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01.01.2012 | Research

Immunohistochemical Study of the Angiogenetic Network of VEGF, HIF1α, VEGFR-2 and Endothelial Nitric Oxide Synthase (eNOS) in Human Breast Cancer

verfasst von: Maria Kafousi, Thomas Vrekoussis, Eleftheria Tsentelierou, Kitty Pavlakis, Iordanis Navrozoglou, Vassilios Dousias, Elias Sanidas, Dimitrios Tsiftsis, Vassilios Georgoulias, Efstathios N. Stathopoulos

Erschienen in: Pathology & Oncology Research | Ausgabe 1/2012

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Abstract

Background

The role of Nitric Oxide (NO) in angiogenesis has not been fully clarified yet. A dual role for NO, either inductive or inhibitory, has been proposed on the basis of different effects that high or low concentrations of NO may exert on the angiogenic process. Additionally, it has been referred that NO may induce VEGF production, while VEGF may induce NO production via up-regulation of the endothelial nitric oxide synthase (eNOS), the two pathways being reverse. The aim of the current study was to investigate the expression of key molecules involved in these opposite pathways in primary breast cancer.

Methods

Representative tumor samples from 242 patients with early-stage breast cancer (invasive ductal breast carcinomas) were investigated for the expression of VEGF, VEGFR-2, HIF1α, iNOS, and eNOS using immunohistochemistry.

Results

Endothelial NOS was found in 159 cases, VEGF in 131 cases, HIF-1α in 139 cases, VEGFR2 in 185 cases and inducible NOS (iNOS) in 22 cases. There was a significant correlation between the expression of VEGF and VEGFR-2, eNOS and VEGF, eNOS and VEGFR-2, eNOS and HIF1α. No statistically significant correlation was found between iNOS and the rest of the studied molecules.

Conclusions

In breast cancer cases, the major molecules regulating NO and VEGF production can be co-expressed in the individual carcinomas implying a possibility for the relevant pathways to be active; however appropriate functional experiments remain to be conducted to prove such a hypothesis

Fox SB, Generali DG, Harris AL (2007) Breast tumour angiogenesis. Breast Canc Res 9:216CrossRef

Kimura H, Esumi H (2003) Reciprocal regulation between nitric oxide and vascular endothelial growth factor in angiogenesis. Acta Biochim Pol 50:49–59PubMed

Amano K, Matsubara H, Iba O et al (2003) Enhancement of ischemia-induced angiogenesis by eNOS overexpression. Hypertension 41:156–62PubMedCrossRef

Fukumura D, Gohongi T, Kadambi A et al (2001) Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability. Proc Natl Acad Sci USA 98:2604–9PubMedCrossRef

Sandau KB, Fandrey J, Brune B (2001) Accumulation of HIF-1alpha under the influence of nitric oxide. Blood 97:1009–15PubMedCrossRef

Sandau KB, Faus HG, Brune B (2000) Induction of hypoxia-inducible-factor 1 by nitric oxide is mediated via the PI 3 K pathway. Biochem Biophys Res Commun 278:263–7PubMedCrossRef

Ghiso N, Rohan RM, Amano S, Garland R, Adamis AP (1999) Suppression of hypoxia-associated vascular endothelial growth factor gene expression by nitric oxide via cGMP. Invest Ophthalmol Vis Sci 40:1033–9PubMed

Choi KS, Bae MK, Jeong JW, Moon HE, Kim KW (2003) Hypoxia-induced angiogenesis during carcinogenesis. J Biochem Mol Biol 36:120–7PubMedCrossRef

Tsuzuki Y, Fukumura D, Oosthuyse B, Koike C, Carmeliet P, Jain RK (2000) Vascular endothelial growth factor (VEGF) modulation by targeting hypoxia-inducible factor-1alpha– > hypoxia response element– > VEGF cascade differentially regulates vascular response and growth rate in tumors. Cancer Res 60:6248–52PubMed

10.

Chou MT, Wang J, Fujita DJ (2002) Src kinase becomes preferentially associated with the VEGFR, KDR/Flk-1, following VEGF stimulation of vascular endothelial cells. BMC Biochem 3:32PubMedCrossRef

11.

Duval M, Le Boeuf F, Huot J, Gratton JP (2007) Src-mediated phosphorylation of Hsp90 in response to vascular endothelial growth factor (VEGF) is required for VEGF receptor-2 signaling to endothelial NO synthase. Mol Biol Cell 18:4659–68PubMedCrossRef

12.

He H, Venema VJ, Gu X, Venema RC, Marrero MB, Caldwell RB (1999) Vascular endothelial growth factor signals endothelial cell production of nitric oxide and prostacyclin through flk-1/KDR activation of c-Src. J Biol Chem 274:25130–5PubMedCrossRef

13.

Hood JD, Meininger CJ, Ziche M, Granger HJ (1998) VEGF upregulates ecNOS message, protein, and NO production in human endothelial cells. Am J Physiol 274:H1054–8PubMed

14.

