angiogenesis, anti angiogenic agents, angiogenic mechanism, types of angiogenesis, wound healing, disorders of angiogenesis, tumour angiogenesis, factors of angiogenesis, theurepeutic angiogenesis, father of tumour angiogenesis, terminology of angiogenesis, angiogenesis in health and disease, diabetic retinopathy, retinopathy of prematurity, macular degeneration, rheumatoid arthritis, arteriogenesis, intussusceptive agiogenesis, angioblasts, angiogenesis inhibitors, william harvey, judah folkman, interferon, thromospondin,sprouting angiogenesis, VEGF,FGF, PDGF, matrix metalloproteinases ,
6. ➤ Vasculogenesis: Formation of new vessels from EC
precursors
➤ Angiogenesis: Formation of new vessels from pre existing
Blood vessels by sprouting
➤ Arteriogenesis : Subsequent Stabilisation and maturation
➤ Collateralisation: Enlarging existing vessels as bridges
between networks
16. ➤ Angiogenesis is the growth of blood vessels from the existing
vasculature.
➤ It occurs throughout life in both health and disease, beginning in
utero and continuing on through old age.
➤ Capillaries are needed in all tissues for diffusion and exchange of
nutrients and metabolites.
➤ Changes in metabolic activity lead to proportional changes in
angiogenesis and, hence, proportional changes in capillarity.
➤ Oxygen plays a pivotal role in this regulation.
19. SPROUTING ANGIOGENESIS
➤ Sprouting angiogenesis is characterized by sprouts composed
of endothelial cells
➤ They grow towards an angiogenic stimulus such as VEGF-A.
➤ It can add blood vessels to portions of tissues previously
devoid of blood vessels.
➤ It is initiated in poorly perfused tissues
24. INTUSSUSCEPTIVE ANGIOGENESIS
➤ Intussusceptive angiogenesis is also called splitting
angiogenesis
➤ The vessel wall extends into the lumen causing a single
vessel to split in two
➤ . This type of angiogenesis is thought to be fast and efficient
compared with sprouting angiogenesis:
1. Reorganization of existing endothelial cells
2. No immediate endothelial proliferation
3. Migration
25.
26. ➤ Occurs throughout life
➤ But plays a prominent role in vascular development in
embryos where growth is fast and resources are limited
➤ However, intussusception mainly causes new capillaries to
develop where capillaries already exist.
➤ Both types of angiogenesis are thought to occur in virtually all
tissues and organs
30. VEGF
VEGF-A VEGF -B VEGF C&D
After injury
Tumors
Embryonic vessel
development
Lymphangiogene
sis
31. ➤ VEGF is a survival factor for endothelial cells in vivo and in vitro
➤ It prevents apoptosis of endothelial cells caused by the lack of serum .
➤ It is also known to induce expression of antiapoptotic proteins Bcl- 2 in
endothelial cells
➤ It is also known as a factor regulating vascular permeability.
32. ➤ The ability of VEGF to enhance vascular permeability defines its important
role in inflammation and other pathological processes.
➤ The tumor vessels are characterized by enhanced permeability
➤ Also the ability of VEGF isoforms to bind to heparin,
defines whether the secreted protein will be accumulated in extracellular matrix
➤ or will be released and thus become accessible for interaction with other
cells.
33. VEGF RECEPTORS
➤ Growth factors of the VEGF family exert their biological effect via
interaction with receptors located on endothelial cell membranes.
➤ Three receptors have been identified that bind different VEGF
growth factors: VEGFR1 , VEGFR2 and VEGFR3
➤ These receptors belong to the superfamily of receptor tyrosine
kinases (RTK)
➤ They are transmembrane proteins with a single domain
44. INTEGRINS
➤ Angiogenic endothelium over expresses INTEGRIN family of
ECM binding proteins that mediate EC adhesion, migration,
survival
➤ αv
β3
, αv
β5
, α5
β1
➤ Mediates spreading and migration of EC’S
➤ αvβ3 forms cell surface complexes with matrix metalloproteinases that cleave ECM proteins
45. MATRIX METALLOPROTEINASE
➤ Major contributor to angiogenesis
➤ Zinc requiring proteases that cleave the extracellular matrix
proteins
➤ This proteolysis allows the endothelial cells to escape into the
interstitial matrix (as seen in sprouting angiogenesis)
47. ➤ The healthy body controls angiogenesis through a
series of on and off switches:
➤ On switches– angiogenesis stimulating growth factors
➤ Off switches- angiogenesis inhibiting growth factors
➤ The normal healthy body maintains a perfect balance
of angiogenesis modulators.
