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BIOM 4150 Cancer Biology > Unit 6- Tumor Angiogenesis & Anti-Angiogenic Therapy > Flashcards

Unit 6- Tumor Angiogenesis & Anti-Angiogenic Therapy Flashcards

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1
Q

Although previously believed that tumors result from the homogenous proliferation of tumur cells (false), what is true?

A
  • tumor microenvironment
    > tumors are complex heterogenous multi-cellular structures
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2
Q

What is angiogenesis?

A
  • formation of new blood vessels from preexisting vasculature
  • involved in physiological/ pathological processes
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3
Q

What are the layers (anatomy) of a blood vessel?

A

lumen > endothelial cell lining > basal lamina > elastin fibers > smooth muscle > loose connective tissue

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4
Q

What are the layers (anatomy) of a capillary?

A

lumen > endothelial cell lining > basal lamina
- pericytes

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5
Q

What are the 4 steps in angiogenesis?

A
  1. Disruption of basal lamina of existing vessel
  2. Migration of endothelial cells toward a chemotactic signal
  3. Proliferation of endothelial cells
  4. Formation of tubes/ maturation of new vessel
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6
Q

What are the 2 main types of angiogenesis?

A

Sprouting Angiogenesis
- endothelial cells activated/ protease degradation basal lamina
- EC proliferation/ migration > vessel stabilization

Intussusceptive Angiogenesis
- faster/ no extensive proliferation of endothelial cells
- ECs make transluminal bridge > reorganization of vessel
- bifurcation/ vessel splitting due to ↑ pressure

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7
Q

What are examples of physiological angiogenesis?

A
  • embryo development
  • wound healing
  • female reproductive system
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8
Q

What is tumor/ pathologic angiogenesis?

A
  • tumors must recruit own blood supply > growth/ metastasis
    > get nutrients from blood/ for metastatic spread
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9
Q

What stimulates tumor angiogenesis?

A

“Angiogenic Switch”
- when tissue ↑ secretion of pro-angiogenic growth factors
- usually concurrent with ↓ expression of anti-angiogenic factors

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10
Q

What is Folkman’s hypothesis?

A
  • tumors smaller than 2 mm3 can exist with limited blood supply
  • once beyond 2mm3 they must recruit new blood vessels
    (O2 can passively diffuse from vessel > tissue under 2mm)
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11
Q

What is the most potent pro-angiogenic factor?

A

VEGF = vascular endothelial growth factor

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12
Q

How does VEGF mediate angiogenesis?

A
  1. Upstream activators stimulate VEGF production
  2. VEGF binds to specific receptors on endothelial cells
  3. Angiogenesis is primarily mediated through interaction of VEGF-A with VEGFR-2
  4. Other variants of VEGF ligand/ receptor have a secondary role in this process
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13
Q

How is angiogenesis primarily mediated?

A
  • primarily through interaction of VEGF-A/ VEGFR-2
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14
Q

What kind of receptor is VEGFR?

A

Tyrosine kinase

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15
Q

What is the role of the ECM in tumor angiogenesis?

A
  • in initial phase of angiogenesis > proteases degrade basement membrane/ destabilize ECM
  • allows migration of endothelial cells toward chemotactic signal/ tumor
  • integrin helps pull the sprouting new blood vessel forward
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16
Q

After endothelial cell migration/ proliferation to tumor, what helps stabilize the new blood vessel?

A
  • integrin molecules pull the sprouting new blood vessel forward
  • endothelial cells deposit a new basement membrane/ secrete growth factors like PDGF (attract supporting cells to stabilize the new vessel)
17
Q

What is the role of hypoxia in tumor angiogenesis?

A
  • cells closest to vasculature have sufficient blood supply
  • O2 supply diminishes further from blood vessels
  • as O2 supply ↓ cells become hypoxic/ necrotic
  • tumor is not homogenously perfused (some areas high/low O2)
18
Q

How do hypoxic signals influence O2/nutrient delivery?

A

Hypoxia > HIF-1 activated > blood vessel growth
- hypoxic signals elicit mechanisms to ↑ nutrient/ O2 delivery

19
Q

What is the role of HIF-1/ when is it active?

