Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Tumor Biology
Published in: Tumor Biology 5/2011

01-10-2011 | Research Article

BMP-4 expression has prognostic significance in advanced serous ovarian carcinoma and is affected by cisplatin in OVCAR-3 cells

Authors: Liisa Laatio, Päivi Myllynen, Raisa Serpi, Jaana Rysä, Mika Ilves, Elisa Lappi-Blanco, Heikki Ruskoaho, Kirsi Vähäkangas, Ulla Puistola

Published in: Tumor Biology | Issue 5/2011

Login to get access

Abstract

Several angiogenesis-promoting factors have prognostic significance in ovarian cancer. The objective of this study was to evaluate whether traditional chemotherapy affects angiogenesis-related factors in ovarian carcinoma and to assess the clinical significance of these effects. To screen for angiogenesis-related factors of possible relevance, OVCAR-3 and A2780 ovarian cancer cells were treated with IC50 doses of cisplatin (CDDP) or docetaxel, or with bevacizumab, and mRNA expression of several angiogenesis-related factors was analyzed. Thrombospondin-1 (TSP-1), bone morphogenetic protein-4 (BMP-4), endothelin-1, and placental growth factor-2 were statistically significantly induced by CDDP. At protein level, CDDP also induced hypoxia-inducible factor-1α but not vascular endothelial growth factor. In carcinoma samples taken before and after platinum-based neoadjuvant chemotherapy from 28 patients with advanced, high-grade serous ovarian carcinoma, CD105 and factors most induced by CDDP (TSP-1 and BMP-4) were analyzed by immunohistochemistry. Strong expression of BMP-4 before chemotherapy was an independent prognostic factor of longer progression-free time (p = 0.002) and overall survival (p = 0.02), but it was not associated with neovascularization (as evaluated by CD105). However, changes in BMP-4 expression in samples analyzed before and after chemotherapy (observed in 22/28 patients) were not associated with prognosis. TSP-1 expression was not associated with clinical parameters. Our results indicate that in serous ovarian carcinoma, BMP-4 has prognostic significance, which is not angiogenesis-related. We also show that CDDP induces several angiogenesis-related growth factors in vitro and future studies are warranted to clarify the clinical significance of this phenomenon.
Literature
1.
Ozols RF. Challenges for chemotherapy in ovarian cancer. Ann Oncol. 2006;17:181–7.CrossRef
2.
Ramakrishnan S, Subramanian IV, Yokoyama Y, Geller M. Angiogenesis in normal and neoplastic ovaries. Angiogenesis. 2005;8:169–82.PubMedCrossRef
3.
Tarallo V, Vesci L, Capasso O, Esposito MT, Riccioni T, Pastore L, et al. A placental growth factor variant unable to recognize vascular endothelial growth factor (VEGF) receptor-1 inhibits VEGF-dependent tumor angiogenesis via heterodimerization. Cancer Res. 2010;70:1804–13.PubMedCrossRef
4.
Rosanò L, Spinella F, Bagnato A. The importance of endothelin axis in initiation, progression, and therapy of ovarian cancer. Am J Physiol Regul Integr Comp Physiol. 2010;299:R395–404.PubMedCrossRef
5.
Taraboletti G, Morbidelli L, Donnini S, Parenti A, Granger HJ, Giavazzi R, et al. The heparin binding 25 kDa fragment of thrombospondin-1 promotes angiogenesis and modulates gelatinase and TIMP-2 production in endothelial cells. FASEB J. 2000;14:1674–6.PubMed
6.
Shepherd TG, Thériault BL, Nachtigal MW. Autocrine BMP4 signalling regulates ID3 proto-oncogene expression in human ovarian cancer cells. Gene. 2008;414:95–105.PubMedCrossRef
