Platelets are associated with xenograft tumor growth and the clinical malignancy of ovarian cancer through an angiogenesis-dependent mechanism

Yuan,Lei; Liu,Xishi

doi:10.3892/mmr.2014.3082

Platelets are associated with xenograft tumor growth and the clinical malignancy of ovarian cancer through an angiogenesis-dependent mechanism

Authors:
- Lei Yuan
- Xishi Liu
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Affiliations: Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, P.R. China
Published online on: December 11, 2014 https://doi.org/10.3892/mmr.2014.3082
Pages: 2449-2458
Copyright: © Yuan et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Platelets are known to facilitate tumor metastasis and thrombocytosis has been associated with an adverse prognosis in ovarian cancer. However, the role of platelets in primary tumour growth remains to be elucidated. The present study demonstrated that the expression levels of various markers in platelets, endothelial adherence and angiogenesis, including, platelet glycoprotein IIb (CD41), platelet endothelial cell adhesion molecule 1 (CD31), vascular endothelial growth factor (VEGF), lysyl oxidase, focal adhesion kinase and breast cancer anti‑estrogen resistance 1, were expressed at higher levels in patients with malignant carcinoma, compared with those with borderline cystadenoma and cystadenoma. In addition, the endothelial markers CD31 and VEGF were found to colocalize with the platelet marker CD41 in the malignant samples. Since mice transplanted with human ovarian cancer cells (SKOV3) demonstrated elevated tumor size and decreased survival rate when treated with thrombin or thrombopoietin (TPO), the platelets appeared to promote primary tumor growth. Depleting platelets using antibodies or by pretreating the cancer cells with hirudin significantly attenuated the transplanted tumor growth. The platelets contributed to late, but not early stages of tumor proliferation, as mice treated with platelet‑depleting antibody 1 day prior to and 11 days after tumor transplantation had the same tumor volumes. By contrast, tumor size in the early TPO‑injected group was increased significantly compared with the late TPO‑injected group. These findings suggested that the interplay between platelets and angiogenesis may contribute to ovarian cancer growth. Therefore, platelets and their associated signaling and adhesive molecules may represent potential therapeutic targets for ovarian cancer.

