Top

Published in:

01-10-2009 | Research Paper

Activated platelets enhance ovarian cancer cell invasion in a cellular model of metastasis

Authors: C. E. Holmes, J. E. Levis, D. L. Ornstein

Published in: Clinical & Experimental Metastasis | Issue 7/2009

Abstract

Increased platelet counts and systemic coagulation activation are associated with ovarian cancer progression. Platelet activation occurs in the tumor microenvironment and may influence local invasion and metastasis. We used a cellular model of tumor invasion to investigate the effect of activated platelets on the human ovarian cancer cell line, SKOV3. SKOV3 cells were exposed to washed, thrombin receptor activating peptide (TRAP)-activated or TRAP-naïve platelets under various experimental conditions, and tumor cell invasion was assayed in Matrigel^® chambers. The effect of platelets on the content of urokinase plasminogen activator (uPA) and VEGF in SKOV3 cell conditioned medium was measured using an ELISA assay. TRAP-activated platelets stimulated a dose-dependent increase in SKOV3 cell invasion. Exposure to activated platelet membranes and to soluble proteins contained in activated platelet releasate both contributed to the observed increase in invasion. The inhibition of platelet activation with prostaglandin E1 (PGE₁) attenuated the invasive capacity of SKOV3 cells. Exposure to platelets resulted in significantly increased uPA and VEGF content of SKOV3 cell conditioned medium. Activated platelets enhance SKOV3 human ovarian cancer cell invasion through Matrigel^® and increase the amount of uPA and VEGF secreted into SKOV3 cell conditioned medium. If generalizable to additional cell lines and human disease, this observation may partially explain the adverse prognosis associated with thrombocytosis in ovarian cancer. Platelets, therefore, may represent a potential target for therapeutic intervention in human ovarian cancer.

Sarach MA, Rovasio RA, Eynard AR (1993) Platelet factors induce chemotactic migration of murine mammary adenocarcinoma cells with different metastatic capabilities. Int J Exp Pathol 74(5):511–517PubMed

Poggi A, Vicenzi E, Cioce V et al (1988) Platelet contribution to cancer cell growth and migration: the role of platelet growth factors. Haemostasis 18(1):18–28PubMed

Belloc C, Lu H, Soria C et al (1995) The effect of platelets on invasiveness and protease production of human mammary tumor cells. Int J Cancer 60(3):413–417. doi:10.1002/ijc.2910600324 CrossRefPubMed

Lewalle JM, Castronovo V, Goffinet G et al (1991) Malignant cell attachment to endothelium of ex vivo perfused human umbilical vein. Modulation by platelets, plasma and fibronectin. Thromb Res 62(4):287–298. doi:10.1016/0049-3848(91)90149-Q CrossRefPubMed

Felding-Habermann B, O’Toole TE, Smith JW et al (2001) Integrin activation controls metastasis in human breast cancer. Proc Natl Acad Sci USA 98(4):1853–1858. doi:10.1073/pnas.98.4.1853 CrossRefPubMed

Jones DS, Wallace AC, Fraser EE (1971) Sequence of events in experimental metastases of Walker 256 tumor: light, immunofluorescent, and electron microscopic observations. J Natl Cancer Inst 46(3):493–504PubMed

Nash GF, Turner LF, Scully MF et al (2002) Platelets and cancer. Lancet Oncol 3(7):425–430. doi:10.1016/S1470-2045(02)00789-1 CrossRefPubMed

Alonso-Escolano D, Medina C, Cieslik K et al (2006) Protein kinase C{delta} mediates platelet-induced breast cancer cell invasion. J Pharmacol Exp Ther 318(1):373–380. doi:10.1124/jpet.106.103358 CrossRefPubMed

Boucharaba A, Serre CM, Gres S et al (2004) Platelet-derived lysophosphatidic acid supports the progression of osteolytic bone metastases in breast cancer. J Clin Invest 114(12):1714–1725PubMed

10.

Assoian RK, Sporn MB (1986) Type beta transforming growth factor in human platelets: release during platelet degranulation and action on vascular smooth muscle cells. J Cell Biol 102(4):1217–1223. doi:10.1083/jcb.102.4.1217 CrossRefPubMed

11.

Verheul HM, Hoekman K, Luykx-de Bakker S et al (1997) Platelet: transporter of vascular endothelial growth factor. Clin Cancer Res 3(12 Pt 1):2187–2190PubMed

12.

