Hostname: page-component-8448b6f56d-c4f8m Total loading time: 0 Render date: 2024-04-24T17:58:55.678Z Has data issue: false hasContentIssue false
  • English
  • Français

Ex vivo Determination of an Estradiol Analogue-Induced Changes on Platelet Morphology and Angiogenic Biomarkers

Published online by Cambridge University Press:  24 September 2015

Lisa Repsold ,
Etheresia Pretorius  and
Annie M. Joubert
Lisa Repsold
Affiliation:
Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria, Gauteng 0001, South Africa
Etheresia Pretorius
Affiliation:
Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria, Gauteng 0001, South Africa
Annie M. Joubert*
Affiliation:
Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria, Gauteng 0001, South Africa
*
*Corresponding author. annie.joubert@up.ac.za
Get access

Abstract

Angiogenesis is a closely controlled biological process that takes place during fetal development of blood vessels and wound healing, and includes the development of new blood vessels from preexisting blood vessels. Tumor angiogenesis is a means by which tumors obtain oxygen, nutrition and promote tumor growth. Angiogenesis-regulating proteins are therefore ideal biomarkers in the study of tumor pathophysiology. In our laboratory, a new in silico-designed analogue of 2-methoxyestradiol has been synthesized with angiogenic properties, namely 2-ethyl-3-O-sulfamoyl-estra-1,3,5(10)16-tetraene (ESE-16). The ex vivo influence of ESE-16 on angiogenesis and morphology in platelets of healthy participants was investigated. Scanning electron microscopy revealed no morphological changes in ESE-16-treated platelets. The possible antiangiogenic effect of ESE-16-exposed platelets was determined by means of flow cytometry measurement of angiogenic protein levels, which were significantly increased after platelets were added to tumorigenic breast epithelial cells. This indicates that binding of platelets to cancer cells causes differential release of platelet constituents. Vascular endothelial growth factor levels were decreased in platelets, whereas platelet-derived growth factor and matrix metallopeptidase-9 levels were not significantly affected in platelets. In light of the above-mentioned data, further investigation of ESE-16’s influence on morphology and angiogenic markers in platelets of cancer patients is warranted.