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1	Felding-Habermann B, Habermann R, Saldivar E and Ruggeri ZM: Role of beta3 integrins in melanoma cell adhesion to activated platelets under flow. J Biol Chem. 271:5892–5900. 1996. View Article : Google Scholar : PubMed/NCBI
2	Borsig L, Wong R, Feramisco J, et al: Heparin and cancer revisited: mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis. Proc Natl Acad Sci USA. 98:3352–3357. 2001. View Article : Google Scholar : PubMed/NCBI
3	Labelle M, Begum S and Hynes RO: Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell. 20:576–590. 2011. View Article : Google Scholar : PubMed/NCBI
4	Buergy D, Wenz F, Groden C and Brockmann MA: Tumor-platelet interaction in solid tumors. Int J Cancer. 130:2747–2760. 2012. View Article : Google Scholar : PubMed/NCBI
5	Rao AK and Rao DA: Platelets signal and tumors take off. Blood. 120:4667–4668. 2012. View Article : Google Scholar : PubMed/NCBI
6	Douglas VK, Tallman MS, Cripe LD and Peterson LC: Thrombopoietin administered during induction chemotherapy to patients with acute myeloid leukemia induces transient morphologic changes that may resemble chronic myeloproliferative disorders. Am J Clin Path. 117:844–850. 2002. View Article : Google Scholar : PubMed/NCBI
7	Stone RL, Nick AM, McNeish IA, et al: Paraneoplastic thrombocytosis in ovarian cancer. N Engl J Med. 366:610–618. 2012. View Article : Google Scholar : PubMed/NCBI
8	Wang-Tilz Y, Tilz C, Wang B, Tilz GP and Stefan H: Influence of lamotrigine and topiramate on MDR1 expression in difficult-to-treat temporal lobe epilepsy. Epilepsia. 47:233–239. 2006. View Article : Google Scholar : PubMed/NCBI
9	Ma S, Liu X, Geng JG and Guo SW: Increased SLIT immunoreactivity as a biomarker for recurrence in endometrial carcinoma. Am J Obstet Gynecol. 202:68e61–e68. e112010. View Article : Google Scholar
10	Feng W, Madajka M, Kerr BA, et al: A novel role for platelet secretion in angiogenesis: mediating bone marrow-derived cell mobilization and homing. Blood. 117:3893–3902. 2011. View Article : Google Scholar : PubMed/NCBI
11	Manetta A, Satyaswaroop PG, Hamilton T, et al: Radio imaging of human ovarian carcinoma xenograft in nude mice. Gynecol Oncol. 28:292–299. 1987. View Article : Google Scholar : PubMed/NCBI
12	Holmes CE, Levis JE and Ornstein DL: Activated platelets enhance ovarian cancer cell invasion in a cellular model of metastasis. Clin Exp Metastasis. 26:653–661. 2009. View Article : Google Scholar : PubMed/NCBI
13	Trikha M, Zhou Z, Timar J, et al: Multiple roles for platelet GPIIb/IIIa and alphavbeta3 integrins in tumor growth, angiogenesis, and metastasis. Cancer Res. 62:2824–2833. 2002.PubMed/NCBI
14	Dardik R, Savion N, Kaufmann Y and Varon D: 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. 77:2069–2075. 1998. View Article : Google Scholar : PubMed/NCBI
15	Matsui H, Harada I and Sawada Y: Src, p130Cas, and Mechanotransduction in Cancer Cells. Genes Cancer. 3:394–401. 2012. View Article : Google Scholar : PubMed/NCBI
16	Nick AM, Stone RL, Armaiz-Pena G, et al: Silencing of p130cas in ovarian carcinoma: a novel mechanism for tumor cell death. J Natl Cancer Inst. 103:1596–1612. 2011. View Article : Google Scholar : PubMed/NCBI
17	Sawada Y, Tamada M, Dubin-Thaler BJ, et al: Force sensing by mechanical extension of the Src family kinase substrate p130Cas. Cell. 127:1015–1026. 2006. View Article : Google Scholar : PubMed/NCBI
18	Zhang P, Guo A, Possemato A, et al: Identification and functional characterization of p130Cas as a substrate of protein tyrosine phosphatase nonreceptor 14. Oncogene. 32:2087–2095. 2013. View Article : Google Scholar :
19	Chatzizacharias NA, Kouraklis GP and Theocharis SE: Clinical significance of FAK expression in human neoplasia. Histol Histopathol. 23:629–650. 2008.PubMed/NCBI
20	Goel HL and Mercurio AM: VEGF targets the tumour cell. Nat Rev Cancer. 13:871–882. 2013. View Article : Google Scholar : PubMed/NCBI
21	Hanahan D and Weinberg RA: Hallmarks of cancer: the next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
22	Prow D and Vadhan-Raj S: Thrombopoietin: biology and potential clinical applications. Oncology (Williston Park). 12:1597–1604. 1607–1598; discussion 1611–1594. 1998.
23	Dardik R, Kaufmann Y, Savion N, et al: Platelets mediate tumor cell adhesion to the subendothelium under flow conditions: involvement of platelet GPIIb-IIIa and tumor cell alpha(v) integrins. Int J Cancer. 70:201–207. 1997. View Article : Google Scholar : PubMed/NCBI
