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BIMM 134 - Cancer > Final content - week 9 > Flashcards

Final content - week 9 Flashcards

1
Q

What is VEGF? is it considered a tumor suppressor? or pro-oncogenic?

A

a major pro-angiogenic factor

a pro-oncogene

oncogene, if mutated, promoting the formation of cancer cells

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2
Q

what is TAM? TAMR?

define TAM + what kind or receptor

A

(a) tumor-Associated Macrophage - a type of white blood cell involved in the immune system’s response to inflammation and tissue repair

(b) tyrosine kinases receptor

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3
Q

what is CAF?

3 points

A
  • Cancer-Associated Fibroblast - a type of connective tissue cell involved in wound healing and tissue structure
  • Activated CAFs create an environment that prmotes growth of pre-exsisting tumors
  • CAF activation is up-regulated in cancer

regardless of how they’re activated

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4
Q

Steps of angiogenesis

A

step 1: Activation of the angiogenic switch via oncogene activation/tumor suppressor mutations/hypoxia

step 2: VEGF production via cancer cells, TAM, and CAF

step 3: VEGF binds to VEGFR triggering downstream signaling pathways in endothelial cells

step 4: Endothelial cell responses

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5
Q

how is the angiogenic switch turned on? what happens once its turned on?

A

via oncogene activation/tumor suppressor mutations/hypoxia

Decreased anti-angiogenic factors (thrombospondin & statins)

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6
Q

How do Endothelial cell responses to form new blood vessel formation?

A

Via Proliferation, matrix degradation, survival, motility

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7
Q

what is thrombospondin?

A

a natural inhibitor of angiogenesis

downregulated in cancer
–> reduced levels or activity can contribute to uncontrolled blood vessel growth

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8
Q

what is statins?

A
  • Inhibit the production of pro-angiogenic factors like VEGF
  • inhibit the growth of new blood vessels
  • downregulated in cancer
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9
Q

what do endostatins - a type of statins - bind?

what does binding lead to?

A

bind integrins found on endothelial cells

leads to the inhibition of migration, proliferation, and survival

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10
Q

what do angiostatins - a type of statins - bind?

A

bind integrins found on endothelial cells

inhibits endothelial cells

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11
Q

VEGF and VEGFR: what does VEGFA binding VEGFR-2 promote? how?

A
  • vascular permeability, cell proliferation, survival, motility, protease production
  • via increase in NOS
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12
Q

what is NOS?

A

Nitric Oxide Synthase

enzymes responsible for producing nitric oxide

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13
Q

is VEFG increased or decreased in cancer cells?

A

increased

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14
Q

VEGF and VEGFR: VEGF receptors are

(a) what kind of receptors?

(b) what does it increase?

A

(a) tyrosine kinase receptors

(b) RAS/MAPK/PI3K pathway which are downstream of VEGFR

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15
Q

VEGF has how many isoforms? VEGF-A

A

VEGF has 6 isoforms A -E

VEGF-A has 4 isoforms

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16
Q

VEGFR have how many isoforms?

A

three isoforms (1-3)

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17
Q

what does VEGFA-VEGFR2 binding do?

A

stimulates angiogenesis

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18
Q

what does VEGFA-VEGFR1 binding do?

A

modulates VEGFR2 such that it prevents excessive angiogenesis

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19
Q

what does VEGFA-NRP binding do?

A

stimulates angiogeneses indirectly

enhance VEGFR-2 signaling

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20
Q

what does VEGFA-VEGFR3 binding do?

A

lymph angiogenesis - growth of lymph system

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21
Q

what are EPHRINS?

A

ligands - signaling molecules

bind to tyrosine kinase receptors on cell surface

Control blood vessel formation

Altered levels in cancer angiogenesis

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22
Q

what are some examples of EPHRINS?

A

B4 and B2

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23
Q

What EPHRINS does VEGF increase in cancer? which does it decrease? why do levels have to change?

