tumor cell ….

A

survival andgrowth in a secondary organ.

143
Q

The metabolic landscape of each organ is …

A

unique

144
Q

Tumor cells in a secondary site need to adapt….

A

metabolically to
the new organ site to produce ATP and to survive

145
Q

Dormancy may also result from the inability of tumor cells to …

A

reprogram metabolically

146
Q

true or false: in the target organ, some cells will enter a dormant state

A

true

147
Q
A

EXMD 504 (12 decks)

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