52. In females, angiogenesis also occurs
➤ During the monthly reproductive cycle -to rebuilt the
uterus lining
➤ To mature the egg during ovulation
➤ During pregnancy (to built the placenta)
55. ➤ 1945 Algire and Chalkley concluded that the growth of a solid
tumor is closely connected to the development of an intrinsic
vascular network.
➤ 1970s, the surgeon Folkman: hypothesized that targeting the
blood supply by inhibiting blood vessel formation will lead to
arrest of tumor growth or even tumor shrinkage.
➤ In 2004, the first antiangiogenic compound bevacizumab
(Avastin) was approved
56.
57. WHY TUMORS REQUIRE
ANGIOGENESIS➤ Tumors less than 1mm3 receive oxygen and nutrients by
diffusion from host vasculature
➤ Larger tumors require new vessel network.
➤ Tumor secretes angiogenic factors that stimulate migration,
proliferation, and neovessels formation by endothelial cells in
adjacent established vessels.
58. CHARACTERISTICS OF TUMOUR
VESSELS
Chaotic architecture and heterogeneous blood flow that leads to
abnormal growth
1. Excessively dilated blood vessels
2. Extreme corkscrew like tortuosities
3. Lack of pericyte support or abnormal pericytic function
4. Permeability strongly increased fenestrae
74. ORGAN DYFUNCTION MECHANISM
SKIN HAIR LOSS
Retarded hair growth by
angiogenesis inhibitors
REPRODUCTIVE
SYSTEM
PRE ECLAMPISA
Decreased VEGF
production
LUNG
NEONATAL
RESPIRATORY
DISTRESS
Insufficient lung
maturation due to
decreased HIF ,VEGF
NERVOUS SYSTEM
ALZHEIMERS
DISEASE
Vasoconstriction,
Microvascular
degeneration,
DISEASES DUE TO DECREASES
ANGIOGENESIS
76. ➤ Several studies show a correlation between production of
angiogenic factors and relapse, metastasis and poor
prognosis in human cancer patients.
➤ Renal cancer patients with high levels of the angiogenic factor
bFGF in their primary tumors have a poorer survival rate than
those patients with lower bFGF levels
➤ In breast cancer, VEGF production correlates with early
relapse .
77. ➤ Because the plasticity of the tumor cell population allows the
development of cells that produce other angiogenic factors and
thus the tumor may become resistant to treatment.
➤ But if the treatments directly target the endothelial compartment by
inhibiting components of the angiogenic process such as
1. Endothelial cell adhesion or
2. Migration
➤ This may generate tumor treatments that do not lead to the
78. THROMBOSPONDIN
➤ Thrombospondin is confirmed to be an inhibitor of:
1.Endothelial cell proliferation
2.Motility
3.Morphogenesis
➤ The initial correlation of thrombospondin production with tumor
suppression was reported that the tumor suppressor P53 could
repress angiogenesis by up-regulating the production of
thrombospondin
79. INTERFERON
➤ Interferon inhibits the migration of capillary endothelial cells, a
critical step in angiogenesis
➤ Interferon action may also block the production or efficacy of
angiogenic factors produced by tumor cells .
➤ Some vascular tumors are more sensitive to the inhibitory activity
of interferon.
80. METALLOPROTEINASES
➤ These are matrix metalloproteinases (MMPs) because of their ability to
degrade extracellular matrix
➤ These enzymes inhibit both angiogenesis and tumor metastasis .
➤ The mechanism whereby TIMPs inhibit angiogenesis and metastasis
1. Their ability to suppress matrix degradation
2. They also directly block proliferation and migration of both tumor cells and
endothelial cells
➤ The combined activities of this class of inhibitor make them potent anti-tumor
agents.
81. ANGIOSTATIN
➤ Angiostatin was the first molecule specifically isolated as a potential
tumor-derived angiogenesis inhibitor .
➤ Angiostatin itself is not produced by tumor cells but rather that certain
tumors can produce or activate proteases capable of generating
angiostatin from circulating plasminogen.