A

non-hypoxic (normal) conditions > VHL tumor suppressor targets HIF-1 for rapid ubiquitination (degraded as not in use)

hypoxic conditions > HIF-1 recognizes/ binds to genes that mediate angiogenesis like VEGF

20
Q

What are the characteristics of tumor blood vessels?

A
  • very different than normal blood vessels (chaos)
  • hyperactivated VEGF > uncontrolled perfusion > malformed vessels
  • blind ends/ vessel breaks/ AV shunts ext
  • ↑ permeability/ immaturity
21
Q

Dr. Petriks lab uses what model of tumor angiogenesis?

A

EOC = Epithelial ovarian cancer
- VEGF is ↑ in tumor-bearing mice

22
Q

What are microstructural changes in tumor vessels?

A
  • disrupted basal membrane
  • absence of pericytes/ smooth muscle cells
  • fenestrated endothelial cells (spaces between them)
23
Q

Why is poor vasculature in tumors a problem?

A
  • a lot of fluid leakage/ accumulation between cells > ↑ pressure
  • poor perfusion > hypoxia > necrosis
  • leaky/ poor blood flow > hard to get drugs into tumors
24
Q

What is anti-angiogenic therapy?

A
  • use of “angiogenesis inhibitors” to destroy tumor blood vessels/ starve the tumor
25
Q

What are 3 anti-angiogenic strategies?

A
  1. Drugs that stop new blood vessels from sprouting
    - true angiogenesis inhibitors
  2. Drugs that attack a tumors established blood supply
    - vascular disrupting agents
  3. Drugs with a dual effect (attack cancer and blood vessel cells)
26
Q

What is the difference between tumor vascular disrupting agents/ anti-angiogenic agents?

A

Vascular Disrupting Agent > attack a tumors established blood supply
- cause extensive tumor necrosis
- activity primarily at tumor core of large tumor masses

Anti-Angiogenic Agent > stop new blood vessel sprouting
- interfere with new blood vessel formation
- prevent tumor growth/ limit metastatic potential
- activity primarily at tumor periphery of small tumor masses

27
Q

What are the basic strategies of angiogenesis inhibition?

A
  • use anti-angiogenic compounds
  • inhibit pro-angiogenic factors
28
Q

What are some specific angiogenesis inhibitors?

A

Avastin/ Celebrex/ Angiostatin/ Endostatin

29
Q

What is Avastin?

A
  • humanized antibody that binds VEGF, neutralizing its angiogenic effects (preventing interaction with VEGFR)
  • inhibits VEGF, but VEGF is needed to make blood vessels!
    side effects > GI perforation (↓ blood flow) > necrosis > sepsis
  • impaired wound healing/ hemorrhage/ expensive
30
Q

What is Celebrex?

A
  • non-steroidal/ anti-inflammatory drug for osteoarthritis
    = COX2 inhibitor
  • overexpression of COX2 induces VEGF production
  • COX2 ↑ vascular permeability/ ↑ endothelial cell proliferation
  • through COX2 inhibition, Celebrex inhibits formation of new vessels
  • ↓ expression of survivin (tumor survival protein)
31
Q

What is angiostatin?

A
  • endogenous angiogenesis inhibitor
  • produced by cleavage of plasminogen
  • inhibits endothelial cell migration/ proliferation/ initiates apoptosis
32
Q

How do VEGF-R2 inhibitors work?

A
  • inhibit receptor directly (not VEGF-a ligand)
33
Q

What is vascular targeting? (VTA’s = vascular targeting agents)

A
  • vascular targeting attacks existing tumor vessels
    (unlike anti-angiogenic approaches that inhibit further vessel development)
34
Q

What is Thrombospondin-1?

A

TSP-1 = endogenous inhibitor of angiogenesis
- causes endothelial cell apoptosis/ ↓ migration/ inhibited chemotaxis
- also directly inhibits VEGF expression

35
Q

How is Jim’s lab researching Thrombospondin-1?

A

TSP-1- has 5 domains/ too big to be a therapeutic compound
1 main domain > inhibits VEGF-induced angiogenesis/ EC migration

  • 3TSR induces ovarian tumor/ endothelial cell death BUT…
  • induces tumor regression/ vessel normalization/ ↑ tumor perfusion
  • exploit this to ↑ chemo uptake/ improve drug therapy
    > combination therapy

BIOM 4150 Cancer Biology (6 decks)

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