7.
Gialeli C, Theocharis AD, Karamanos NK. Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS J. 2011;278:16–27.PubMedCrossRef
8.
Wang Z, Ahmad A, Li Y, Kong D, Azmi AS, Banerjee S, et al. Emerging roles of PDGF-D signaling pathway in tumor development and progression. Biochim Biophys Acta. 2010;1806:122–30.PubMed
9.
Yamada Y, Arao T, Matsumoto K, et al. Plasma concentrations of VCAM-1 and PAI-1: a predictive biomarker for post-operative recurrence in colorectal cancer. Cancer Sci. 2010;101:1886–90.PubMedCrossRef
10.
Giaginis C, Tsantili-Kakoulidou A, Theocharis S. Peroxisome proliferator-activated receptor-gamma ligands: potential pharmacological agents for targeting the angiogenesis signaling cascade in cancer. PPAR Res. 2008;2008:431763.PubMedCrossRef
11.
Perez-Pinera P, Berenson JR, Deuel TF. Pleiotrophin, a multifunctional angiogenic factor: mechanisms and pathways in normal and pathological angiogenesis. Curr Opin Hematol. 2008;15:210–4.PubMedCrossRef
12.
Rubatt JM, Darcy KM, Hutson A, Bean S, Havrilesky LJ, Grace LA, et al. Independent prognostic significance of microvessel density in advanced epithelial ovarian cancer and associations between CD31, CD105, p53 status and angiogenic marker expression: a Gynecologic Oncology Group study. Gynecol Oncol. 2009;112:469–74.PubMedCrossRef
13.
Delli Carpini J, Karam AK, Montgomery L. Vascular endothelial growth factor and its relationship to the prognosis and treatment of breast, ovarian, and cervical cancer. Angiogenesis. 2010;13:43–58.PubMedCrossRef
14.
Burger RA. Overview of anti-angiogenic agents in development for ovarian cancer. Gynecol Oncol. 2011;121:230–8.PubMedCrossRef
15.
Bagnato A, Spinella F, Rosanò L. Emerging role of the endothelin axis in ovarian tumor progression. Endocr Relat Cancer. 2005;12:761–72.PubMedCrossRef
16.
Maeda K, Nishiguchi Y, Yashiro M, Yamada S, Onoda N, Sawada T, et al. Expression of vascular endothelial growth factor and thrombospondin-1 in colorectal carcinoma. Int J Mol Med. 2000;5:373–8.PubMed
17.
Yamaguchi M, Sugio K, Ondo K, Yano T, Sugimachi K. Reduced expression of thrombospondin-1 correlates with a poor prognosis in patients with non-small cell lung cancer. Lung Cancer. 2002;36:143–50.PubMedCrossRef
18.
Kodama J, Hashimoto I, Seki N, Hongo A, Yoshinouchi M, Okuda H, et al. Thrombospondin-1 and −2 messenger RNA expression in epithelial ovarian tumor. Anticancer Res. 2001;21:2983–7.PubMed
19.
Karavasilis V, Malamou-Mitsi V, Briasoulis E, Tsanou E, Kitsou E, Pavlidis N. Clinicopathologic study of vascular endothelial growth factor, thrombospondin-1, and microvessel density assessed by CD34 in patients with stage III ovarian carcinoma. Int J Gynecol Cancer. 2006;16:241–6.PubMedCrossRef
20.
Secord AA, Darcy KM, Hutson A, Lee PS, Havrilesky LJ, Grace LA, et al. Gynecologic Oncology Group study. Co-expression of angiogenic markers and associations with prognosis in advanced epithelial ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol. 2007;106:221–32.PubMedCrossRef
21.
Wild R, Dings RP, Subramanian I, Ramakrishnan S. Carboplatin selectively induces the VEGF stress response in endothelial cells: Potentiation of antitumor activity by combination treatment with antibody to VEGF. Int J Cancer. 2004;110:343–51.PubMedCrossRef
22.