Shen BQ, Lee DY, Zioncheck TF (1999) Vascular endothelial growth factor governs endothelial nitric-oxide synthase expression via a KDR/Flk-1 receptor and a protein kinase C signaling pathway. J Biol Chem 274:33057–63PubMedCrossRef

15.

Beleslin-Cokic BB, Cokic VP, Yu X, Weksler BB, Schechter AN, Noguchi CT (2004) Erythropoietin and hypoxia stimulate erythropoietin receptor and nitric oxide production by endothelial cells. Blood 104:2073–80PubMedCrossRef

16.

Loibl S, Strank C, von Minckwitz G et al (2005) Immunohistochemical evaluation of endothelial nitric oxide synthase expression in primary breast cancer. Breast 14:230–5PubMedCrossRef

17.

Mortensen K, Christensen IJ, Nielsen HJ, Hansen U, Larsson LI (2004) High expression of endothelial cell nitric oxide synthase in peritumoral microvessels predicts increased disease-free survival in colorectal cancer. Cancer Lett 216:109–14PubMedCrossRef

18.

Mortensen K, Holck S, Christensen IJ et al (1999) Endothelial cell nitric oxide synthase in peritumoral microvessels is a favorable prognostic indicator in premenopausal breast cancer patients. Clin Cancer Res 5:1093–7PubMed

19.

Nakamura Y, Yasuoka H, Tsujimoto M et al (2006) Nitric oxide in breast cancer: induction of vascular endothelial growth factor-C and correlation with metastasis and poor prognosis. Clin Cancer Res 12:1201–7PubMedCrossRef

20.

Kwan ML, Kushi LH, Weltzien E et al (2009) Epidemiology of breast cancer subtypes in two prospective cohort studies of breast cancer survivors. Breast Cancer Res 11:R31PubMedCrossRef

21.

Kalmanti L, Dampaki K, Dimitriou H, Stiakaki E, Chaniotis V, Stathopoulos E (2005) A morphometric approach for the evaluation of angiogenesis in acute lymphoblastic leukemia of childhood. Leuk Res 29:673–7PubMedCrossRef

22.

Aebersold DM, Burri P, Beer KT et al (2001) Expression of hypoxia-inducible factor-1alpha: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer. Cancer Res 61:2911–16PubMed

23.

Nakopoulou L, Stefanaki K, Panayotopoulou E et al (2002) Expression of the vascular endothelial growth factor receptor-2/Flk-1 in breast carcinomas: correlation with proliferation. Hum Pathol 33:863–70PubMedCrossRef

24.

Takahashi Y, Tucker SL, Kitadai Y et al (1997) Vessel counts and expression of vascular endothelial growth factor as prognostic factors in node-negative colon cancer. Arch Surg 132:541–6PubMedCrossRef

25.

Meunier-Carpentier S, Dales JP, Djemli A et al (2005) Comparison of the prognosis indication of VEGFR-1 and VEGFR-2 and Tie2 receptor expression in breast carcinoma. Int J Oncol 26:977–84PubMed

26.

Mylona E, Alexandrou P, Giannopoulou I et al (2007) The prognostic value of vascular endothelial growth factors (VEGFs)-A and -B and their receptor, VEGFR-1, in invasive breast carcinoma. Gynecol Oncol 104:557–63PubMedCrossRef

27.

Trastour C, Benizri E, Ettore F et al (2007) HIF-1alpha and CA IX staining in invasive breast carcinomas: prognosis and treatment outcome. Int J Cancer 120:1451–8PubMedCrossRef

28.

Hayes DF, Miller K, Sledge G (2007) Angiogenesis as targeted breast cancer therapy. Breast 16(Suppl 2):S17–19PubMedCrossRef

29.

Namba T, Koike H, Murakami K et al (2003) Angiogenesis induced by endothelial nitric oxide synthase gene through vascular endothelial growth factor expression in a rat hindlimb ischemia model. Circulation 108:2250–7PubMedCrossRef

30.

Duenas-Gonzalez A, Isales CM, del Mar Abad-Hernandez M, Gonzalez-Sarmiento R, Sangueza O, Rodriguez-Commes J (1997) Expression of inducible nitric oxide synthase in breast cancer correlates with metastatic disease. Mod Pathol 10:645–9PubMed

31.

Vleugel MM, Greijer AE, Shvarts A et al (2005) Differential prognostic impact of hypoxia induced and diffuse HIF-1alpha expression in invasive breast cancer. J Clin Pathol 58:172–7PubMedCrossRef

32.

Lundgren K, Holm C, Landberg G (2007) Hypoxia and breast cancer: prognostic and therapeutic implications. Cell Mol Life Sci 64:3233–47PubMedCrossRef

33.

Lechner M, Lirk P, Rieder J (2005) Inducible nitric oxide synthase (iNOS) in tumor biology: the two sides of the same coin. Semin Cancer Biol 15:277–89PubMedCrossRef

34.

