The angiogenesis process, the factors regulating it, different assays for it, a little about tumour angiogenesis, the drugs and new therapeutic approaches towards inhibiting or augmenting the process.
1. ANGIOGENESIS
IN
HEALTH AND DISEASE
DR DIBYAJYOTI PRUSTY
1ST Year PG
Moderator:
Dr Pranati Mohanty
Asst. Professor
Department of Pathology
SCB Medical College, Cuttack
6. The process of angiogenesis occurs as an orderly series of
events :
1. Vasodilation and increased permeability
2. Separation of pericytes
3. Migration of endothelial cells
4. Proloferation of endothelial cells behind the leading
‘tip’ cell
5. Remodelling in to capillary tubes
6. Recruitment of periendothelial cells
7. Suppression of endothelial proliferation and deposition
of basement membrane
Folkman J, D’Amore PA. Blood vessel formation: what is its molecular basis?
Cell 1996;87:1153-1155.
8. REGULATION OF ANGIOGENESIS
METABOLIC FACTORS:
a. Capillary growth is proportional to metabolic activity
b. Increase in metabolic activity stimulates blood vessel growth
c. Decrease in metabolic activity causes vascular regression ;
d. Over oxygenation often leads to capillary rarefaction in sedentary
muscles by auto regulatory vasoconstriction of arterioles.
e. Long term increase in BP leads to vascular rarefaction by auto
regulatory vasoconstriction mechanism.
f. OXYGEN is the master signal in growth regulation of vascular
system. Chronic exposure to hypoxia leads to increase in arterial
diameter .
g. Role of Adenosine:
Vasodialatory property- restores balance between O2 demand and
supply
Serve as a negative signal to maintain tissue oxygenation in normal
range.
9. MECHANICAL FACTORS:
1. PHYSICAL FORCES acting on the wall of blood
vessels
Shear stress is sensed by the endothelium. This stress acts
as a proangiogenic factor.
REGULATION OF ANGIOGENESIS
10. 2.MECHANOSENSORY MECHANISMS
EpNaC Proteins : Localised in ECs, Smooth muscle cell
membranes.
Both these cells express alha-, beta-, and gamma-
subunits of EpNaC.
Mechanosensory complex formed by
- endothelium & smooth muscle cell(cytoskeletons and
EpNaCs)
- extra cellula matrix
It plays a critical role in angiogenic process- as
mechanosensor for migration of endothelial cells and
smooth muscle cells.
Specific EpNaC inhibitor used- Benzanil- to prevent
angiogenesis.
11. ROLE OF PERICYTES
Pericytes are single layer of periendothelial smooth
muscle cells that modulate endothelial cell function.
Regulate vascular function:
-vascular diameter
-vascular permeability
- endothelial survival
14. VASCULAR ENDOTHELIAL GROWTH FACTOR
Glycoproteins consisting of A-, B-, C-, D-, E- forms and
Placental Growth Factor (PlGF)
Within the six subtypes multiple isoforms exists
Loss of even a single VEGF-A allele results in embryonic
lethality
Angiogenesis is primarily mediated through interaction of
VEGF-A with VEGFR-2
VEGF RECEPTORS
3 types of receptors- VEGFR-1, VEGFR-2 (KDR, Flk-1), VEGFR-3
Tyrosine kinases
15.
16. VEGF production is under control of :
hypoxia-inducible transcription factors(HIFs)
VEGF receptor expression is up-regulated under:
hypoxic or ischemic conditions;
(30-fold within minutes)
17. VEGF is a major player in angiogenesis initiation:
it cause:
1. Endothelial cell survival
2. Stimulates endothelial division, induce
locomotion/migration
3. Induce the expression of proteases and receptors
4. Prevent endothelial cell apoptosis
5. Increase in vascular permeability by upregulating
second messengers such as NO
18.
19. Fibroblast growth factor
Basic Fibroblast growth factor (bFGF) family are also
potent inducers of angiogenesis. The effects of FGFs are
mediated via high-affinity tyrosine kinase receptors.
