Angiogenesis

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As angiogenesis ( ancient Greek ἄγγος angos "vessel" and γένεσις génesis "Origin") refers to the growth of blood vessels , by Sprossungs- or fission processes from already pre-formed blood vessels. This is to be distinguished from the formation of new blood vessels from endothelial precursor cells , which is referred to as vasculogenesis .

Forms of new blood vessel formation

  • Vasculogenesis : The formation of new vascular structures by circulating stem cells ( angioblasts ), which develop into de novo endothelial cells . This form of new vessel formation plays a role in the development of the vascular system during the embryonic period.
  • Angiogenesis: Formation of new vascular structures that have an endothelial cell lining as well as smooth muscle cells and pericytes. Angiogenesis plays an important role as a repair process in wound healing .
  • Arteriogenesis : Formation of arteries and smaller arterioles that obtain a complete vessel wall through the recruitment of smooth muscle cells . The formation of veins occurs according to the same principle.

Regardless of their type, all forms of new blood vessel formation in the adult organism belong to neovascularization .

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The term angiogenesis is increasingly being used today as an umbrella term for all forms of new vessel formation, as it is sometimes difficult to differentiate the three forms mentioned and the underlying principle is uniform. A distinction can also be made according to function, with regular angiogenesis and pathological (i.e. disease-promoting) angiogenesis. The latter, in turn, can be divided into increased (excessive angiogenesis, e.g. during tumor growth ) and insufficient angiogenesis (insufficient angiogenesis, e.g. in the case of wound healing disorders ).

It is a complex process in which the endothelial cells , pericytes and smooth muscle cells necessary for the formation of the vessel walls are activated by various angiogenic growth factors such as fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF). In this process, the connective tissue surrounding the capillary is lysed ( digested ), and there is a migration ( cell migration ) of small cell extensions into the tissue . New capillaries are created by the proliferation (reproduction) and migration (migration) of pre-existing endothelial cells. The later transformation of the capillaries into arterioles and arteries and venules and veins represents the conclusion of the process of angiogenesis triggered by growth factors and is determined by the activation of certain genes . While members of the Notch family are responsible for arteriogenesis, the formation of the veins is controlled by the transcription factor COUP-TFII. The final wall formation is regulated in both cases by FGF and Platelet Derived Growth Factor (PDGF) and angiopoietin -1.

Therapeutic angiogenesis

FGF-1 induced angiogenesis in the human myocardium: left, angiographic evidence of newly formed vessels ( blushing ) in the area of ​​the anterior wall of the left ventricle. Right, gray value analysis with evidence of an approximately three-fold increase in the vascular density in the myocardium compared to the control.
Stress SPECT examination of the human heart after intramyocardial FGF-1 application: normalization of blood flow in the anterior cardiac wall (3 months after treatment).
FGF-1 induced angiogenesis in the human myocardium: Evidence of the improvement in blood flow after FGF-1 injection into the myocardium using stress-SPECT examination.

Angiogenesis is of considerable biological and medical importance. In modern medicine, a distinction is made between two forms of therapeutic application of the angiogenesis principle :

  • Anti-angiogenic therapy
  • Pro-angiogenic therapy

Solid tumors are (tumor induced angiogenesis or Angio depending on a grow-along capillary neo genesis) that the tumor with oxygen supplied and nutrients. For the growth of a solid tumor beyond a volume of 1 to 2 mm³, the formation of new blood vessels is necessary. Without the ability to develop new blood vessels for supply, the non-angiogenic neoplasms remain limited to a symptom-free and clinically irrelevant size. If angiogenesis is suppressed, the state of tumor Dormancy is reached. Accordingly, anti-angiogenic therapeutic approaches ( antiangiogenesis ) try to reduce / block the vascular supply and thus the blood flow to a tumor. The first anti-tumor therapy with a VEGF-neutralizing monoclonal antibody ( bevacizumab - rhuMAb-VEGF) was approved by the FDA in 2004 for metastatic colorectal cancer . The active ingredient bevacizumab is now also used in the treatment of breast cancer , lung cancer and kidney cancer . The application of the principle of anti-angiogenesis for the treatment of malignant tumors can be traced back to the research work of Judah Folkman , who had been intensively involved with angiogenesis and anti-angiogenesis since the 1970s. The antibody ramucirumab binds to the VEGF R2 receptor and thus also prevents the formation of blood vessels to supply a tumor with nutrients. Ramucirumab is used in the treatment of gastric cancer .

