Unit 6- Tumor Angiogenesis & Anti-Angiogenic Therapy Flashcards
Although previously believed that tumors result from the homogenous proliferation of tumur cells (false), what is true?
- tumor microenvironment
> tumors are complex heterogenous multi-cellular structures
What is angiogenesis?
- formation of new blood vessels from preexisting vasculature
- involved in physiological/ pathological processes
What are the layers (anatomy) of a blood vessel?
lumen > endothelial cell lining > basal lamina > elastin fibers > smooth muscle > loose connective tissue
What are the layers (anatomy) of a capillary?
lumen > endothelial cell lining > basal lamina
- pericytes
What are the 4 steps in angiogenesis?
- Disruption of basal lamina of existing vessel
- Migration of endothelial cells toward a chemotactic signal
- Proliferation of endothelial cells
- Formation of tubes/ maturation of new vessel
What are the 2 main types of angiogenesis?
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
What are examples of physiological angiogenesis?
- embryo development
- wound healing
- female reproductive system
What is tumor/ pathologic angiogenesis?
- tumors must recruit own blood supply > growth/ metastasis
> get nutrients from blood/ for metastatic spread
What stimulates tumor angiogenesis?
“Angiogenic Switch”
- when tissue ↑ secretion of pro-angiogenic growth factors
- usually concurrent with ↓ expression of anti-angiogenic factors
What is Folkman’s hypothesis?
- 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)
What is the most potent pro-angiogenic factor?
VEGF = vascular endothelial growth factor
How does VEGF mediate angiogenesis?
- Upstream activators stimulate VEGF production
- VEGF binds to specific receptors on endothelial cells
- Angiogenesis is primarily mediated through interaction of VEGF-A with VEGFR-2
- Other variants of VEGF ligand/ receptor have a secondary role in this process
How is angiogenesis primarily mediated?
- primarily through interaction of VEGF-A/ VEGFR-2
What kind of receptor is VEGFR?
Tyrosine kinase
What is the role of the ECM in tumor angiogenesis?
- 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
After endothelial cell migration/ proliferation to tumor, what helps stabilize the new blood vessel?
- 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)
What is the role of hypoxia in tumor angiogenesis?
- 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)
How do hypoxic signals influence O2/nutrient delivery?
Hypoxia > HIF-1 activated > blood vessel growth
- hypoxic signals elicit mechanisms to ↑ nutrient/ O2 delivery
What is the role of HIF-1/ when is it active?
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
What are the characteristics of tumor blood vessels?
- very different than normal blood vessels (chaos)
- hyperactivated VEGF > uncontrolled perfusion > malformed vessels
- blind ends/ vessel breaks/ AV shunts ext
- ↑ permeability/ immaturity
Dr. Petriks lab uses what model of tumor angiogenesis?
EOC = Epithelial ovarian cancer
- VEGF is ↑ in tumor-bearing mice
What are microstructural changes in tumor vessels?
- disrupted basal membrane
- absence of pericytes/ smooth muscle cells
- fenestrated endothelial cells (spaces between them)
Why is poor vasculature in tumors a problem?
- a lot of fluid leakage/ accumulation between cells > ↑ pressure
- poor perfusion > hypoxia > necrosis
- leaky/ poor blood flow > hard to get drugs into tumors
What is anti-angiogenic therapy?
- use of “angiogenesis inhibitors” to destroy tumor blood vessels/ starve the tumor
What are 3 anti-angiogenic strategies?
- Drugs that stop new blood vessels from sprouting
- true angiogenesis inhibitors - Drugs that attack a tumors established blood supply
- vascular disrupting agents - Drugs with a dual effect (attack cancer and blood vessel cells)
What is the difference between tumor vascular disrupting agents/ anti-angiogenic agents?
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
What are the basic strategies of angiogenesis inhibition?
- use anti-angiogenic compounds
- inhibit pro-angiogenic factors
What are some specific angiogenesis inhibitors?
Avastin/ Celebrex/ Angiostatin/ Endostatin
What is Avastin?
- 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
What is Celebrex?
- 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)
What is angiostatin?
- endogenous angiogenesis inhibitor
- produced by cleavage of plasminogen
- inhibits endothelial cell migration/ proliferation/ initiates apoptosis
How do VEGF-R2 inhibitors work?
- inhibit receptor directly (not VEGF-a ligand)
What is vascular targeting? (VTA’s = vascular targeting agents)
- vascular targeting attacks existing tumor vessels
(unlike anti-angiogenic approaches that inhibit further vessel development)
What is Thrombospondin-1?
TSP-1 = endogenous inhibitor of angiogenesis
- causes endothelial cell apoptosis/ ↓ migration/ inhibited chemotaxis
- also directly inhibits VEGF expression
How is Jim’s lab researching Thrombospondin-1?
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