Cellular responses mediated by FGFs include
cell migration
proliferation
differentiation
Platelet-derived growth factor
The platelet-derived growth factor (PDGF) regulates
the recruitment of PERICYTES and
smooth muscle cells
required for further stabilization of the new capillaries
20. ENDOSTATIN
Produced by proteolytic cleavage of collagen
ANGIOSTATIN
Produced by proteolytic cleavage of plasminogen,
THROMBOSPONDIN-1(TSP-1)
Adhesive glycoprotein in matrix.
P53 up regulates TSP-1
INHIBITORS OF ANGIOGENESIS
21. CELL ADHESION MOLECULES(CAM)
1. Integrins, cadherins
2.Vascular cell adhesion molecule-1,
3.P-selectin and E-selectin
Integrins are expressed at high levels in :
tumor vasculature and wound-healing tissues ,
but at extremely low levels in normal blood
vessels. 21
22. PROTEASES
Matrix metalloproteases Plasminogen activator(PA) /
(MMPs) plasmin system
PAs activate the plasminogen
degrade different into plasmin, which degrades
protein types several components of
extracellular matrix (ECM)
Both PAs and MMPs are secreted together with their
inhibitors.
It ensures a stringent control of local proteolytic activity.
22
23.
24. Why Tumors require Angiogenesis?
A, Tumors less than 1 mm3
receive oxygen and nutrients by
diffusion from host vasculature.
B, Larger tumors require new
vessel network. Tumor secretes
angiogenic factors that
stimulate migration,
proliferation, and neovessel
formation by endothelial cells
in adjacent established vessels.
C, Newly vascularized tumor
no longer relies solely on
diffusion from host vasculature,
facilitating progressive growth.
25. STRUCTURE AND FUNCTION OF TUMOR VESSELS:
Chaotic architecture and heterogeneous blood flow that leads
to abnormal growth
Excessively dilated blood vessels
Extreme corkscrew like tortuosities
Lack of pericyte support or abnormal pericytic function:
Permeability strongly increased
-fenestrae
-enlarged Junctions
No functional lymphatics inside the tumor
-enlarged in surrounding,
-increases metastasis
36. CURRENT ANGIOGENIC INHIBITORS IN CLINICAL
USE AND CLINICAL TRIALS
Bevacizumab (Avastin™)
Sunitinib (Sutent™)
Sorafenib (Nexavar™)
Cederanib (Recentin™ - AZD- 2171)
Many others in development
37. FUTURE DIRECTIONS-VEGF-TRAP
Composite decoy receptor based on VEGFR-1 and
VEGFR-2 fused to a human Fc segment of IgG1 that
binds VEGF
Decreases free VEGF to bind to receptors and prevent
vessel growth
FDA approved for neovascular macular degeneration
38. THE CHALLENGES!!!
Proangiogenic growth factor redundancy
Selection of hypoxia-resistant cells
Co-option of normal organ vasculature
Vascular remodelling
Angiogenesis contributing to growth of ‘liquid’
hematologic malignancies, not just solid tumors
Circulating endothelial progenitor cells or
precursor cells
Diverse array of molecular mediators of
angiogenesis
39. CONCLUSION
Historically, angiogenesis is only implicated in cancer,
arthritis, psoriasis…etc. In recent years it is evident that
excessive, insufficient or abnormal angiogenesis
contributes many more disorders.
Both pro- & antiangiogenic therapy with single
angiogenic molecule is more challenging than
anticipated
Monotherapy with a single angiogenic inhibitor may not
suffice to combat the angiogenic factors produced by
cancer cells
Understanding the complex interplay of molecular
signals in more integrated manner to develop efficient
and safe therapies.
40. INHIBITION OF BLOOD VESSEL GROWTH WITHIN A
TUMOR COULD PROLONG TUMOR DORMANCY
AND IMPROVE SURVIVAL OF PATIENTS WITH
MINIMAL TOXICITY.