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Angiogenesis
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- 6. ➤ Vasculogenesis: Formationof 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
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- 9. ENDOTHELIAL CELLS ➤ Spindleshaped cells ➤ Microvilli - 200 to 400nm ➤ Supported by thin basement membrane and adjacent collagen fibrils ➤ Bound together by tight junctions ➤ Weibel palade bodies ➤ Pinocytic Vesicles
- 11. PERICYTES ➤ Periendothelial smooth musclecells ➤ Mesenchymal origin ➤ Mechanical support and stability ➤ Contractile in nature
- 12. ORIGIN OF BLOODVESSELS
- 13. MESODERMAL STEM CELLS HEMANGIOBLASTS HAEMATOPOIETICCELLS ENDOTHELIAL CELLS DIFFERENTIA TION ANGIOBLASTS BLOOD CELLS
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- 16. ➤ Angiogenesis isthe 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.
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- 19. SPROUTING ANGIOGENESIS ➤ Sproutingangiogenesis 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
- 22. CAPILLARY BASEMENT MEMBRANE ENDOTHELIAL CELLPROLIFERATION DIRECTED MIGRATION OF ENDOTHELIAL CELLS TUBULOGENESIS VESSEL FUSION PERICYTE STABILIZATION
- 24. INTUSSUSCEPTIVE ANGIOGENESIS ➤ Intussusceptiveangiogenesis 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
- 26. ➤ Occurs throughoutlife ➤ 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
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- 28. ➤ GROWTH PROMOTERS: 1.VEGF 2. PDGF 3. TGF 4. TNF ➤ CYTOKINES : A. IL- 1,6,8 ➤ PROTEASES: ➤ MMP ➤ CATHEPSIN ➤ ADHESION MOLECULES AND RECEPTORS : ➤ ANG 1 ➤ AT 1 ➤ OTHERS : ➤ Hypoxia ➤ Nitric oxide synthase
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- 30. VEGF VEGF-A VEGF -BVEGF C&D After injury Tumors Embryonic vessel development Lymphangiogene sis
- 31. ➤ VEGF isa 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 abilityof 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 ➤ Growthfactors 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
- 34. ➤ Tyrosine kinasereceptors ➤ VEGF-2 mediates all cellular responses
- 35. HYPOXIA HYPOXIA INDUCIBLE FACTOR-1 RELEASE VEGF-A
- 37. FUNCTIONS ➤ ANGIOGENESIS: ➤ Migrationof endothelial cells ➤ Mitosis of endothelial cells ➤ Matrix metalloproteinase activity ➤ Creation blood vessel lumen ➤ CHEMOTACTIC: ➤ Macrophages and granulocytes ➤ VASODILATION ➤ By NO release
- 38. PDGF PLATELETS MACROPHAGES ENDOTHELIUM Recruitment of pericytes Alpha and Beta receptors Induces Fibroblast, endothelialcells, smooth muscle proliferation
- 39. FGF MACROPHAG ES MAST CELLS ENDOTHELIAL CELLS FGF-1 FGF-2 Proliferation and differentiation of allcell types Chemotactic and mitogenic for fibroblasts and endothelial cells
- 40. TGF TGF beta 1,2 ,3 Platelets,EC, Lymphocytes , Macrophages Suppresses proliferation,migrati on,survival and differentiation of EC Enhances extracellular membrane synthesis production of collagen, fibronectin, proteoglycans
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- 44. INTEGRINS ➤ Angiogenic endotheliumover 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 ➤ Majorcontributor 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)
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- 47. ➤ The healthybody 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.
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- 52. In females, angiogenesisalso occurs ➤ During the monthly reproductive cycle -to rebuilt the uterus lining ➤ To mature the egg during ovulation ➤ During pregnancy (to built the placenta)
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- 55. ➤ 1945 Algireand 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
- 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 Chaoticarchitecture 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
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- 60. NEOPLASTIC MUTATION AVASCULAR PHASEOF TUMOR TUMOUR GROWTH IS ARRESTED TUMOUR DORMANCY
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- 74. ORGAN DYFUNCTION MECHANISM SKINHAIR 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
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- 76. ➤ Several studiesshow 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 theplasticity 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 isconfirmed 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 inhibitsthe 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 arematrix 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 wasthe 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 isreported 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 arecent 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 wasobserved 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 TumorRegression be Achieved by Administration of Angiogenic Inhibitors?
- 87. ➤ Antiangiogenic treatmentcan 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.
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- 89. ➤ APPROVED INDICATION: ➤Chronic wound- Diabetic ulcer ➤ ➤ EXPERIMENTAL INDICATION: ➤ Myocardial infarction ➤ Peripheral ischemia ➤ Cerebral ischemia ➤ Reconstructive surgery ➤ Gastro duodenal ulcer
- 90. ➤ APPROVED INHIBITION ➤Advanced cancer ➤ Ocular Neovascularisation ➤ Kaposis sarcoma ➤ ➤ EXPERIMENTAL INHIBITION ➤ Haemangioma ➤ Psoriasis ➤ Rheumatoid Arthritis ➤ Endometriosis
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- 92. 1. Robbins andCotran- 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 ofangiogenesis 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
- #4 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.
- #5 This is the inside view of john hunter museum which is under the royal college of surgeons
- #10 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
- #14 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.
- #17 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.
- #20 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
- #22 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.
- #23 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.
- #33 and this peculiarity contributes to tumor cell penetration into vascular networks and metastasis.
- #37 Under Normoxjmic conditions HiF levels are maintained low by proteasome mediated destruction
- #43 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.
- #50 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
- #56 by the Food and Drug Administration as first-line therapy in combination with 5-fluorouracil-based chemotherapy in patients with advanced colorectal cancer.
- #58 Newly vascularized tumor no longer relies solely on diffusion from host vasculature, facilitating progressive growth.
- #59 No functional lymphatics inside the tumour enlarged in surrounding, Increases metastasis
- #61 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
- #62 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.
- #65 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
- #66 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.
- #67 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.
- #68 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.
- #70 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.
- #72 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.
- #73 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
- #74 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
- #76 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,
- #77 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.
- #78 Angiogenesis inhibition can lead to tumor regression and, in some cases, to complete elimination of the tumor.
- #80 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
- #81 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.
- #82 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.
- #83 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
- #85 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.
- #86 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.
- #88 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.