Das Renin-Angiotensin-System als Target für neue antiangiogene Therapiestrategien in der Gynäkologie

Zusammenfassung

Angiogenese ist essenziell für die Funktion der Zellen im Organismus, um die Zufuhr von Nährstoffen, Sauerstoff und Hormonen zu garantieren. Der Hauptinitiator von Angiogenese ist der „Vascular endothelial growth factor“ (VEGF). Neben VEGF sind weitere Faktoren in die Angiogeneseregulation involviert, die als selbstständige angiogene Faktoren oder aber als regulatorische Faktoren des VEGF-Systems wirken. Hierzu zählt das Renin-Angiotensin-System (RAS), dessen Haupteffektor Angiotensin II ist. Angiotensin II wirkt durch Steigerung der VEGF-Sekretion proangiogen, weshalb Angiotensin II sowohl unter physiologischen als auch unter pathologischen Bedingungen (Ovarial-, Endometrium-, Zervix- und Mammakarzinom) bei der Regulation von Angiogenese eine bedeutende Rolle spielt. In vitro lässt sich der proangiogene Effekt durch eine Antagonisierung von Angiotensin II hemmen. Klinische Daten zu den genannten Tumorentitäten konnten diesen zunächst theoretischen Ansatz bestätigen. Daher erscheint zukünftig, insbesondere für die gynäkologischen Malignome die Inhibition des Angiotensin-II-Effekts eine vielversprechende Option für die Entwicklung neuer antiangiogener Therapiekonzepte.

Abstract

Angiogenesis is essential for the functioning of cells in an organism in order to maintain the supply of nourishment, oxygen, and hormones. The main effector of angiogenesis is “vascular endothelial growth factor” (VEGF). In addition to VEGF, several other factors are involved in the regulation of angiogenesis, either as independent angiogenic factors or as regulators of the VEGF system. One such pathway is the renin-angiotensin system (RAS) with its main protein angiotensin II. Angiotensin II has been shown to be a potent angiogenic factor inducing endothelial proliferation via VEGF. Therefore angiotensin II has been proposed as an important regulator of angiogenesis in both physiological and pathological conditions (ovarian cancer, breast cancer, cervical cancer, endometrial cancer). In vitro, it was demonstrated that antagonising angiotensin II suppresses angiogenesis. Clinical data of the above-mentioned tumor entities support the idea of anti-angiogenic treatment by inhibition of angiotensin II. Therefore, especially for the gynecological cancers, inhibition of the angiotensin II effect seems to be an auspicious option for the development of new anti-angiogenic therapies.

