Angiogeneza sprawa Ŝycia lub śmierci

Transcription

1 Angiogeneza sprawa Ŝycia lub śmierci

2 Carmeliet, Nature 2000

3 vascular system veins (3 cm) arteries (0.5 cm) capillaries (6 µm) arterioles (30 µm)

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5 Schematic structure of capillary Endothelium regulates: - vascular tone, - thrombosis, - fibrinolysis, - inflammation, - vascular wall remodeling - angiogenesis

6 Capillaries in skeletal muscle Erytrocytes leak from a ruptured blood vessel Ganglion cells in retina (by Anne Weston, Cancer Research UK)

7 Physiological angiogenesis is relatively rare event placenta uterus growth of hair wound healing Blood vessels

8 Blood vessel formation

9 Blood vessel formation short history of studies * Roman physician Claudius Galen of Pergamon ( ) found that vessels are filled with blood. Then,, sir William Harvey ( ) discovered the circulation of blood. * The word angiogenesis was used for the first time in 1787 by british surgeon, Dr.. John Hunter, to describe the growth of blood vessels in reindeer antler. * Observation of vessels in chicken chorio-allantoic membrane by F. Fuelleborn in 1895). * Detailed study on vasculogenesis in chick embryo and lymphangiogenesis by Florence Sabin in 1902, 1913, * First in vivo observations of sprouting capillaries in the transparent tails of amphibian larvae by Elliot Clark in 1918.

10 New Era in studies of blood vessel formation Judah Folkman, In 1971 Dr. Judah Folkman suggested that growth of tumors depends of neovascularization. Original drawing by Folkman (Folkman et al. 1971) First inhibitor of angiogenesis (CDI) was discovered by Dr. Judah Folkman and Dr. Henry Brem in 1975 during studies on cartilage. First proangiogenic factor Vascular Permeability Factor (VPF/VEGF) was discovered by Dr.. Harold Dvorak in 1983 during studies on tumors.

11 Blood vessel formation short history of studies * Since 1970s the extensive studies on mechanism of angiogenesis have started. * Since 1989 the attemps of pro- and anti-angiogenic angiogenic therapies in humans have started. * Since 1999 the large-scale clinical trials of pro- and anti-angiogenic angiogenic therapies have started. * First angiogenesis-stimulating stimulating drug (Regranex) is FDA- approved for treatment of diabetic foot ulcers * Avastin (an anti-vegf antibody) is FDA approved for the treatment of advanced colorectal cancer. * 2004 Macugen (an anti-vegf aptamer), becomes the first anti- VEGF drug to be FDA approved for the treatment of age-related macular degeneration.

12 stages in angiogenesis

13 Formation of blood vessels in wounded skin healthy tissue tissue 60 h after wounding

14 Carmeliet et al. Nature 2000

15 Capillaries with pericytes pericytes pericytes pericytes pericytes

16 VEGF-A VEGF-A A (vascular( endothelial growth factor, vascular permeability factor, vasculotropin) homodimeric protein, kda Produced by many types of cells (e.g. macrophages, vascular smooth muscle cells, fibroblasts, and cancer cells) Expression is induced in response to hypoxia and proinflammatory cytokines Receptors (VEGF-R1 and VEGF-R2) are present mostly on endothelial cells, therefore VEGF acts specifically on endothelium (but also on neurons and Schwann cells).

17 VEGF-A It protects endothelial cells from apoptosis and induces their proliferation, migration, and formation of capillaries. VEGF acts protectively on neurons. VEGF is required for the normal development of embryonic vasculature, the cyclic growth of blood vessels in the female reproductive tract, and the formation of capillaries during wound repair. However,, VEGF is also involved in abnormal angiogenesis,, as seen in proliferative retinopathies, rheumatoid arthritis, psoriasis, and malignancies.

18 Embryonic development is disrupted by modest increases in VEGF gene expression 2-3 fold overexpression is deletorious to embryonic development Enlarged hearts Embryos died between E12.5 and E14.5 Miquerol L, Langille BL, Nagy A. Development, 2000: 127:3941-6

19 Too high and unbalanced expression of VEGF after gene delivery using adenoviral vectors A and B. Note prominent tissue edema and new blood vessel formation. C. Note also a prominent leakage of plasma protein complexes from locally hyperpermeable ear vessels.

20 artery vein

21 Diabetic retinopathy

22 Antiangiogenic Therapy: Antiangiogenic therapy is a new form of treatment using drugs called 'angiogenesis inhibitors' that specifically halt new blood vessel l growth. More than 300 angiogenesis inhibitor molecules have been discovered so far: Some angiogenesis inhibitors are naturally present in the human body, because healthy tissues appear to resist cancer growth by containing ning these antiangiogenic compounds. Other angiogenesis inhibitors have been found in nature - in green tea, soy beans, fungi, mushrooms, tree bark, shark tissues, snake venom and many other substances. Still other angiogenesis inhibitors have been manufactured synthetically in the laboratory. Some FDA-approved medicines have also been "re-discovered" to have antiangiogenic properties. Currently, more than 40 antiangiogenic drugs are being tested clinical trials.