Zhong XS, Liu LZ, Skinner HD, Cao Z, Ding M, Jiang BH. Mechanism of vascular endothelial growth factor expression mediated by cisplatin in human ovarian cancer cells. Biochem Biophys Res Commun. 2007;s358:92–8.CrossRef
23.
Duyndam MC, van Berkel MP, Dorsman JC, Rockx DA, Pinedo HM, Boven E. Cisplatin and doxorubicin repress vascular endothelial growth factor expression and differentially down-regulate hypoxia-inducible factor I activity in human ovarian cancer cells. Biochem Pharmacol. 2007;74:191–201.PubMedCrossRef
24.
Siddiqui GK, Maclean AB, Elmasry K. Wong Te Fong A, Morris RW, Rashid M, et al. Immunohistochemical expression of VEGF predicts response to platinum based chemotherapy in patients with epithelial ovarian cancer. Angiogenesis. 2011;14(2):155–61.PubMedCrossRef
25.
Kigawa J, Sato S, Shimada M, Takahashi M, Itamochi H, Kanamori Y, et al. p53 gene status and chemosensitivity in ovarian cancer. Hum Cell. 2001;14:165–71.PubMed
26.
Myllynen P, Kurttila T, Vaskivuo L, Vähäkangas K. DNA damage caused by benzo(a)pyrene in MCF-7 cells is increased by verapamil, probenecid and PSC833. Toxicol Lett. 2007;169:3–12.PubMedCrossRef
27.
Nagai N, Kinoshita M, Ogata H, et al. Relationship between pharmacokinetics of unchanged cisplatin and nephrotoxicity after intravenous infusions of cisplatin to cancer patients. Cancer Chemother Pharmacol. 1996;39:131–7.PubMedCrossRef
28.
Presta LG, Chen H, O’Connor SJ, Chisholm V, Meng YG, Krummen L, et al. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res. 1997;57:4593–9.PubMed
29.
Lu JF, Bruno R, Eppler S, Novotny W, Lum B, Gaudreault J. Clinical pharmacokinetics of bevacizumab in patients with solid tumors. Cancer Chemother Pharmacol. 2008;62:779–86.PubMedCrossRef
30.
Rysä J, Leskinen H, Ilves M, Ruskoaho H. Distinct upregulation of extracellular matrix genes in transition from hypertrophy to hypertensive heart failure. Hypertension. 2005;45:927–33.PubMedCrossRef
31.
Majalahti-Palviainen T, Hirvinen M, Tervonen V, Ilves M, Ruskoaho H, Vuolteenaho O. Gene structure of a new cardiac peptide hormone: a model for heart-specific gene expression. Endocrinology. 2000;141:731–40.PubMedCrossRef
32.
Rustin GJ, Vergote I, Eisenhauer E, et al. Definitions for response and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer Intergroup (GCIG). Int J Gynecol Cancer. 2011;21:419–23.PubMedCrossRef
33.
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47.PubMedCrossRef
34.
Vaskivuo L, Rysä J, Koivupera J, Myllynen P, Vaskivuo T, Chvalova K, et al. Azidothymidine and cisplatin increase p14ARF expression in OVCAR-3 ovarian cancer cell line. Toxicol Appl Pharmacol. 2006;216:89–97.PubMedCrossRef
35.
Thériault BL, Shepherd TG, Mujoomdar ML, Nachtigal MW. BMP4 induces EMT and Rho GTPase activation in human ovarian cancer cells. Carcinogenesis. 2007;28:1153–62.PubMedCrossRef
36.
Shepherd TG, Mujoomdar ML, Nachtigal MW. Constitutive activation of BMP signalling abrogates experimental metastasis of OVCA429 cells via reduced cell adhesion. J Ovarian Res. 2010;3:5.PubMedCrossRef
37.
Sorescu GP, Song H, Tressel SL, Hwang J, Dikalov S, Smith DA, et al. Bone morphogenic protein 4 produced in endothelial cells by oscillatory shear stress induces monocyte adhesion by stimulating reactive oxygen species production from a nox1-based NADPH oxidase. Circ Res. 2004;95:773–9.PubMedCrossRef
38.