Research into pro-angiogenic forms of therapy began at the end of the 1990s, when angiogenic growth factors were first used to treat arteriosclerosis (especially coronary artery disease (CHD) and peripheral occlusive disease (PAOD)). The world's first clinical study on the treatment of CHD patients was carried out in Germany in 1998 and used the potent angiogenic growth factor FGF -1. To date (2007), FGF -1 has been investigated in four completed clinical studies - for the treatment of CAD and chronic wound healing disorders; further studies - also on the treatment of PAD - are ongoing.

With regard to the methodology of the pro-angiogenic forms of therapy, three forms can be distinguished today:

  • Protein therapy
  • Gene therapy
  • Cell therapy.

The protein therapy is growth factors having angiogenic potency an, especially Fibroblast Growth Factor -1 (FGF-1) and Vascular Endothelial Growth Factor (VEGF); The greatest clinical experience is available with these growth factors. But the growth factors interleukin -8 (IL-8), epidermal growth factor (EGF), platelet-derived endothelial cell growth factor (PD-ECFG) and platelet-derived growth factor (PDGF) and transforming growth factor (TGF) also have a certain level angiogenic potency. The experience gained so far in clinical studies, particularly with FGF-1, is very promising: both new vessels in the human myocardium and an improvement in myocardial blood flow (accompanied by an increase in the patient's stress levels) have been demonstrated.

In gene therapy studies , the gene coding for an angiogenic growth factor is applied - either as so-called naked DNA ( plasmid DNA ) or as adenovirus- mediated gene transfer . Many as yet unsolved problems burden gene therapy , in particular the problem of inefficient gene transfection , undesirable immune reactions, and the potential toxicity of the viruses used as carriers .

Cell therapy based on the transfer of different cell types is still in the early stages of research; there are only studies with small patient numbers and with different, sometimes contradicting results. In particular, the type and number (dose) of cells used is very different: various forms of adult stem cells (such as endothelial progenitor cells (EPCs), hematopoietic stem cells (HPSCs), mesenchymal stem cells (MSCs)) were used in the first clinical pilot Studies.

literature

  • Ran Kornowski, Stephen E. Epstein, Martin B. Leon (Eds.): Handbook of myocardial revascularization and angiogenesis . Martin Dunitz, London 2000, ISBN 1-85317-782-2 .
  • Roger J. Laham, Donald S. Baim: Angiogenesis and direct myocardial revascularization . Humana Press, Totowa, NJ 2005, ISBN 1-59259-934-6 .
  • Mohan K. Raizada, Julian F. Paton, Sergej Kasparov, Michael J. Katovich (eds.): Cardiovascular genomics . Humana Press, Totowa NJ 2005, ISBN 1-58829-400-5 .
  • Gabor M. Rubanyi (Ed.): Angiogenesis in health and disease. Basic mechanisms and clinical applications . Dekker, New York 2000, ISBN 0-8247-8102-3 .
  • Thomas J. Stegmann: New Vessels for the Heart. Angiogenesis as New Treatment for Coronary Heart Disease; The Story of its Discovery and Development . CardioVascular BioTherapeutics Inc., Henderson NV 2004, ISBN 0-9765583-0-0 .