Keywords

angiogenesis-regulating proteinsex vivotumorsESE-16platelets
Type
Biological Applications
Information
Microscopy and Microanalysis , Volume 21 , Issue 6 , December 2015 , pp. 1491 - 1503
Copyright
© Microscopy Society of America 2015 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Andrae, J., Gallini, R. & Betsholtz, C. (2008). Role of platelet-derived growth factors in physiology and medicine. Genes Dev 22(10), 1276–1312.Google Scholar
Baj-Krzyworzeka, M., Majka, M., Pratico, D., Ratajczak, J., Vilaire, G., Kijowski, J., Reca, R., Janowska-Wieczorek, A. & Ratajczak, M.Z. (2002). Platelet-derived microparticles stimulate proliferation, survival, adhesion, and chemotaxis of hematopoietic cells. Exp Hematol 30(5), 450–459.Google Scholar
Battinelli, E.M., Markens, B.A. & Italiano, J.E. Jr. (2011). Release of angiogenesis regulatory proteins from platelet alpha granules: Modulation of physiologic and pathologic angiogenesis. Blood 118(5), 1359–1369.Google Scholar
Bhat, T.A. & Singh, R.P. (2008). Tumor angiogenesis—A potential target in cancer chemoprevention. Food Chem Toxicol 46, 1334–1345.Google Scholar
Bierie, B. & Moses, H.L. (2010). Transforming growth factor beta (TGF-ß) and inflammation in cancer. Cytokine Growth Factor Rev 21, 49–59.Google Scholar
Brecher, G. & Cronkite, E.P. (1950). Morphology and enumeration of human blood platelets. J Appl Physiol 3(6), 365–377.Google Scholar
Bruserud, O., Hatfield, K.J., Kalland, K.H., Kittang, A.O., Oyan, A.M. & Reikvam, H. (2010). Primary human acute myelogenous leukemia cells release matrix metalloproteases and their inhibitors: Release profile and pharmacological modulation. Eur J Haematol 84, 239–251.Google Scholar
Carmeliet, P. & Jain, R.K. (2000). Angiogenesis in cancer and other diseases. Nature 407(6801), 249–257.Google Scholar
Childs, C.B., Proper, J.A., Tucker, R.F. & Moses, H.L. (1982). Serum contains a platelet-derived transforming growth factor. Proc Natl Acad Sci U S A 79(17), 5312–5316.Google Scholar
Ciardiello, F., Caputo, R., Bianco, R., Damiano, V., Fontanini, G., Cuccato, S., De Placido, S., Bianco, A.R. & Tortora, G. (2001). Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor. Clin Cancer Res 7(5), 1459–1465.Google Scholar
Coupland, L.A., Chong, B.H. & Parish, C.R. (2013). Beware of NK cells in pre-clinical metastasis models. Clin Exp Metastasis 30(7), 945–947.Google Scholar
De Boeck, M. & Dijke, P.T. (2012). Key role for ubiquitin protein modification TGFß signal transduction. Ups J Med Sci 117, 153–165.Google Scholar
Dunn, I.F., Heese, O. & Black, P.M. (2000). Growth factors in glioma angiogenesis: FGFs, PDGF, EGF, and TGFs. J Neurooncol 50(1–2), 121–137.Google Scholar
Duque, J.L., Loughlin, K.R., Adam, R.M., Kantoff, P.W., Zurakowski, D. & Freeman, M.R. (1999). Plasma levels of vascular endothelial growth factor are increased in patients with metastatic prostate cancer. Urology 54(3), 523–527.Google Scholar
Folkman, J. & Shing, Y. (1992). Angiogenesis. J Biol Chem 267(16), 10931–10934.CrossRefGoogle ScholarPubMed
Gibbons, J. (2010). Angiogenesis: Emerging roles for the TGFβ superfamily. Pathw Rev 11, 14–16.Google Scholar
Grabowski, E.F., Boor, S.E., Rodino, L.J., Jang, I.K., Gold, H. & Michelson, A.D. (1996). Platelets are degranulated by some, but not all, contrast media. Acad Radiol 3(2), S328–S330.Google Scholar
Guijarro-Muñoz, I., Cuesta, A.M., Alvarez-Cienfuegos, A., Geng, J.G., Alvarez-Vallina, L. & Sanz, L. (2012). The axonal repellent Slit2 inhibits pericyte migration: Potential implications in angiogenesis. Exp Cell Res 318(4), 371–378.Google Scholar
Hall, M., Gourley, C., Mcneish, I., Ledermann, J., Gore, M., Jayson, G., Perren, T., Rustin, G. & Kaye, S. (2013). Targeted anti-vascular therapies for ovarian cancer: Current evidence. Br J Cancer 108(2), 250–258.Google Scholar
Italiano, J.E., Richardson, J.L., Patel-Hett, S., Battinelli, E., Zaslavsky, A., Short, S., Ryeom, S., Folkman, J. & Klement, G.L. (2008). Angiogenesis is regulated by a novel mechanism: Pro- and antiangiogenic proteins are organized into separate platelet alpha granules and differentially released. Blood 111(3), 1227–1233.Google Scholar
