title: BMP-4 expression has prognostic significance in advanced serous ovarian carcinoma and is affected by cisplatin in OVCAR-3 cells.
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 IC(50) 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.
authors.affiliation: Department of Obstetrics and Gynecology, University of Oulu, 90014, Oulu, Finland. liisa.laatio@oulu.fi
authors.forename: Liisa
authors.initials: L
authors.lastname: Laatio
authors.forename: Päivi
authors.initials: P
authors.lastname: Myllynen
authors.forename: Raisa
authors.initials: R
authors.lastname: Serpi
authors.forename: Jaana
authors.initials: J
authors.lastname: Rysä
authors.forename: Mika
authors.initials: M
authors.lastname: Ilves
authors.forename: Elisa
authors.initials: E
authors.lastname: Lappi-Blanco
authors.forename: Heikki
authors.initials: H
authors.lastname: Ruskoaho
authors.forename: Kirsi
authors.initials: K
authors.lastname: Vähäkangas
authors.forename: Ulla
authors.initials: U
authors.lastname: Puistola
mesh_terms: D000368:Aged; D015703:Antigens, CD / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D055415:Bone Morphogenetic Protein 4 / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000071063:Endoglin; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008875:Middle Aged; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019700:Thrombospondin 1 / Q000096:biosynthesis
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; D019700:Thrombospondin 1; D002945:Cisplatin