Web links

Individual evidence

  1. ^ W. Risau: Mechanisms of angiogenesis. In: Nature . Volume 386, Number 6626, April 1997, pp. 671-674. ISSN  0028-0836 . doi: 10.1038 / 386671a0 . PMID 9109485 . (Review).
  2. ^ Thomas H. Adair, Jean-Pierre Montani: Angiogenesis. Morgan & Claypool Life Sciences, San Rafael, CA 2010.
  3. ^ Pschyrembel Online. Retrieved December 19, 2019 .
  4. ↑ Michael H. Antoni, Susan Lutgendorf: Psychoendocrinology and psychoimmunology in oncology . In: Ulrike Ehlert, Roland von Känel (ed.): Psychoendocrinology and Psychoimmunology . Springer, Berlin 2011, ISBN 978-3-642-16963-2 , pp. 293-312 .
  5. ^ N. Almog: Molecular mechanisms underlying tumor dormancy. In: Cancer Lett . 294, 2010, pp. 139-146. PMID 20363069
  6. ↑ H. Hurwitz et al. a .: Bevacizumab plus Irinotecan, Fluorouracil and Leucovorin for Metastatic Colorectal Cancer. In: N Engl J Med . 350, 2004, pp. 2335-2342.
  7. ^ BJ Klencke u. a .: Independent review of E2100 progression-free survival (PFS) with the addition of bevacizumab (B) to paclitaxel (P) as initial chemotherapy for metastatic breast cancer (MBC). ( Memento of the original from May 13, 2016 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. (abstract). In: J Clin Oncol . Vol 26, No 15S (May 20 Supplement), 2008, p. 1036. @1@ 2Template: Webachiv / IABot / meeting.ascopubs.org
  8. ↑ A. Sandler et al. a .: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. In: N Engl J Med. 255, 2006, pp. 2542-2550.
  9. ↑ B. Escudier et al. a .: Bevacizumab plus interferon alfa2a for treatment of metastatic renal cell carcinoma: a randomized, double-blind phase III trial (AVOREN). In: The Lancet . 370, 2007, pp. 2103-2111.
  10. ↑ J. Folkman, M. Klagsbrun: Angiogenetic factors. In: Science . 235, 1987, pp. 442-447.
  11. ^ J. Folkman: Fighting cancer by attacking its blood supply. In: Sci Am. 275, 1996, pp. 150-154.
  12. Jump up ↑ O. Benny, O. Fainaru, A. Adini, F. Cassiola, L. Bazinet, I. Adini, E. Pravda, Y. Nahmias, S. Koirala, G. Corfas, RJ D'Amato, J. Folkman: An orally delivered small-molecule formulation with antiangiogenic and anticancer activity. In: Nat Biotechnol . 26 (7), Jul 2008, pp. 799-807. Epub 2008 Jun 29. PMID 18587385
  13. ↑ FDA approves Cyramza for stomach cancer. FDA, accessed August 25, 2014 .
  14. ↑ M. Simons, RO Bonow, NA Chronos, DJ Cohen, FJ Giordano, HK Hammond, RJ Laham, W. Li, M. Pike, FW Sellke, TJ Stegmann, JE Udelson, TK Rosengart: Clinical trials in coronary angiogenesis: issues , problems, consensus: an expert panel summary. In: Circulation. 102, 2000, pp. E73-E86.
  15. ↑ B. Schumacher, P. Pecher, BU von Specht, TJ Stegmann: Induction of neoangiogenesis in ischemic myocardium by human growth factors. In: Circulation. 97, 1998, pp. 645-650.
  16. ^ J. Folkman: Angiogenic therapy of the heart. In: Circulation. 97, 1998, pp. 628-629.
  17. ^ TJ Stegmann: A human growth factor in the induction of neoangiogenesis. In: Exp.Opin.Invest.Drugs. 7, 1998, pp. 2011-2015.
  18. ↑ TJ Stegmann, T. Hoppert: Combined local angiogenesis and surgical revascularization for coronary heart disease. In: Current Intervent. Cardiol. Reports. 1, 1999, pp. 172-178.
  19. ↑ TJ Stegmann, T. Hoppert, A. Schneider, M. Popp, G. Strupp, RO Ibing, A. Hertel: Therapeutic angiogenesis: intramyocardial growth factor delivery of FGF-1 as sole therapy in patients with chronic coronary artery disease. In: CVR. 1, 2000, pp. 259-267.
  20. ^ DM Ornitz, N. Itoh: Fibroblast growth factors . Genome Biol 2, 2001, pp. 1-12.
  21. ↑ M. Blaber, J. DiSalvo, KA Thomas: X-ray crystal structure of human acidic fibroblast growth factor. In: Biochemistry . 35, 1996, pp. 2086-2094.
  22. ↑ R. Khurana, M. Simons: Insights from angiogenesis trials using fibroblast growth factor for advanced arteriosclerotic disease. In: Trends Cardiovasc. Med. 13, 2003, pp. 116-122.
  23. ^ TJ Stegmann: New Vessels for the Heart. Angiogenesis as New Treatment for Coronary Heart Disease: The Story of its Discovery and Development . CardioVascular BioTherapeutics, Henderson, Nevada 2004.
  24. ↑ LE Wagoner, DD Snavely, GA Conway, EA Hauntz, WH Merrill: Intramyocardial injection of fibroblast growth factor-1 for treatment of refractory angina pectoris: the initial US experience. In: Circulation. 110, 2004, p. 395.
  25. Jump up ↑ LE Wagoner, W. Merrill, J. Jacobs, G. Conway, J. Boehmer, K. Thomas, TJ Stegmann: Angiogenesis Protein Therapy With Human Fibroblast Growth Factor (FGF-1): Results Of A Phase I Open Label, Dose Escalation Study In Subjects With CAD Not Eligible For PCI Or CABG. In: Circulation. 116, 2007, p. 443.