Schlüsselwörter

Renin‐Angiotensin‐System - Angiogenese - Tumor

Key words

renin‐angiotensin system - angiogenesis - tumor

Literatur

• 1 Shalaby F, Rossant J, Yamaguchi T P. et al . Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice.  Nature. 1995;  376 62-66
• 2 Lee A H, Dublin E A, Bobrow L G. et al . Invasive lobular and invasive ductal carcinoma of the breast show distinct patterns of vascular endothelial growth factor expression and angiogenesis.  J Pathol. 1998;  185 394-401
• 3 Bolat F, Kayaselcuk F, Nursal T Z. et al . Microvessel density, VEGF expression, and tumor-associated macrophages in breast tumors: correlations with prognostic parameters.  J Exp Clin Cancer Res. 2006;  25 365-372
• 4 Weidner N, Semple J P, Welch W R. et al . Tumor angiogenesis and metastasis – correlation in invasive breast carcinoma.  N Engl J Med. 1991;  324 1-8
• 5 Anton L, Merrill D C, Neves L A. et al . Angiotensin-(1-7) inhibits in vitro endothelial cell tube formation in human umbilical vein endothelial cells through the AT(1–7) receptor.  Endocrine. 2007;  32 212-218
• 6 Sampaio W O, Henrique de Castro C, Santos R A. et al . Angiotensin-(1-7) counterregulates angiotensin II signaling in human endothelial cells.  Hypertension. 2007;  50 1093-1098
• 7 Timmermans P B, Chiu A T, Herblin W F. et al . Angiotensin II receptor subtypes.  Am J Hypertens. 1992;  5 (6 Pt 1) 406-410
• 8 Egami K, Murohara T, Shimada T. et al . Role of host angiotensin II type 1 receptor in tumor angiogenesis and growth.  J Clin Invest. 2003;  112 67-75
• 9 De Paepe B, Verstraeten V L, De Potter C R. et al . Growth stimulatory angiotensin II type-1 receptor is upregulated in breast hyperplasia and in situ carcinoma but not in invasive carcinoma.  Histochem Cell Biol. 2001;  116 247-254
• 10 Goto M, Mukoyama M, Sugawara A. et al . Expression and role of angiotensin II type 2 receptor in the kidney and mesangial cells of spontaneously hypertensive rats.  Hypertens Res. 2002;  25 125-133
• 11 Silvestre J S, Tamarat R, Senbonmatsu T. et al . Antiangiogenic effect of angiotensin II type 2 receptor in ischemia-induced angiogenesis in mice hindlimb.  Circ Res. 2002;  90 1072-1079
• 12 Herr D, Rodewald M, Fraser H. et al . Regulation of endothelial proliferation by the renin-angiotensin-system in human umbilical vein endothelial cells.  Reproduction. 2008;  136 (1) 125-130
• 13 Lonchampt M, Pennel L, Duhault J. Hyperoxia/normoxia-driven retinal angiogenesis in mice: a role for angiotensin II.  Invest Ophthalmol Vis Sci. 2001;  42 429-432
• 14 Raz A, Gamliel-Lazarovich A, Bogner I. et al . The importance of ACE2 in regulating the cardiovascular system.  Harefuah. 2007;  146 703-706 733
• 15 Davie A P, McMurray J J. Effect of angiotensin-(1-7) and bradykinin in patients with heart failure treated with an ACE inhibitor.  Hypertension . 1999;  34 457-460
• 16 Suganuma T, Ino K, Shibata K. et al . Functional expression of the angiotensin II type 1 receptor in human ovarian carcinoma cells and its blockade therapy resulting in suppression of tumor invasion, angiogenesis, and peritoneal dissemination.  Clin Cancer Res. 2005;  11 2686-2694
• 17 Wulff C, Wilson H, Largue P. et al . Angiogenesis in the human corpus luteum: localization and changes in angiopoietins, tie-2, and vascular endothelial growth factor messenger ribonucleic acid.  J Clin Endocrinol Metab. 2000;  85 4302-4309
• 18 Wulff C, Dickson S E, Duncan W C. et al . Angiogenesis in the human corpus luteum: simulated early pregnancy by HCG treatment is associated with both angiogenesis and vessel stabilization.  Hum Reprod. 2001;  16 2515-2524
• 19 Harata T, Ando H, Iwase A. et al . Localization of angiotensin II, the AT1 receptor, angiotensin-converting enzyme, aminopeptidase A, adipocyte-derived leucine aminopeptidase, and vascular endothelial growth factor in the human ovary throughout the menstrual cycle.  Fertil Steril. 2006;  86 433-439
