Tumorangiogenese: Neue Ansätze in der Krebstherapie

Zusammenfassung

Solide Tumoren können ohne Versorgung über das Blutgefäßsystem nur bis zu einem Durchmesser von wenigen Millimetern wachsen. Erst wenn der Tumor beginnt, angiogene Wachstumsfaktoren zu produzieren, setzt die Neubildung von Gefäßen durch Aussprossen aus dem bestehenden Gefäßsystem ein. Der Tumor wächst, und Krebszellen gelangen durch die neuen permeablen Kapillaren in den Kreislauf. Der »vascular endothelial growth factor« (VEGF) ist der für die Tumorangiogenese bedeutsamste angiogene Wachstumsfaktor. Er wird von fast allen soliden Tumoren gebildet. Seine Rezeptoren werden nur auf Gefäßendothelien und vornehmlich auf solchen in der Nähe des Tumors exprimiert. Das VEGF/VEGF-Rezeptorsystem bietet sich als Angriffsart für eine antiangiogene Krebstherapie an. Experimentelle Therapieversuche zeigen, dass eine Hemmung der VEGF-vermittelten Endothelzellaktivierung sowohl das Wachstum des Primärtumors als auch die Metastasierung hemmt. Entsprechende therapeutische Strategien werden derzeit klinisch erprobt.

Summary

Solid tumors do not grow beyond a size of a few millimetres without supply of nutrients and growth factors by the vascular system. Only when tumors produce angiogenic growth factors new vessels are formed by sprouting of capillaries from the existing vascular system. The tumor can grow and tumor cells reach the circulation through these new and permeable vessels. The vascular endothelial growth factor (VEGF) is the most prominent angiogenic growth factor. VEGF is produced by almost all solid tumors: its receptors are expressed only on vascular endothelial cells and predominantly in vessels in the proximity of the tumor. Therefore, the VEGF/VEGF-receptor system is a target for anti-angiogenic cancer therapy. Experiments show that inhibition of the VEGF-mediated endothelial cell activation interferes with tumor growth and metastases formation. Appropriate therapeutic strategies are currently under clinical investigation.

Schlüsselwörter

Tumorangiogenese - Onkologie - VEGF - antiangiogene Therapie

Key words

Tumor angiogenesis - Oncology - VEGF - anti-angiogenic therapy

• Literatur

• 1 Barleon B, Siemeister G, Martiny-Baron G, Weinde I K. et al. Vascular endothelial growth factor up-regulates its receptor fms-like tyrosine kinase 1 (FLT-1) and a soluble variant of FLT-1 in human vascular endothelial cells. Cancer Res 1997; 57: 5421.
• 2 Boehm T, Folkman J, Browder T, O’Reilly MS. Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature 1997; 390: 404.
• 3 Dumont DJ, Gradwohl GJ, Fong GH, Auerbach R, Breitman ML. The endothelial-specific receptor tyrosine kinase tek is a member of a new subfamily of receptors. Oncogene 1993; 8: 1293.
• 4 Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev 1993; 18: 4.
• 5 Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996; 86: 353.
• 6 Kong HL, Hecht D, Song W, Kovesdi I. et al. Regional suppression of tumor growth by in vivo transfer of a cDNA encoding a secreted form of the extracellular domain of the flt-1 vascular endothelial growth factor receptor. Hum Gene Ther 1998; 9: 823.
• 7 Kremer C, Breier G, Risau W, Plate KH. Upregulation of tlk-1/vascular endothelial growth factor receptor 2 by its ligand in a cerebral slice culture system. Cancer Res 1997; 57: 3852.
• 8 Li J, Brown LF, Hibberd MG, Grossman JD. et al. VEGF, Flk-1 and Flt-1 expression in a rat myocardial infarction model of angiogenesis. Am J Physiol 1996; 270: 1803.
• 9 Lin P, Buxton JA, Acheson A, Radziejewski C. et al. Antiangiogenic gene therapy targeting the endothelium-specific receptor tyrosine kinase Tie-2. Proc Natl Acad Sci USA 1998; 95: 8829.
• 10 Lin P, Polverini P, Dewhirst M, Shan S. et al. Inhibition of tumor angiogenesis using a soluble receptor establishes a role for Tie-2 in pathologic vascular growth. J Clin Invest 1997; 100: 2072.
• 11 Millauer B, Shawver KL, Plate KH, Risau W, Ullrich A. Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature 1994; 367: 576.
• 12 Pepper MS. Manipulating angiogenesis: from basic science to the bedside. Arterioscler Thromb Vasc Bio 1997; 117: 605.
• 13 Rosen LS, Kabbinavar F, Rosen P, Mulay M. et al. Phase I tf\al of SU5416, a novel angiogenesis inhibitor, in patients with advanced malignancies. Ann Oncol 1998; 9: 290.
• 14 Saleh M, Stacker SA, Wilks AF. Inhibition of growth of C6 glioma cells in vivo by expression of antisense vascular endothelial growth factor sequence. Cancer Res 1996; 56: 393.
• 15 Siemeister G, Martiny-Baron G, Marmé D. The pivotal role of VEGF in tumor angiogenesis: Molecular facts and therapeutic opportunities. Cancer Metastasis Rev 1998; 17: 241.
• 16 Skobe M, Rockwell P, Goldstein N, Vosseler S, Fusenig NE. Halting angiogenesis suppresses carcinoma cell invasion. Nature Med 1997; 3: 1222.
• 17 Suri C, Jones PF, Patan S, Bartunkova PC. et al. Requisite role of angiopoietin-l, a ligand for the Tie2 receptor, during embryonic angiogenesis. Cell 1996; 87: 1171.
• 18 Tuder RM, Flook BE, Voelkel NF. Increased gene expression for VEGF and the VEGF receptor KDR/Flk and FIt in lungs exposed to acute or chronic hypoxia. J Clin Invest 1995; 95: 1798.
• 19 Warren RA, Yuan H, Matli MR, Gillett NA, Ferrara N. Regulation by vascular endothelial growth factor of human Colon cancer tumorigeneses in a mouse model of experimental liver metastasis. J Clin Invest 1995; 95: 1789.
• 20 Wood J, Buchdunger E, Cozens R, Hofman F. et al. Pharmacological profile of a potent and orally active inhibitor of VEGF receptor kinases. Proc AACR 1997; a255.