A

increase B2

decrease B4

they change for the max amount of vascular growth

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24
Q

VEGF binding to epithelial cells promotes…

A

angiogenesis

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25
Q

if B4 is on the surface of the cell, what will happen?

A

it will decrease cell sprouting which DECREASES angiogenesis

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26
Q

if B2 is on the surface of the cell, what will happen?

A

it will INCREASE cell sprouting

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27
Q

what surface will B4 bind to? what about B2?

A

surface of veins

surface of arterioles

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28
Q

what happens when B4 binds to its receptor ?

what decreases?

A

decrease VEGF

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29
Q

what happens when B2 binds to its receptor ?

A

veins + arterials will grow inconjunction to one another

such that they are developing together in a way that complements each ot

30
Q

what is ANGIOPOIETINS 1?

A

a protein that promotes structural integrity of existing blood vessels

31
Q

what is ANGIOPOIETINS 2?

A

a protein that promotes the formation of NEW blood vessels

32
Q

what happens when ANGIOPOIETINS 1 binds to its receptor? what receptor does it bind?

A

it promotes survival + pericyte attachment

it binds to TIE-2, a TKR receptor located on the surface of endothelial cells in the blood vessel

33
Q

what happens when ANGIOPOIETINS 2 binds to its receptor? what receptor does it bind?

A

it promotes pericyte Detachment + proliferation

it binds to TIE-2, a TKR receptor located on the surface of endothelial cells in the blood vessel

34
Q

ANGIOPOIETINS 2: are they tumor suppressors or pro-oncogenes?

A

pro-oncogene

35
Q

endothelial vs epithelial cells

A

endo: Endothelial cells line the inner surface of blood vessels (arteries, veins, and lymphatics)

epa: Epithelial cells form the lining of various surfaces throughout the body, both internal and external

36
Q

how are ANGIOPOIETINS secreted

A

by pericyetes

37
Q

what are pericytes?

A

supporting cells recruited upon vessel formation

38
Q

what is meant by angiogenic effect observed after the binding of ANGIOPOIETINS2 - TIE2

aka. what is needed to form angiogenic vaasculature? 2 things

A

to form angiogenic vasculature…
permeability has to increase and tear down existing vasculature in order to form NEW vessels

39
Q

ANGIOGENIC PROMOTERS: purpose?

A

drives angiogenesis

40
Q

example of ANGIOGENIC PROMOTERS

A

PDGFB

41
Q

PDGFB function?

what to they bind?

what and when are they released

A

released by endothelial cells once blood vessels are formed

they will bind to receptor on surface of pericytes

indirect function

42
Q

what happens once PDGFB binds to PDGFR?

A

it tells the pericyte to begin association to existing epithelial cells

43
Q

matrix degradation: what is MMP?

A

Matrix metalloproteinases - zinc dependent protease degrade ECM (extra cellular matrix)

44
Q

MMP: what is it and what is its purpose?

A

enzyme that degrades the extracellular matrix (ECM)

45
Q

Matrix degradation steps

A

step 1: MMPs degrade the ECM during angiogenesis

step 2: endothelial cells migrate and sprout through the newly created gaps in the matrix.
–> These endothelial cells then proliferate and form new blood vessels.

step 3: Growth factors + VEGF are released to bind receptors on endothelial cells

step 4: Degradation of the ECM reveals matrix components

46
Q

what are INTEGRINS?

type of receptor AND location

A

dimeric transmembrane receptor proteins

located on surface of blood vessels

interact with cell-matrix

47
Q

which INTEGRINS does cancer upregulate?

A

AVB3 + AVB5

48
Q

how do INTEGRINS interact with the cell matrix?

bind what and promote what?

A

bind to matrix components promoting survival, growth, and motility

49
Q

what will increased interactions with cell matrix components lead to?

A

leads to the release of more VEGF and more MMP

50
Q

What is VEGFR-2?

what type of receptor

A

A pro-angiogenic receptor

51
Q

what is TSP (thrombospondin)

what type of proteins?