Jain, S., Harris, J. & Ware, J. (2010). Platelets: Linking hemostasis and cancer. Arterioscler Thromb Vasc Biol 30(12), 2362–2367.Google Scholar
Lee, C.C., Liu, K.J. & Huang, T.S. (2006). Tumor-associated macrophage: Its role in tumor angiogenesis. J Cancer Mol 2(4), 135–140.Google Scholar
Mabjeesh, N.J., Escuin, D., Lavallee, T.M., Pribluda, V.S., Swartz, G.M., Johnson, M.S., Willard, M.T., Zhong, H., Simons, J.W. & Giannakakou, P. (2003). 2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF. Cancer Cell 3, 363–375.Google Scholar
Mannello, F. & Medda, V. (2011). Differential expression of MMP-2 and MMP-9 activity in megakaryocytes and platelets. Blood 118(24), 6470–6471.Google Scholar
Mannello, F. & Tonti, G.A. (2007). Concise review: No breakthroughs for human mesenchymal and embryonic stem cell culture: Conditioned medium, feeder layer, or feeder-free; medium with fetal calf serum, human serum, or enriched plasma; serum-free, serum replacement nonconditioned medium, or ad hoc formula? All that glitters is not gold!. Stem Cells 25(7), 1603–1609.Google Scholar
Min Soon, C., Bottsford-Miller, J., Vasquez, H.G., Stone, R., Zand, B., Kroll, M.H., Sood, A.K. & Afshar-Kharghan, V. (2012). Platelets increase the proliferation of ovarian cancer cells. Blood 120(24), 4869–4872.Google Scholar
Nieswandt, B., Hafner, M., Echtenacher, B. & Mannel, D.N. (1999). Lysis of tumor cells by natural killer cells in mice is impeded by platelets. Cancer Res 59(6), 1295–1300.Google Scholar
Nkandue, D.S., Mqoco, T.V., Visagie, M.H., Stander, B.A., Wolmarans, E., Cronje, M.J. & Joubert, A.M. (2013). In vitro changes in mitochondrial potential, aggresome formation and caspase activity by a novel 17-beta-estradiol analogue in breast adenocarcinoma cells. Cell Biochem Funct 31(7), 566–574.Google Scholar
Oida, T. & Weiner, H.L. (2010). Depletion of TGF-β from fetal bovine serum. J Immunol Methods 362(1–2), 195–198.Google Scholar
Pandey, K.B. & Rizvi, S.I. (2011). Biomarkers of oxidative stress in red blood cells. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 155(2), 131–136.Google Scholar
Papetti, M. & Herman, I.M. (2002). Mechanisms of normal and tumor-derived angiogenesis. Am J Physiol Cell Physiol 282(5), C947–C970.Google Scholar
Peterson, J.E., Zurakowski, D., Italiano, J.E., Michel, L.V., Connors, S., Oenick, M., D’amato, R.J., Klement, G.L. & Folkman, J. (2012). VEGF, PF4 and PDGF are elevated in platelets of colorectal cancer patients. Angiogenesis 15(2), 265–273.Google Scholar
Plake, K.H. & Warnke, P.C. (1997). Vascular endothelial growth factor. J Neurooncol 35, 365–372.Google Scholar
Pratheeshkumar, P., Budhraja, A., Son, Y.-O., Wang, X., Zhang, Z., Ding, S., Wang, L., Hitron, A., Lee, J.C., Xu, M., Chen, G., Luo, J. & Shi, X. (2012). Quercetin inhibits angiogenesis mediated human prostate tumor growth by targeting VEGFR-2 regulated AKT/mTOR/P70S6K signaling pathways. PLoS One 7(10), e47516.CrossRefGoogle ScholarPubMed
Pretorius, E. (2011). Traditional coating techniques in scanning electron microscopy compared to uncoated charge compensator technology: Looking at human blood fibrin networks with the ZEISS ULTRA Plus FEG‐SEM. Microsc Res Tech 74(4), 343–346.Google Scholar
Pretorius, E. (2013). The adaptability of red blood cells. Cardiovasc Diabetol 12(1), 63.Google Scholar
Radziwon-Balicka, A., Medina, C., O’driscoll, L., Treumann, A., Bazou, D., Inkielewicz-Stepniak, I., Radomski, A., Jow, H. & Radomski, M.W. (2012). Platelets increase survival of adenocarcinoma cells challenged with anticancer drugs: Mechanisms and implications for chemoresistance. Br J Pharmacol 167(4), 787–804.CrossRefGoogle ScholarPubMed
Radziwon-Balicka, A., Moncada De La Rosa, C., Zielnik, B., Doroszko, A. & Jurasz, P. (2013). Temporal and pharmacological characterization of angiostatin release and generation by human platelets: Implications for endothelial cell migration. PLoS One 8(3), 1–11.Google Scholar