➤ Angiostatin has been reported to be an endothelial-specific inhibitor of
both endothelial cell proliferation and migration
➤ It can act as a circulating angiogenesis inhibitor that suppresses angio-
genesis at downstream sites distant from the tumor.
82. ENDOSTATIN
➤ Endostatin is reported to be a highly active endothelial-specific
inhibitor that inhibits microvascular endothelial cell proliferation
➤ Endostatin inhibits primary tumor growth as well as establishment
and growth of metastases.
83. CAI
➤ Carboxyamidotriazole (CAI) is a calcium channel inhibitor that blocks
tumor cell migration and proliferation and has antiangiogenic activity.
➤ CAI retards metastasis in experiment animals and has completed
phase I clinical trials in cancer patients.
➤ Published results from trials showed disease stabilization in 49% of
the patients who had disease progression before starting CAI
treatment
84. THALIDOMIDE
➤ In a recent finding, D’Amato and colleagues reported that the drug
thalidomide has potent antiangiogenic activity
➤ The antiangiogenic activity of thalidomide now provides a potential
mecha- nism for this teratogenic activity, as growing limbs are sensitive
to the vascular density
➤ Thalidomide is relatively nontoxic when taken by nonpregnant adults
It is now being tested in clinical trials as a
1. Potential anticancer agent
2. Treatment for vascular eye diseases
85. AGM1470
➤ It was observed that the fungal antibiotic fumagillin was a potent
angiogenesis inhibitor.
➤ This agent inhibits endothelial cell proliferation in vitro and
angiogenesis in vivo .
➤ The drug is being used both as a primary antitumor treatment and
also as a sequel to other treatments.
86. Can Total Tumor Regression be
Achieved by Administration of Angiogenic
Inhibitors?
87. ➤ Antiangiogenic treatment can reduce a tumor mass back to its
avascular size.
➤ It may not completely eliminate tumors that regress to sizes no
longer dependent on increased vascularity.
➤ The antiangiogenic agents may also be useful for prolonged
treatment to prevent regrowth of dormant micrometastases.
➤ There are, however, sporadic reports of tumors that have
been completely eliminated by antiangiogenic therapy alone.
92. 1. Robbins and Cotran- Pathological basis of diseases: 9th edition
2. Walter and Israel- General Pathology: 7th edition
3. Anderson’s Pathology: 10th Edition
4. Karamysheva AF. Mechanisms of angiogenesis. Biochemistry
(Moscow). 2008 Jul 1;73(7):751.
5. Eichhorn ME, Kleespies A, Angele MK, Jauch KW, Bruns CJ.
Angiogenesis in cancer: molecular mechanisms, clinical impact.
Langenbeck's archives of surgery. 2007 May 1;392(3):371-9.
6. Zetter BR. Angiogenesis and tumor metastasis. Annual review of
medicine. 1998 Feb;49(1):407-24.
7. Blood CH, Zetter BR. Tumor interactions with the vasculature:
angiogenesis and tumor metastasis. Biochimica et Biophysica Acta
(BBA)-Reviews on Cancer. 1990 Jun 1;1032(1):89-118.
8. Hart IR, Saini A. Biology of tumour metastasis. The lancet. 1992 Jun
13;339(8807):1453-7.
93. THANK YOU
Modulation of angiogenesis may
have an impact on diseases in the
21st century .
Similar to that which the discovery
of antibiotics had in the 20th century
Editor's Notes
The Scottish anatomist and surgeon John Hunter provided the first recorded scientific insights into the field of angiogenesis.
His observations suggested that proportionality between vascularity and metabolic requirements occurs in both health and disease.
This is the inside view of john hunter museum which is under the royal college of surgeons
weibel salade body is a unique cytoplasmic structure that contains VWF and a protein GP 140 which is exposed on the cell surface shortly after injury
Vasculogenesis is the de novo formation of blood vessels from angioblasts .
The cardiovascular system is the first organ system to develop in the embryo . The luminal surface of the circulatory system in contact with blood is a single layer of endothelial cells: these are derived from mesoderm. Hemangioblasts differentiate from mesodermal stem cells and give rise to hematopoietic stem cells and angioblasts. Angioblasts are a cell type with potency to differentiate into endothelial cells.
