Final content - week 9 Flashcards
What is VEGF? is it considered a tumor suppressor? or pro-oncogenic?
a major pro-angiogenic factor
a pro-oncogene
oncogene, if mutated, promoting the formation of cancer cells
what is TAM? TAMR?
define TAM + what kind or receptor
(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
what is CAF?
3 points
- 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
Steps of angiogenesis
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
how is the angiogenic switch turned on? what happens once its turned on?
via oncogene activation/tumor suppressor mutations/hypoxia
Decreased anti-angiogenic factors (thrombospondin & statins)
How do Endothelial cell responses to form new blood vessel formation?
Via Proliferation, matrix degradation, survival, motility
what is thrombospondin?
a natural inhibitor of angiogenesis
downregulated in cancer
–> reduced levels or activity can contribute to uncontrolled blood vessel growth
what is statins?
- Inhibit the production of pro-angiogenic factors like VEGF
- inhibit the growth of new blood vessels
- downregulated in cancer
what do endostatins - a type of statins - bind?
what does binding lead to?
bind integrins found on endothelial cells
leads to the inhibition of migration, proliferation, and survival
what do angiostatins - a type of statins - bind?
bind integrins found on endothelial cells
inhibits endothelial cells
VEGF and VEGFR: what does VEGFA binding VEGFR-2 promote? how?
- vascular permeability, cell proliferation, survival, motility, protease production
- via increase in NOS
what is NOS?
Nitric Oxide Synthase
enzymes responsible for producing nitric oxide
is VEFG increased or decreased in cancer cells?
increased
VEGF and VEGFR: VEGF receptors are
(a) what kind of receptors?
(b) what does it increase?
(a) tyrosine kinase receptors
(b) RAS/MAPK/PI3K pathway which are downstream of VEGFR
VEGF has how many isoforms? VEGF-A
VEGF has 6 isoforms A -E
VEGF-A has 4 isoforms
VEGFR have how many isoforms?
three isoforms (1-3)
what does VEGFA-VEGFR2 binding do?
stimulates angiogenesis
what does VEGFA-VEGFR1 binding do?
modulates VEGFR2 such that it prevents excessive angiogenesis
what does VEGFA-NRP binding do?
stimulates angiogeneses indirectly
enhance VEGFR-2 signaling
what does VEGFA-VEGFR3 binding do?
lymph angiogenesis - growth of lymph system
what are EPHRINS?
ligands - signaling molecules
bind to tyrosine kinase receptors on cell surface
Control blood vessel formation
Altered levels in cancer angiogenesis
what are some examples of EPHRINS?
B4 and B2
What EPHRINS does VEGF increase in cancer? which does it decrease? why do levels have to change?
increase B2
decrease B4
they change for the max amount of vascular growth
VEGF binding to epithelial cells promotes…
angiogenesis
if B4 is on the surface of the cell, what will happen?
it will decrease cell sprouting which DECREASES angiogenesis
if B2 is on the surface of the cell, what will happen?
it will INCREASE cell sprouting
what surface will B4 bind to? what about B2?
surface of veins
surface of arterioles
what happens when B4 binds to its receptor ?
what decreases?
decrease VEGF
what happens when B2 binds to its receptor ?
veins + arterials will grow inconjunction to one another
such that they are developing together in a way that complements each ot
what is ANGIOPOIETINS 1?
a protein that promotes structural integrity of existing blood vessels
what is ANGIOPOIETINS 2?
a protein that promotes the formation of NEW blood vessels
what happens when ANGIOPOIETINS 1 binds to its receptor? what receptor does it bind?
it promotes survival + pericyte attachment
it binds to TIE-2, a TKR receptor located on the surface of endothelial cells in the blood vessel
what happens when ANGIOPOIETINS 2 binds to its receptor? what receptor does it bind?
it promotes pericyte Detachment + proliferation
it binds to TIE-2, a TKR receptor located on the surface of endothelial cells in the blood vessel
ANGIOPOIETINS 2: are they tumor suppressors or pro-oncogenes?
pro-oncogene
endothelial vs epithelial cells
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
how are ANGIOPOIETINS secreted
by pericyetes
what are pericytes?