• 20 Herr D DW, Hack G, Konrad R. et al .Regulated expression of the renin-angiotensin-system in human luteinised granulosa cells: Angiotensin II increases VEGF expression but its synthesis is reduced by hCG. Submitted 2008
• 21 Ino K, Shibata K, Kajiyama H. et al . Angiotensin II type 1 receptor expression in ovarian cancer and its correlation with tumour angiogenesis and patient survival.  Br J Cancer. 2006;  94 552-560
• 22 Stanojkovic T P, Zizak Z, Mihailovic-Stanojevic N. et al . Inhibition of proliferation on some neoplastic cell lines-act of carvedilol and captopril.  J Exp Clin Cancer Res. 2005;  24 387-395
• 23 Liao Y D, Xu H, Han Q. et al . Expression of angiotensin II type 1 receptor in cervical squamous cell carcinoma and its clinical significance.  Zhonghua Zhong Liu Za Zhi. 2007;  29 360-364
• 24 Kikkawa F, Mizuno M, Shibata K. et al . Activation of invasiveness of cervical carcinoma cells by angiotensin II.  Am J Obstet Gynecol. 2004;  190 1258-1263
• 25 Watanabe Y, Shibata K, Kikkawa F. et al . Adipocyte-derived leucine aminopeptidase suppresses angiogenesis in human endometrial carcinoma via renin-angiotensin system.  Clin Cancer Res. 2003;  9 6497-6503
• 26 Shibata K, Kikkawa F, Mizokami Y. et al . Possible involvement of adipocyte-derived leucine aminopeptidase via angiotensin II in endometrial carcinoma.  Tumour Biol. 2005;  26 9-16
• 27 Freitas-Silva M, Pereira D, Coelho C. et al . Angiotensin I-converting enzyme gene insertion/deletion polymorphism and endometrial human cancer in normotensive and hypertensive women.  Cancer Genet Cytogenet. 2004;  155 42-46
• 28 Herr D, Rodewald M, Fraser H M. et al . Potential role of renin-angiotensin-system for tumor angiogenesis in receptor negative breast cancer.  Gynecol Oncol. 2008;  109 (3) 418-425
• 29 Chua C C, Hamdy R C, Chua B H. Upregulation of vascular endothelial growth factor by angiotensin II in rat heart endothelial cells.  Biochim Biophys Acta. 1998;  1401 187-194
• 30 Pupilli C, Lasagni L, Romagnani P. et al . Angiotensin II stimulates the synthesis and secretion of vascular permeability factor/vascular endothelial growth factor in human mesangial cells.  J Am Soc Nephrol. 1999;  10 245-255
• 31 Wang X D, Chen X M, Wang J Z. et al . Signal transducers and activators of transcription 3 mediates up-regulation of angiotensin II-induced tissue inhibitor of metalloproteinase-1 expression in cultured human senescent fibroblasts.  Chin Med J (Engl). 2006;  119 1094-1102
• 32 Chen T H, Wang J F, Chan P. et al . Angiotensin II stimulates hypoxia-inducible factor 1alpha accumulation in glomerular mesangial cells.  Ann N Y Acad Sci. 2005;  1042 286-293
• 33 Sanchez-Lopez E, Lopez A F, Esteban V. et al . Angiotensin II regulates vascular endothelial growth factor via hypoxia-inducible factor-1alpha induction and redox mechanisms in the kidney.  Antioxid Redox Signal. 2005;  7 1275-1284
• 34 Zhao Y, Chen X, Cai L. et al . Angiotensin II suppresses adriamycin-induced apoptosis through activation of phosphatidylinositol 3-kinase/Akt signaling in human breast cancer cells.  Acta Biochim Biophys Sin (Shanghai). 2008;  40 304-310
• 35 Yuan J M, Koh W P, Sun C L. et al . Green tea intake, ACE gene polymorphism and breast cancer risk among Chinese women in Singapore.  Carcinogenesis. 2005;  26 1389-1394
• 36 Koh W P, Yuan J M, Sun C L. et al . Angiotensin I-converting enzyme (ACE) gene polymorphism and breast cancer risk among Chinese women in Singapore.  Cancer Res. 2003;  63 573-578
• 37 Yaren A, Turgut S, Kursunluoglu R. et al . Association between the polymorphism of the angiotensin-converting enzyme gene and tumor size of breast cancer in premenopausal patients.  Tohoku J Exp Med. 2006;  210 109-116
• 38 van der Knaap R, Siemes C, Coebergh J W. et al . Renin-angiotensin system inhibitors, angiotensin I-converting enzyme gene insertion/deletion polymorphism, and cancer: the Rotterdam Study.  Cancer. 2008;  112 748-757