No metabolically active tissue in the body is more than a few hundred micrometers from a blood capillary, which is formed by the process of angiogenesis.
when oxygen sensing mechanisms detect a level of hypoxia that demands the formation of new blood vessels to satisfy the metabolic requirements of parenchymal cells
this shows sprouting of new blood vessels from the aorta. within the tube a single endothelial cell gets activated by the angiogenic stimulus. this forms the tip cell which develops into a capillary sprout. then there is formation of pinocytic vesicles which fuse and form a tube inside the capillary sprout. this leads to the formation of lumen.
The basic steps of sprouting angiogenesis include enzymatic degradation of capillary basement membrane, endothelial cell (EC) proliferation, directed migration of ECs, tubulogenesis (EC tube formation), vessel fusion, vessel pruning, and pericyte stabilization.
and this peculiarity contributes to tumor cell penetration into vascular networks and metastasis.
Under Normoxjmic conditions HiF levels are maintained low by proteasome mediated destruction
The ANGIOPOIETINS have recently joined the members of the VEGF family as the only known growth factors largely specific for vascular endothelium.
They include a naturally occurring agonist : ANGIOPOIETIN-1
A naturally occurring antagonist: ANGIOPOIETIN-2,
They act by means of the Tie2 receptor.
there are 3 phases of wound repair.
inflammatory phase is characterised by haemorrhage and plasma exudation in wound site. a fibrin clot forms as a result of coagulation cascade.then inflammatory cells enter the site and phagocytosize the bacteria.
The second phase is proliferative phase which is characterised by accumulation of proliferating fibroblasts, myofibroblasts and endothelial cells. these cells secrete many growth factors and promote development of immature vascular tissue which is known to have granular appearance called granulation tissue. new vessels sprout from existing blood vessels. these capillaries have poorly formed inter cellular attachments and are thus leaky leading to oedema and they bleed easily
Maturation phase is characterised by some level of restitution or restoration of prior tissue with replacement of that tissue by fibrous connective tissue or scar
by the Food and Drug Administration as first-line therapy in combination with 5-fluorouracil-based chemotherapy in patients with advanced colorectal cancer.
Newly vascularized tumor no longer relies solely on diffusion from host vasculature, facilitating progressive growth.
No functional lymphatics inside the tumour enlarged in surrounding,Increases metastasis
Once a neoplastic mutation has occurred, an avascular phase of tumor growth follows. Tumor cells are supplied by diffusion, and tumor growth is arrested at a size of 1– 2 mm3. The following stadium of ‘tumor dormancy’ can last up to years Today, the theory of an angiogenic switch, controlled by the balance between pro- and antiangiogenic molecules in the solid tumor microenvironment, is accepted
The switch clearly involves proangiogenic factors over- come the effect of angiostatic molecules, the tumor acquires an angiogenic phenotype that leads to the formation of new blood vessels.
Increased angiogenesis has been associated with various inflammatory disease states including rheumatoid arthritis (RA). Angiogenic mediators released by various types of cells within the synovium activate EC. ECs then proliferate and emigrate into the interstitial tissue. Hence externally administered organic or synthetic compounds may disrupt neovascularization. These agents are used to suppress angiogenesis in inflammatory
Two major retinal problems cause most of the diabetes related vision loss: diabetic macular edema and diabetic retinopathy.Diabetic retinopathy, a secondary microvascular complication of diabetes mellitus is the leading cause of blindness Secondary to angiogenesis, increased retinal blood flow is of pathogenic importance in the progression of diabetic retinopathy.Hypoxia is a key regulator of VEGF induced ocular neovascularization. Hence utilizing anti-VEGF treatments has proved to be a successful protocol in the treatment of proliferative diabetic retinopathy.
Retinopathy of prematurity (ROP), also called retrolental fibroplasia is a disease of the eye affecting prematurely born babies generally having received intensive neonatal care, in which oxygen therapy is used on them due to the premature development of their lungs. It is thought to be caused by disorganized growth of retinal blood vessels which may result in scarring and retinal detachment. ROP can be mild and may resolve spontaneously, but it may lead to blindness in serious cases.