Wong WT, Tian XY, Chen Y, Leung FP, Liu L, Lee HK, et al. Bone morphogenic protein-4 impairs endothelial function through oxidative stress-dependent cyclooxygenase-2 upregulation: implications on hypertension. Circ Res. 2010;107:984–91.PubMedCrossRef
39.
Fang J, Nakamura H, Iyer AK. Tumor-targeted induction of oxystress for cancer therapy. J Drug Target. 2007;15:475–86.PubMedCrossRef
40.
Wu YJ, Muldoon LL, Neuwelt EA. The chemoprotective agent N-acetylcysteine blocks cisplatin-induced apoptosis through caspase signaling pathway. J Pharmacol Exp Ther. 2005;312:424–31.PubMedCrossRef
41.
Galanis A, Pappa A, Giannakakis A, Lanitis E, Dangaj D, Sandaltzopoulos R. Reactive oxygen species and HIF-1 signalling in cancer. Cancer Lett. 2008;266:12–20.PubMedCrossRef
42.
Campbell NE, Greenaway J, Henkin J, Moorehead RA, Petrik J. The thrombospondin-1 mimetic ABT-510 increases the uptake and effectiveness of cisplatin and paclitaxel in a mouse model of epithelial ovarian cancer. Neoplasia. 2010;12:275–83.PubMed
43.
Manni A, Rager T, Kimball SR, Jefferson LS, Washington S, Hu X, et al. Effects of alpha-difluoromethylornithine on thrombospondin-1 production by human breast cancer cells. Int J Oncol. 2007;31:1187–91.PubMed
44.
Rhee WJ, Ni CW, Zheng Z, Chang K, Jo H, Bao G. HuR regulates the expression of stress-sensitive genes and mediates inflammatory response in human umbilical vein endothelial cells. Proc Natl Acad Sci USA. 2010;107:6858–63.PubMedCrossRef
45.
Heinke J, Wehofsits L, Zhou Q, Zoeller C, Baar KM, Helbing T, et al. BMPER is an endothelial cell regulator and controls bone morphogenetic protein-4-dependent angiogenesis. Circ Res. 2008;103:804–12.PubMedCrossRef
46.
Moll F, Millet C, Noël D, Orsetti B, Bardin A, Katsaros D, et al. Chordin is underexpressed in ovarian tumors and reduces tumor cell motility. FASEB J. 2006;20:240–50.PubMedCrossRef
47.
Del Bufalo D, Di Castro V, Biroccio A, Varmi M, Salani D, Rosanò L, et al. Endothelin-1 protects ovarian carcinoma cells against paclitaxel-induced apoptosis: requirement for Akt activation. Mol Pharmacol. 2002;61:524–32.PubMedCrossRef
Metadata
Title
BMP-4 expression has prognostic significance in advanced serous ovarian carcinoma and is affected by cisplatin in OVCAR-3 cells
Authors
Liisa Laatio
Päivi Myllynen
Raisa Serpi
Jaana Rysä
Mika Ilves
Elisa Lappi-Blanco
Heikki Ruskoaho
Kirsi Vähäkangas
Ulla Puistola
Publication date
01-10-2011
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 5/2011
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-011-0200-7

Other articles of this Issue 5/2011

Tumor Biology 5/2011 Go to the issue

Research Article

Plasma membrane proteomic analysis of human osteosarcoma and osteoblastic cells: revealing NDRG1 as a marker for osteosarcoma

Research Article

Expression of PIK3CA and FOXP1 in gastric and intestinal non-Hodgkin’s lymphoma of mucosa-associated lymphoid tissue type

Research Article

The nucleosome binding protein NSBP1 is highly expressed in human bladder cancer and promotes the proliferation and invasion of bladder cancer cells

Research Article

Detection of Brk expression in non-small cell lung cancer: clinicopathological relevance

Research Article

p53 regulates Ki-67 promoter activity through p53- and Sp1-dependent manner in HeLa cells

Research Article

Differential expression of TNF-α signaling molecules and ERK1 in distal and proximal colonic tumors associated with obesity
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
Image Credits