supporting cells recruited upon vessel formation
what is meant by angiogenic effect observed after the binding of ANGIOPOIETINS2 - TIE2
aka. what is needed to form angiogenic vaasculature? 2 things
to form angiogenic vasculature…
permeability has to increase and tear down existing vasculature in order to form NEW vessels
ANGIOGENIC PROMOTERS: purpose?
drives angiogenesis
example of ANGIOGENIC PROMOTERS
PDGFB
PDGFB function?
what to they bind?
what and when are they released
released by endothelial cells once blood vessels are formed
they will bind to receptor on surface of pericytes
indirect function
what happens once PDGFB binds to PDGFR?
it tells the pericyte to begin association to existing epithelial cells
matrix degradation: what is MMP?
Matrix metalloproteinases - zinc dependent protease degrade ECM (extra cellular matrix)
MMP: what is it and what is its purpose?
enzyme that degrades the extracellular matrix (ECM)
Matrix degradation steps
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
what are INTEGRINS?
type of receptor AND location
dimeric transmembrane receptor proteins
located on surface of blood vessels
interact with cell-matrix
which INTEGRINS does cancer upregulate?
AVB3 + AVB5
how do INTEGRINS interact with the cell matrix?
bind what and promote what?
bind to matrix components promoting survival, growth, and motility
what will increased interactions with cell matrix components lead to?
leads to the release of more VEGF and more MMP
What is VEGFR-2?
what type of receptor
A pro-angiogenic receptor
what is TSP (thrombospondin)
what type of proteins?
glycoproteins found in the extracellular matrix
anti-angiogenic - inhibit the growth of new blood vessels
what is one of the things TSP does?
e.g. what does it bind?
2 points
bind endothelial cells via CD36R
binding leads to inhibition of angiogenesis
binding leads to apoptosis
what is one of the things TSP does?
e.g. what does it release?
2 points
FASL released upon TSP-CD36 binding
FASL-FASR interaction triggers endothelial cell apoptosis
Where is FASR present?
Only in endothelial cells
what is one of the things TSP does?
e.g. what does it inhibit?
TSP-CD47R binding on endothelial surface inhibits VEGFR2 activity
what is one of the things TSP does?
e.g. what does it sequester?
Sequesters growth factors making them unavailable for endothelial cells
what is one of the things TSP does?
e.g. what does it inhibit?
inhibits MMP when released by cancer and endothelial cells - prevents them from aiding blood vessel growth
is TSP considered a tumor suppressor? or pro-oncogenic?
a tumor suppressor and if mutated, it will promote formation of cancer cells
Therapeutics - VEGF inhibitors: Aflibercept
soluble VEGF receptor
Therapeutics - VEGF inhibitors: Avastin
monoclonal antibody (mAb) against VEGF
Therapeutics - VEGF inhibitors: Ramucirumab
mAb against VEGFR-2
Therapeutics - VEGF inhibitors: Small molecule inhibitors
TK inhibitors
Therapeutics - Pericytes: SU688
PDGFB receptor inhibitor
Combining pericyte and EC therapy -> removing pericyte protection before targeting endothelial cells
Angiogenic vasculature can result
in poor chemotherapeutic delivery
Incentive used to normalize cancer
vasculature. Why?
how can this be treated?
its easy for therapeutics to leak out or get wedged into cancer vasculature
can deliver drugs that improve their vasculature surrounding cancer cells
Hallmarks of resistance: Redundancy of growth factors
explain
endothelial cells release several growth factors so if there is 1 GF that docent work , its okay bc others are present
Hallmarks of resistance: cancer cells engage in bone marrow cell recruitment
explain
what is recruited?
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
Hallmarks of resistance: Increasing metastatic properties
explain
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
Hallmarks of resistance: Activation of stroma cells
explain
Stromal cells such as CAF and pericytes are the connective tissue components surrounding tumors
CAF releases SDF-1 and MMP
Pericytes release PDGFB
Hallmarks of resistance: Alternative vascularization
explain
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
explain what the Metastatic Cascade is.
What are the steps? 5 total
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