Loibl S, Buck A, Strank C et al (2005) The role of early expression of inducible nitric oxide synthase in human breast cancer. Eur J Cancer 41:265–71PubMedCrossRef

35.

Vakkala M, Paakko P, Soini Y (2000) eNOS expression is associated with the estrogen and progesterone receptor status in invasive breast carcinoma. Int J Oncol 17:667–71PubMed

36.

Sumi D, Ignarro LJ (2003) Estrogen-related receptor alpha 1 up-regulates endothelial nitric oxide synthase expression. Proc Natl Acad Sci USA 100:14451–6PubMedCrossRef

37.

Loibl S, Bratengeier J, Farines V et al (2006) Investigations on the inducible and endothelial nitric oxide synthases in human breast cancer cell line MCF-7 - estrogen has an influence on e-NOS, but not on i-NOS. Pathol Res Pract 202:1–7PubMedCrossRef

38.

Gavin KM, Seals DR, Silver AE, Moreau KL (2009) Vascular endothelial estrogen receptor alpha is modulated by estrogen status and related to endothelial function and endothelial nitric oxide synthase in healthy women. J Clin Endocrinol Metab 94:3513–20PubMedCrossRef

39.

Oishi A, Ohmichi M, Takahashi K et al (2004) Medroxyprogesterone acetate attenuates estrogen-induced nitric oxide production in human umbilical vein endothelial cells. Biochem Biophys Res Commun 324:193–8PubMedCrossRef

40.

Zerr-Fouineau M, Chataigneau M, Blot C, Schini-Kerth VB (2007) Progestins overcome inhibition of platelet aggregation by endothelial cells by down-regulating endothelial NO synthase via glucocorticoid receptors. FASEB J 21:265–73PubMedCrossRef

41.

Chi JT, Wang Z, Nuyten DS et al (2006) Gene expression programs in response to hypoxia: cell type specificity and prognostic significance in human cancers. PLoS Med 3:e47PubMedCrossRef

42.

Milani M, Harris AL (2008) Targeting tumour hypoxia in breast cancer. Eur J Cancer 44:2766–73PubMedCrossRef

43.

Kurebayashi J, Otsuki T, Moriya T, Sonoo H (2001) Hypoxia reduces hormone responsiveness of human breast cancer cells. Jpn J Cancer Res 92:1093–101PubMedCrossRef

44.

Yamamoto Y, Ibusuki M, Okumura Y et al (2008) Hypoxia-inducible factor 1alpha is closely linked to an aggressive phenotype in breast cancer. Breast Cancer Res Treat 110:465–75PubMedCrossRef

45.

Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL (2001) HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol 21:3995–4004PubMedCrossRef

46.

Giatromanolaki A, Koukourakis MI, Simopoulos C et al (2004) c-erbB-2 related aggressiveness in breast cancer is hypoxia inducible factor-1alpha dependent. Clin Cancer Res 10:7972–7PubMedCrossRef

47.

Traina TA, Rugo HS, Dickler M (2007) Bevacizumab for advanced breast cancer. Hematol Oncol Clin North Am 21:303–19PubMedCrossRef

48.

Marty M, Pivot X (2008) The potential of anti-vascular endothelial growth factor therapy in metastatic breast cancer: Clinical experience with anti-angiogenic agents, focusing on bevacizumab. Eur J Cancer 44:912–20PubMedCrossRef

49.

Patiar S, Harris AL (2006) Role of hypoxia-inducible factor-1alpha as a cancer therapy target. Endocr Relat Cancer 13(Suppl 1):S61–75PubMedCrossRef

50.

Melillo G (2007) Targeting hypoxia cell signaling for cancer therapy. Cancer Metastasis Rev 26:341–52PubMedCrossRef

51.

Coulet F, Nadaud S, Agrapart M, Soubrier F (2003) Identification of hypoxia-response element in the human endothelial nitric-oxide synthase gene promoter. J Biol Chem 278:46230–40PubMedCrossRef

Titel: Immunohistochemical Study of the Angiogenetic Network of VEGF, HIF1α, VEGFR-2 and Endothelial Nitric Oxide Synthase (eNOS) in Human Breast Cancer
verfasst von: Maria Kafousi
Thomas Vrekoussis
Eleftheria Tsentelierou
Kitty Pavlakis
Iordanis Navrozoglou
Vassilios Dousias
Elias Sanidas
Dimitrios Tsiftsis
Vassilios Georgoulias
Efstathios N. Stathopoulos
Publikationsdatum: 01.01.2012
Verlag: Springer Netherlands
Erschienen in: Pathology & Oncology Research / Ausgabe 1/2012
Print ISSN: 1219-4956
Elektronische ISSN: 1532-2807
DOI: https://doi.org/10.1007/s12253-011-9413-8

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Immunohistochemical Study of the Angiogenetic Network of VEGF, HIF1α, VEGFR-2 and Endothelial Nitric Oxide Synthase (eNOS) in Human Breast Cancer