Age-related macular degeneration (AMD) is one of
the most common irreversible causes of severe loss of
vision, including legal blindness, in the elderly population. it is of 2 types The exudative form is linked to choroidal neovascularization directed to the subretinal macular region, with subsequent bleeding and/or fluid leakage, which may result in a sudden loss of central vision; it is the most rapidly progressing form of AMD.
the role of angiogenesis in atherosclerosis is still controversial .bur Intimal angiogenesis has
been hitherto assumed to participate intimately in the promotion of atheroma growth
and intraplaque edema and hemorrhage, possibly resulting in plaque rupture. Attention
has recently refocused on intimal angiogenesis in atherosclerotic plaque.
Capillary hemangioma is the most common benign vascular tumor of infancy,It can affect almost any organ but by far the commonest location is the skin and soft tissues, especially in the head and neck area.
types: capillary hemangimos ,cavernous hemangioma,
epithelioid hemangioma ,deep hemangioma.
Cavernous hemangiomas consist of poorly circumscribed, irregularly dilated blood vessels lined by flat endothelium and with walls of varying thickness. Thrombosis, secondary dystrophic calcification, and mild inflammation are frequently found.
Although the cell of origin remains controversial, most evidence points towards endothelial cells, particularly lymphatic endothelium, as the principal cellular component
associated with hhv8
types classical endemic, AIDS related,immunosuprresive associated ,african ks
Cutaneous angiosarcoma always occurs in one of three different clinical settings: namely, idiopathic angiosarcoma of the head and neck, lymphedema- associated angiosarcoma, and post-irradiation angio- sarcoma
The typical case is an infiltrative dermal tumor, composed of numerous, irregular, anastomosing vascular spaces in a distinctive dissecting pattern between collagen bundles. The vascular channels are lined by variably pleomorphic, hyper- chromatic endothelial cells which frequently show multilayering and papillary formation
The expansion of the primary tumor and metastasis to distant organs depend critically on the formation of new blood vessels
Large solid tumors contain cells that release one or more angiogenic factors such as basic fibroblast growth factor and vascular endothelial growth factor.
Hence the best strategy for inhibiting angiogenesis is to repress the ability of the endothelial cell to participate in the angiogenic process rather than prevent tumor cells from producing one particular angiogenic factor,
Angiogenesis has been implicated in affecting outcomes in human cancer.
suggesting that increased angiogenesis due to bFGF production may lead to increased metastatic potential and con- sequently decreased survival
in addition, it appears that tumors that produce multiple angiogenic factors show increased rates of primary tumor expansion.
Angiogenesis inhibition can lead to tumor regression and, in some cases, to complete elimination of the tumor.
Hemangiomas, are tumors comprised predominantly of endothelial cells, are particularly sensitive to treatment with interferon. Treatment with interferon is one of the first clinically successful treat- ment protocols for patients with proliferating hemangiomas
Invasive events require both active cell migration and the ability to cause lim- ited degradation of the connective tissue in order to allow passage of the tumor cells through tissue. This is accomplished, in part, by the activity of metallo- proteinases that are sequestered on the tumor cell surface and concentrated at the leading edge of the tumor
all members of the TIMP family inhibit angiogenesis.
A serine protease that specifically cleaves angiostatin from plasminogen is pro duced by prostate cancer cells
Angiostatin treatment of tumor-bearing mice causes regression of the primary tumor and prevents vascularization and growth of metastatic colonies.
The finding that both angiostatin and endostatin are fragments of larger precursor forms that have no angiogenic effector activity themselves suggests that the natural control of angiogenesis is much like that of repair processes such as blood clotting in which latent precursors become activated by proteolysis only when needed.
endostatin is a fragment of a larger molecule, in this case collagen XVIII, a novel collagen frequently found near blood vessels
Originally used as a seda- tive, thalidomide’s use was discontinued when it was found to be a potent tera- togen, causing serious birth defects, especially affecting limb development.
diabetic retinopathy, blindness of pre- maturity, and macular degeneration.
gave rise to the testing of synthetic analogs of fumagillin for their relative antiangiogenic activty
Preliminary results suggest that long-term (>1 year) treatments are optimal and that the drug should not be stopped early if the tumor appears to progress, because the effects of the agent take some time to be translated into tumor stasis or regression.
It is therefore possible that strategies will emerge that use antiangiogenic therapies as the primary antitumor therapy, without the addition of cytotoxic agents.
Future clinical trials are necessary to see whether this is a viable strategy in human cancer patients.