A

glycoproteins found in the extracellular matrix

anti-angiogenic - inhibit the growth of new blood vessels

52
Q

what is one of the things TSP does?

e.g. what does it bind?

2 points

A

bind endothelial cells via CD36R

binding leads to inhibition of angiogenesis

binding leads to apoptosis

53
Q

what is one of the things TSP does?

e.g. what does it release?

2 points

A

FASL released upon TSP-CD36 binding

FASL-FASR interaction triggers endothelial cell apoptosis

54
Q

Where is FASR present?

A

Only in endothelial cells

55
Q

what is one of the things TSP does?

e.g. what does it inhibit?

A

TSP-CD47R binding on endothelial surface inhibits VEGFR2 activity

56
Q

what is one of the things TSP does?

e.g. what does it sequester?

A

Sequesters growth factors making them unavailable for endothelial cells

57
Q

what is one of the things TSP does?

e.g. what does it inhibit?

A

inhibits MMP when released by cancer and endothelial cells - prevents them from aiding blood vessel growth

58
Q

is TSP considered a tumor suppressor? or pro-oncogenic?

A

a tumor suppressor and if mutated, it will promote formation of cancer cells

59
Q

Therapeutics - VEGF inhibitors: Aflibercept

A

soluble VEGF receptor

60
Q

Therapeutics - VEGF inhibitors: Avastin

A

monoclonal antibody (mAb) against VEGF

61
Q

Therapeutics - VEGF inhibitors: Ramucirumab

A

mAb against VEGFR-2

62
Q

Therapeutics - VEGF inhibitors: Small molecule inhibitors

A

TK inhibitors

63
Q

Therapeutics - Pericytes: SU688

A

PDGFB receptor inhibitor

Combining pericyte and EC therapy -> removing pericyte protection before targeting endothelial cells

64
Q

Angiogenic vasculature can result
in poor chemotherapeutic delivery

Incentive used to normalize cancer
vasculature. Why?

how can this be treated?

A

its easy for therapeutics to leak out or get wedged into cancer vasculature

can deliver drugs that improve their vasculature surrounding cancer cells

65
Q

Hallmarks of resistance: Redundancy of growth factors

explain

A

endothelial cells release several growth factors so if there is 1 GF that docent work , its okay bc others are present

66
Q

Hallmarks of resistance: cancer cells engage in bone marrow cell recruitment

explain

what is recruited?

A

once endothelial cells release several growth factors…

Myeloid-derived suppressor cells which suppress the immune system

Endothelial progenitor cells which contribute to the formation of new blood vessels

are recruited

67
Q

Hallmarks of resistance: Increasing metastatic properties

explain

A

cancer cells leave if environment isn’t suitable via increasing MMP and GF

create a hypoxic state which leads to HIF-alpha expression

leads to the following:
1) increased metastatic potential
2) Increased Tregs
3) Increased MDSC
4) Increased cancer stem cells
5) Increased tumor-associated cell activation
6) release of VEGF

68
Q

Hallmarks of resistance: Activation of stroma cells

explain

A

Stromal cells such as CAF and pericytes are the connective tissue components surrounding tumors

CAF releases SDF-1 and MMP
Pericytes release PDGFB

69
Q

Hallmarks of resistance: Alternative vascularization

explain

A

vessel co-option: cancer cells grow in the direction of blood vessels to use it for their own blood supply

Vascular mimicry: cancer cells differentiate to a cell of their choice to build their own blood vessels

70
Q

explain what the Metastatic Cascade is.

What are the steps? 5 total

A

series of steps allows cancer cells to spread from the primary tumor to distant organs

Step 1: epithelial state - cancer cells are stationary

step 2: stroma is activated

step 3: cells undergo transition to mesenchymal state - cancer cells are motile, allowing for metastasis

step 4: metastasis - from a secondary tumor

step 5: secondary tumor transitions into the epithelial state

BIMM 134 - Cancer (4 decks)

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