Dubernard V, Arbeille BB, Lemesle MB et al (1997) Evidence for an alpha-granular pool of the cytoskeletal protein alpha-actinin in human platelets that redistributes with the adhesive glycoprotein thrombospondin-1 during the exocytotic process. Arterioscler Thromb Vasc Biol 17(10):2293–2305PubMed

13.

Kaplan KL, Broekman MJ, Chernoff A et al (1979) Platelet alpha-granule proteins: studies on release and subcellular localization. Blood 53(4):604–618PubMed

14.

Coppinger JA, O’Connor R, Wynne K et al (2007) Moderation of the platelet releasate response by aspirin. Blood 109(11):4786–4792. doi:10.1182/blood-2006-07-038539 CrossRefPubMed

15.

Ma L, Perini R, McKnight W et al (2005) Proteinase-activated receptors 1 and 4 counter-regulate endostatin and VEGF release from human platelets. Proc Natl Acad Sci USA 102(1):216–220. doi:10.1073/pnas.0406682102 CrossRefPubMed

16.

Zacharski LR, Memoli VA, Costantini V et al (1990) Clotting factors in tumour tissue: implications for cancer therapy. Blood Coagul Fibrinolysis 1(1):71–78. doi:10.1097/00001721-199003000-00010 CrossRefPubMed

17.

Zacharski LR, Memoli VA, Ornstein DL et al (1993) Tumor cell procoagulant and urokinase expression in carcinoma of the ovary. J Natl Cancer Inst 85(15):1225–1230. doi:10.1093/jnci/85.15.1225 CrossRefPubMed

18.

Bastida E, Ordinas A, Giardina SL et al (1982) Differentiation of platelet-aggregating effects of human tumor cell lines based on inhibition studies with apyrase, hirudin, and phospholipase. Cancer Res 42(11):4348–4352PubMed

19.

Konecny G, Untch M, Pihan A et al (2001) Association of urokinase-type plasminogen activator and its inhibitor with disease progression and prognosis in ovarian cancer. Clin Cancer Res 7(6):1743–1749PubMed

20.

Kuhn W, Schmalfeldt B, Reuning U et al (1999) Prognostic significance of urokinase (uPA) and its inhibitor PAI-1 for survival in advanced ovarian carcinoma stage FIGO IIIc. Br J Cancer 79(11–12):1746–1751. doi:10.1038/sj.bjc.6690278 CrossRefPubMed

21.

Schmalfeldt B, Kuhn W, Reuning U et al (1995) Primary tumor and metastasis in ovarian cancer differ in their content of urokinase-type plasminogen activator, its receptor, and inhibitors types 1 and 2. Cancer Res 55(18):3958–3963PubMed

22.

Agis H, Kandler B, Fischer MB et al. (2008) Activated platelets increase fibrinolysis of mesenchymal progenitor cells. J Orthop Res. doi: 10.1002/jor.20819

23.

Hsu-Lin S, Berman CL, Furie BC et al (1984) A platelet membrane protein expressed during platelet activation and secretion. Studies using a monoclonal antibody specific for thrombin-activated platelets. J Biol Chem 259(14):9121–9126PubMed

24.

Gurney D, Lip GY, Blann AD (2002) A reliable plasma marker of platelet activation: does it exist? Am J Hematol 70(2):139–144. doi:10.1002/ajh.10097 CrossRefPubMed

25.

Rao GH, Rao AT (1994) Pharmacology of platelet activation-inhibitory drugs. Indian J Physiol Pharmacol 38(2):69–84PubMed

26.

Kobayashi H, Ohi H, Sugimura M et al (1992) Inhibition of in vitro ovarian cancer cell invasion by modulation of urokinase-type plasminogen activator and cathepsin B. Cancer Res 52(13):3610–3614PubMed

27.

Wilhelm O, Weidle U, Hohl S et al (1994) Recombinant soluble urokinase receptor as a scavenger for urokinase-type plasminogen activator (uPA). Inhibition of proliferation and invasion of human ovarian cancer cells. FEBS Lett 337(2):131–134. doi:10.1016/0014-5793(94)80259-9 CrossRefPubMed

28.

Mandriota SJ, Seghezzi G, Vassalli JD et al (1995) Vascular endothelial growth factor increases urokinase receptor expression in vascular endothelial cells. J Biol Chem 270(17):9709–9716. doi:10.1074/jbc.270.17.9709 CrossRefPubMed

29.