23 Macugen (aptamer blocking VEGF) first antiangiogenic drug approved for treatment of ophthalmological diseases. Inhibition of VEGF binding to VEGF receptors in cells treated with macugen

24 V.I.S.I.O.N. trial results

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26 VEGF plays a pivotal role in tumor expansion. It locally initiates: permeabilization of blood vessels, extravasation of plasma proteins, invasion of stromal cells, sprouting of new blood blood vessels that supply the tumor with O 2 and nutrients and facilitate metastasis. VEGF in tumor The first in vivo image of tumor angiogenesis rabbit epithelioma (Ide et al. 1939). Corrosion cast of tumor vasculature

27 Vessels in healthy tissue look different than those in tumors: view from outside Vessels of healthy tissue Vessels of tumor

28 Vessels in healthy tissue look different than those in tumors: view from inside Vessels of healthy tissue Vessels of tumor

29 Elongation of capillary by 1 mm allows for growth of ~ cancer cells

30 Effect of anti-angiogenic angiogenic therapy on tumor growth

31 Angiogenesis Inhibitors and Primary Tumors Tumor size in mice Days Start Stop Start Stop Endostatin Treatment National Cancer Institute

32 Angiogenesis Inhibitors and Metastasis Inject cancer cells Let initial tumor grow for several weeks Remove initial tumor Angiostatin injections Allow time for metastases to appear No treatment Few metastases Many metastases National Cancer Institute

33 Antiangiogenic Therapy Differs From Conventional Chemotherapy: Conventional chemotherapy kills all dividing cells in the body,, aiming to do the most damage to dividing cancer cells. However, normally dividing cells (hair cells, intestinal cells, mucous membranes, bone marrow cells) are also destroyed. This leads to well-known severe side effects of chemotherapy: hair loss, diarrhea, mouth ulcer, infection, and low blood counts. Some chemotherapy regimens work very well at treating cancers that are diagnosed early. Antiangiogenic therapy attacks only growing new blood vessel cells, thus the effect of antiangiogenic therapy is concentrated only at the cancer site. Furthermore, endothelial cells are more genetically stable than cancer cells, which decresses the chance that some cells can escape from the therapy.. AntiangiogenicA drugs are better- tolerated compared to chemotherapy, with fewer and less severe side s effects. Most antiangiogenic drugs do not kill cancer cells directly. To keep cancers from regrowing,, patients may need to take antiangiogenic drugs as a chronic therapy for the rest of their life.

34 Three major types of antiangiogenic therapies for cancer 1. Drugs that stop new blood vessels from sprouting (true angiogenesis inhibitors) 2. Drugs that attack a tumor's established blood supply (vascular targeting agents) 3. Drugs that attack both the cancer cells as well as blood vessel cells (the double-barreled barreled approach).

35 Angiogenesis can be inhibited at different phases

36 Angiogenesis can be inhibited at different phases

37 Phase III colorectal cancer study also: breast and lung cancers Avastin plus 5-FU/LV 5 Placebo plus 5-FU/LV5 FU- fluorouracil LV - leucovorin

38 Vessel cooption pushing vascularization The tumor faces normal liver architecture. As a compression of tumor grows, the hepatocytes step back and fusion of sinusoids takes place. The fused vessels, together with newly synthetized connective tissue, is incorporated into the tumor. The pressure of the tumor results in separation of the vessel from the liver parenchyma. The vessel remains connected to the sinusoidal system. Green - tumor; brown hepatocytes, red sinusoids and vessels. Crossection of vascularized liver metastases of colorectal cancer. SMA expressing cells (blue) are facing the tumor tissue; Hepatocytes are crowded in the middle (green); Endothelium (red) is incontact with SMA positive cells. Dome et al. Am J Pathol 2007

39 Glomeruloid vascularization Following extravasation, the tumor cells adhere to the surface of capillary basement membrane (grey). Because of contractile force and proliferation of the tumor cells a loop develops on the capillary, pulling the capillary inward, resulting in the development of further loops and reduction of the diameter of the capillary segment lying outside the glomeruloid body. This leads to formation glomeruloid body built by EC (red), pericytes (brown), and tumor cells (green). Brain metastases of melanoma stained for laminin (tumor, green) and CD31 (endothelium, blue). Glomeruloid bodies are connected to each other by a small capillary. Dome et al. Am J Pathol 2007

40 Vascular mimicry Dome et al. Am J Pathol 2007 The endothelial-line vasculature is closely apposed to the tumor cell-formed fluid conducting meshwork. It is presumed that such vasculature becomes leaky. There is also a physiological connection between the endothelial-lined vasculatureand the extravascular melanoma meshwork.

41 Wydaje się, Ŝe avastin moŝe hamować powstawanie nadmiaru VEGF, przez co przywraca równowagę między aktywatorami i inhibitorami angiogenezy i w początkowym okresie ma raczej działanie korzystne dla naczyń: * stabilizuje naczynia * ułatwia dostęp leków do guza Po dłuŝszym okresie działania hamuje powstawanie i indukuje regresję naczyń.

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