24	Konstantopoulos K and Thomas SN: Cancer cells in transit: the vascular interactions of tumor cells. Annu Rev Biomed Eng. 11:177–202. 2009. View Article : Google Scholar : PubMed/NCBI
25	McCarty OJ, Mousa SA, Bray PF and Konstantopoulos K: Immobilized platelets support human colon carcinoma cell tethering, rolling, and firm adhesion under dynamic flow conditions. Blood. 96:1789–1797. 2000.PubMed/NCBI
26	Ay C, Dunkler D, Pirker R, et al: High D-dimer levels are associated with poor prognosis in cancer patients. Haematologica. 97:1158–1164. 2012. View Article : Google Scholar : PubMed/NCBI
27	Dirix LY, Salgado R, Weytjens R, et al: Plasma fibrin D-dimer levels correlate with tumour volume, progression rate and survival in patients with metastatic breast cancer. Br J Cancer. 86:389–395. 2002. View Article : Google Scholar : PubMed/NCBI
28	Zigler M, Kamiya T, Brantley EC, Villares GJ and Bar-Eli M: PAR-1 and thrombin: the ties that bind the microenvironment to melanoma metastasis. Cancer Res. 71:6561–6566. 2011. View Article : Google Scholar : PubMed/NCBI
29	Cowell LN, Graham JD, Bouton AH, Clarke CL and O’Neill GM: Tamoxifen treatment promotes phosphorylation of the adhesion molecules, p130Cas/BCAR1, FAK and Src, via an adhesion-dependent pathway. Oncogene. 25:7597–7607. 2006. View Article : Google Scholar : PubMed/NCBI
30	McLean GW, Carragher NO, Avizienyte E, et al: The role of focal-adhesion kinase in cancer - a new therapeutic opportunity. Nat Rev Cancer. 5:505–515. 2005. View Article : Google Scholar : PubMed/NCBI
31	Ward KK, Tancioni I, Lawson C, et al: Inhibition of focal adhesion kinase (FAK) activity prevents anchorage-independent ovarian carcinoma cell growth and tumor progression. Clin Exp Metastasis. 30:579–594. 2013. View Article : Google Scholar : PubMed/NCBI
32	Chen XL, Nam JO, Jean C, et al: VEGF-induced vascular permeability is mediated by FAK. Dev Cell. 22:146–157. 2012. View Article : Google Scholar : PubMed/NCBI
33	Erler JT, Bennewith KL, Nicolau M, et al: Lysyl oxidase is essential for hypoxia-induced metastasis. Nature. 440:1222–1226. 2006. View Article : Google Scholar : PubMed/NCBI
34	Kirschmann DA, Seftor EA, Fong SF, et al: A molecular role for lysyl oxidase in breast cancer invasion. Cancer Res. 62:4478–4483. 2002.PubMed/NCBI
35	Baker AM, Bird D, Lang G, Cox TR and Erler JT: Lysyl oxidase enzymatic function increases stiffness to drive colorectal cancer progression through FAK. Oncogene. 32:1863–1868. 2013. View Article : Google Scholar
36	Baker AM, Cox TR, Bird D, et al: The role of lysyl oxidase in SRC-dependent proliferation and metastasis of colorectal cancer. J Natl Cancer Inst. 103:407–424. 2011. View Article : Google Scholar : PubMed/NCBI
37	Lapointe J, Li C, Higgins JP, et al: Gene expression profiling identifies clinically relevant subtypes of prostate cancer. Proc Natl Acad Sci USA. 101:811–816. 2004. View Article : Google Scholar : PubMed/NCBI
38	Battegay EJ, Rupp J, Iruela-Arispe L, Sage EH and Pech M: PDGF-BB modulates endothelial proliferation and angiogenesis in vitro via PDGF beta-receptors. J Cell Biol. 125:917–928. 1994. View Article : Google Scholar : PubMed/NCBI
39	Anglesio MS, George J, Kulbe H, et al: IL6-STAT3-HIF signaling and therapeutic response to the angiogenesis inhibitor sunitinib in ovarian clear cell cancer. Clin Cancer Res. 17:2538–2548. 2011. View Article : Google Scholar : PubMed/NCBI
40	Harker LA, Marzec UM, Kelly AB, et al: Prevention of thrombocytopenia and neutropenia in a nonhuman primate model of marrow suppressive chemotherapy by combining pegylated recombinant human megakaryocyte growth and development factor and recombinant human granulocyte colony-stimulating factor. Blood. 89:155–165. 1997.PubMed/NCBI
41	Grossmann A, Lenox J, Ren HP, et al: Thrombopoietin accelerates platelet, red blood cell, and neutrophil recovery in myelosuppressed mice. Exp Hematol. 24:1238–1246. 1996.PubMed/NCBI
42	Bergmeier W, Piffath CL, Goerge T, et al: The role of platelet adhesion receptor GPIbalpha far exceeds that of its main ligand, von Willebrand factor, in arterial thrombosis. Proc Natl Acad Sci USA. 103:16900–16905. 2006. View Article : Google Scholar : PubMed/NCBI
43	Cho MS, Bottsford-Miller J, Vasquez HG, et al: Platelets increase the proliferation of ovarian cancer cells. Blood. 120:4869–4872. 2012. View Article : Google Scholar : PubMed/NCBI