Pepper MS, Ferrara N, Orci L et al (1991) Vascular endothelial growth factor (VEGF) induces plasminogen activators and plasminogen activator inhibitor-1 in microvascular endothelial cells. Biochem Biophys Res Commun 181(2):902–906. doi:10.1016/0006-291X(91)91276-I CrossRefPubMed

30.

Holmes CE, Huang JC, Pace TR et al (2008) Tamoxifen and aromatase inhibitors differentially affect vascular endothelial growth factor and endostatin levels in women with breast cancer. Clin Cancer Res 14(10):3070–3076. doi:10.1158/1078-0432.CCR-07-4640 CrossRefPubMed

31.

Bozkurt N, Yuce K, Basaran M et al (2004) Correlation of platelet count with second-look laparotomy results and disease progression in patients with advanced epithelial ovarian cancer. Obstet Gynecol 103(1):82–85PubMed

32.

Jain S, Zuka M, Liu J et al (2007) Platelet glycoprotein Ib alpha supports experimental lung metastasis. Proc Natl Acad Sci USA 104(21):9024–9028. doi:10.1073/pnas.0700625104 CrossRefPubMed

33.

Alves CS, Burdick MM, Thomas SN et al (2008) The dual role of CD44 as a functional P-selectin ligand and fibrin receptor in colon carcinoma cell adhesion. Am J Physiol Cell Physiol 294(4):C907–C916. doi:10.1152/ajpcell.00463.2007 CrossRefPubMed

34.

Trikha M, Zhou Z, Timar J et al (2002) Multiple roles for platelet GPIIb/IIIa and alphavbeta3 integrins in tumor growth, angiogenesis, and metastasis. Cancer Res 62(10):2824–2833PubMed

35.

Palumbo JS, Talmage KE, Massari JV et al (2005) Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells. Blood 105(1):178–185. doi:10.1182/blood-2004-06-2272 CrossRefPubMed

36.

Nieswandt B, Hafner M, Echtenacher B et al (1999) Lysis of tumor cells by natural killer cells in mice is impeded by platelets. Cancer Res 59(6):1295–1300PubMed

37.

Kristiansen G, Denkert C, Schluns K et al (2002) CD24 is expressed in ovarian cancer and is a new independent prognostic marker of patient survival. Am J Pathol 161(4):1215–1221PubMed

38.

Suzuki K, Aiura K, Ueda M et al (2004) The influence of platelets on the promotion of invasion by tumor cells and inhibition by antiplatelet agents. Pancreas 29(2):132–140. doi:10.1097/00006676-200408000-00008 CrossRefPubMed

39.

Siess W, Lapetina EG (1990) Functional relationship between cyclic AMP-dependent protein phosphorylation and platelet inhibition. Biochem J 271(3):815–819PubMed

40.

Chung AW, Jurasz P, Hollenberg MD et al (2002) Mechanisms of action of proteinase-activated receptor agonists on human platelets. Br J Pharmacol 135(5):1123–1132. doi:10.1038/sj.bjp.0704559 CrossRefPubMed

41.

Kahn ML, Nakanishi-Matsui M, Shapiro MJ et al (1999) Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin. J Clin Invest 103(6):879–887. doi:10.1172/JCI6042 CrossRefPubMed

42.

Vu TK, Hung DT, Wheaton VI et al (1991) Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 64(6):1057–1068. doi:10.1016/0092-8674(91)90261-V CrossRefPubMed

43.

Nierodzik ML, Karpatkin S (2006) Thrombin induces tumor growth, metastasis, and angiogenesis: evidence for a thrombin-regulated dormant tumor phenotype. Cancer Cell 10(5):355–362. doi:10.1016/j.ccr.2006.10.002 CrossRefPubMed

44.

Dardik R, Savion N, Kaufmann Y et al (1998) Thrombin promotes platelet-mediated melanoma cell adhesion to endothelial cells under flow conditions: role of platelet glycoproteins P-selectin and GPIIb-IIIA. Br J Cancer 77(12):2069–2075PubMed

45.

Janowska-Wieczorek A, Wysoczynski M, Kijowski J et al (2005) Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer. Int J Cancer 113(5):752–760. doi:10.1002/ijc.20657 CrossRefPubMed

46.