Reikvam, H., Hatfield, K.J., Oyan, A.M., Kalland, K.H., Kittang, A.O. & Bruserud, O. (2010). Primary human acute myelogenous leukemia cells release matrix metalloproteases and their inhibitors: Release profile and pharmacological modulation. Eur J Haematol 84(3), 239–251.Google Scholar
Repsold, L., Mqoco, T., Wolmarans, E., Nkandeu, S., Theron, J., Piorkowski, T., Du Toit, P., Van Papendorp, D. & Joubert, A.M. (2014 a). Ultrastructural changes of erythrocytes in whole blood after exposure to prospective in silico-designed anticancer agents: A qualitative case study. Biol Res 47(1), 39.Google Scholar
Repsold, L., Pretorius, E. & Joubert, A.M. (2014 b). An estrogen analogue and promising anticancer agent refrains from inducing morphological damage and reactive oxygen species generation in erythrocytes, fibrin and platelets: A pilot study. Cancer Cell Int 14(1), 48.Google Scholar
Sabrkhany, S., Griffioen, A.W. & Oude Egbrink, M.G. (2011). The role of blood platelets in tumor angiogenesis. Biochim Biophys Acta 1815(2), 189–196.Google Scholar
Seegers, J.C., De Kock, M., Lottering, M.L., Grobler, C.J., Van Papendorp, D.H., Shou, Y., Habbersett, R. & Lehnert, B.E. (1997). Effects of gamma-linolenic acid and arachidonic acid on cell cycle progression and apoptosis induction in normal and transformed cells. Prostaglandins Leukot Essent Fatty Acids 56(4), 271–280.Google Scholar
Sierko, E. & Wojtukiewicz, M.Z. (2004). Platelets and angiogenesis in malignancy. Semin Thromb Hemost 30(1), 95–108.Google Scholar
Stander, A., Joubert, F. & Joubert, A. (2011). Docking, synthesis, and in vitro evaluation of antimitotic estrone analogs. Chem Biol Drug Des 77(3), 173–181.Google Scholar
Stander, B.A., Joubert, F., Tu, C., Sippel, K.H., Mckenna, R. & Joubert, A.M. (2012). In vitro evaluation of ESE-15-ol, an estradiol analogue with nanomolar antimitotic and carbonic anhydrase inhibitory activity. PLoS One 7(12), e52205.Google Scholar
Stander, B.A., Joubert, F., Tu, C., Sippel, K.H., Mckenna, R. & Joubert, A.M. (2013). Signaling pathways of ESE-16, an antimitotic and anticarbonic anhydrase estradiol analog, in breast cancer cells. PLoS One 8(1), e53853.Google Scholar
Theron, A.E., Nolte, E.M., Lafanechere, L. & Joubert, A.M. (2013). Molecular crosstalk between apoptosis and autophagy induced by a novel 2-methoxyestradiol analogue in cervical adenocarcinoma cells. Cancer Cell Int 13, 87.Google Scholar
Trikha, M., Zhou, Z., Timar, J., Raso, E., Kennel, M., Emmell, E. & Nakada, M.T. (2002). Multiple roles for platelet GPIIb/IIIa and alphavbeta3 integrins in tumor growth, angiogenesis, and metastasis. Cancer Res 62(10), 2824–2833.Google Scholar
Van Der Valk, J., Brunner, D., De Smet, K., Fex Svenningsen, Å., Honegger, P., Knudsen, L.E., Lindl, T., Noraberg, J., Price, A., Scarino, M.L. & Gstraunthaler, G. (2010). Optimization of chemically defined cell culture media—Replacing fetal bovine serum in mammalian in vitro methods. Toxicol in Vitro 24(4), 1053–1063.Google Scholar
Wartiovaara, U., Salven, P., Mikkola, H., Lassila, R., Kaukonen, J., Joukov, V., Orpana, A., Ristimäki, A., Heikinheimo, M., Joensuu, H., Alitalo, K. & Palotie, A. (1998). Peripheral blood platelets express VEGF-C and VEGF which are released during platelet activation. Thromb Haemost 80(1), 171–175.Google Scholar
Yan, M., Lesyk, G., Radziwon-Balicka, A. & Jurasz, P. (2014). Pharmacological regulation of platelet factors that influence tumor angiogenesis. Semin Oncol 41(3), 370–377.Google Scholar
Yoon, S.O., Park, S.J., Yun, C.H. & Chung, A.S. (2003). Roles of matrix metalloproteinases in tumor metastasis and angiogenesis. J Biochem Mol Biol 36(1), 128–137.Google Scholar
Yue, T.L., Wang, X., Louden, C.S., Gupta, S., Pillarisetti, K., Gu, J.L., Hart, T.K., Lysko, P.G. & Feuerstein, G.Z. (1997). 2-Methoxyestradiol, an endogenous estrogen metabolite, induces apoptosis in endothelial cells and inhibits angiogenesis: Possible role for stress-activated protein kinase signaling pathway and Fas expression. Mol Pharmacol 51(6), 951–962.Google Scholar