Janowska-Wieczorek A, Marquez-Curtis LA, Wysoczynski M et al (2006) Enhancing effect of platelet-derived microvesicles on the invasive potential of breast cancer cells. Transfusion 46(7):1199–1209. doi:10.1111/j.1537-2995.2006.00871.x CrossRefPubMed

47.

Sieuwerts AM, Klijn JG, Henzen-Logmans SC et al (1999) Cytokine-regulated urokinase-type-plasminogen-activator (uPA) production by human breast fibroblasts in vitro. Breast Cancer Res Treat 55(1):9–20. doi:10.1023/A:1006190729866 CrossRefPubMed

48.

Rodriguez GC, Haisley C, Hurteau J et al (2001) Regulation of invasion of epithelial ovarian cancer by transforming growth factor-beta. Gynecol Oncol 80(2):245–253. doi:10.1006/gyno.2000.6042 CrossRefPubMed

49.

Shiou SR, Datta PK, Dhawan P et al (2006) Smad4-dependent regulation of urokinase plasminogen activator secretion and RNA stability associated with invasiveness by autocrine and paracrine transforming growth factor-beta. J Biol Chem 281(45):33971–33981. doi:10.1074/jbc.M607010200 CrossRefPubMed

50.

Mehta P (1984) Potential role of platelets in the pathogenesis of tumor metastasis. Blood 63(1):55–63PubMed

51.

Pustilnik TB, Estrella V, Wiener JR et al (1999) Lysophosphatidic acid induces urokinase secretion by ovarian cancer cells. Clin Cancer Res 5(11):3704–3710PubMed

52.

Gil OD, Lee C, Ariztia EV et al (2008) Lysophosphatidic acid (LPA) promotes E-cadherin ectodomain shedding and OVCA429 cell invasion in an uPA-dependent manner. Gynecol Oncol 108(2):361–369. doi:10.1016/j.ygyno.2007.10.027 CrossRefPubMed

53.

Amirkhosravi A, Mousa SA, Amaya M et al (2003) Inhibition of tumor cell-induced platelet aggregation and lung metastasis by the oral GpIIb/IIIa antagonist XV454. Thromb Haemost 90(3):549–554PubMed

54.

Nierodzik ML, Klepfish A, Karpatkin S (1995) Role of platelets, thrombin, integrin IIb-IIIa, fibronectin and von Willebrand factor on tumor adhesion in vitro and metastasis in vivo. Thromb Haemost 74(1):282–290PubMed

55.

Stone JP, Wagner DD (1993) P-selectin mediates adhesion of platelets to neuroblastoma and small cell lung cancer. J Clin Invest 92(2):804–813. doi:10.1172/JCI116654 CrossRefPubMed

56.

Italiano JE Jr, Richardson JL, Patel-Hett S et al (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. doi:10.1182/blood-2007-09-113837 CrossRefPubMed

57.

Alonso-Escolano D, Strongin AY, Chung AW et al (2004) Membrane type-1 matrix metalloproteinase stimulates tumour cell-induced platelet aggregation: role of receptor glycoproteins. Br J Pharmacol 141(2):241–252. doi:10.1038/sj.bjp.0705606 CrossRefPubMed

Title: Activated platelets enhance ovarian cancer cell invasion in a cellular model of metastasis
Authors: C. E. Holmes
J. E. Levis
D. L. Ornstein
Publication date: 01-10-2009
Publisher: Springer Netherlands
Published in: Clinical & Experimental Metastasis / Issue 7/2009
Print ISSN: 0262-0898
Electronic ISSN: 1573-7276
DOI: https://doi.org/10.1007/s10585-009-9264-9

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 7/2009

MET Y1253D-activating point mutation and development of distant metastasis in advanced head and neck cancers

Significance of manipulating intratumor hypoxia in the effect on lung metastases in radiotherapy, with reference to its effect on the sensitivity of intratumor quiescent cells

Enhanced expression and shedding of receptor activator of NF-κB ligand during tumor–bone interaction potentiates mammary tumor-induced osteolysis

Hepatocyte growth factor induced up-regulations of VEGF through Egr-1 in hepatocellular carcinoma cells

Establishment and characterization of a new highly metastatic human osteosarcoma cell line

Deficiencies in the CD40 and CD154 receptor-ligand system reduce experimental lung metastasis

Keynote webinar | Spotlight on antibody–drug conjugates in cancer