title: Gene expression profiling of advanced ovarian cancer: characterization of a molecular signature involving fibroblast growth factor 2.
abstract: Epithelial ovarian cancer (EOC) is the gynecological disease with the highest death rate. We applied an automatic class discovery procedure based on gene expression profiling to stages III-IV tumors to search for molecular signatures associated with the biological properties and progression of EOC. Using a complementary DNA microarray containing 4451 cancer-related, sequence-verified features, we identified a subset of EOC characterized by the expression of numerous genes related to the extracellular matrix (ECM) and its remodeling, along with elements of the fibroblast growth factor 2 (FGF2) signaling pathway. A total of 10 genes were validated by quantitative real-time polymerase chain reaction, and coexpression of FGF2 and fibroblast growth factor receptor 4 in tumor cells was revealed by immunohistochemistry, confirming the reliability of gene expression by cDNA microarray. Since the functional relationships among these genes clearly suggested involvement of the identified molecular signature in processes related to epithelial-stromal interactions and/or epithelial-mesenchymal cellular plasticity, we applied supervised learning analysis on ovarian-derived cell lines showing distinct cellular phenotypes in culture. This procedure enabled construction of a gene classifier able to discriminate mesenchymal-like from epithelial-like cells. Genes overexpressed in mesenchymal-like cells proved to match the FGF2 signaling and ECM molecular signature, as identified by unsupervised class discovery on advanced tumor samples. In vitro functional analysis of the cell plasticity classifier was carried out using two isogenic and immortalized cell lines derived from ovarian surface epithelium and displaying mesenchymal and epithelial morphology, respectively. The results indicated the autocrine, but not intracrine stimulation of mesenchymal conversion and cohort/scatter migration of cells by FGF2, suggesting a central role for FGF2 signaling in the maintenance of cellular plasticity of ovary-derived cells throughout the carcinogenesis process. These findings raise mechanistic hypotheses on EOC pathogenesis and progression that might provide a rational underpinning for new therapeutic modalities.
authors.affiliation: Laboratorio Nazionale CIB, Area Science Park, Padriciano 99, 34012 Trieste, Italy.
authors.forename: Loris
authors.initials: L
authors.lastname: De Cecco
authors.forename: Luigi
authors.initials: L
authors.lastname: Marchionni
authors.forename: Manuela
authors.initials: M
authors.lastname: Gariboldi
authors.forename: James F
authors.initials: JF
authors.lastname: Reid
authors.forename: M Stefania
authors.initials: MS
authors.lastname: Lagonigro
authors.forename: Stefano
authors.initials: S
authors.lastname: Caramuta
authors.forename: Cristina
authors.initials: C
authors.lastname: Ferrario
authors.forename: Erica
authors.initials: E
authors.lastname: Bussani
authors.forename: Delia
authors.initials: D
authors.lastname: Mezzanzanica
authors.forename: Fabio
authors.initials: F
authors.lastname: Turatti
authors.forename: Domenico
authors.initials: D
authors.lastname: Delia
authors.forename: Maria G
authors.initials: MG
authors.lastname: Daidone
authors.forename: Maria
authors.initials: M
authors.lastname: Oggionni
authors.forename: Norma
authors.initials: N
authors.lastname: Bertuletti
authors.forename: Antonino
authors.initials: A
authors.lastname: Ditto
authors.forename: Francesco
authors.initials: F
authors.lastname: Raspagliesi
authors.forename: Silvana
authors.initials: S
authors.lastname: Pilotti
authors.forename: Marco A
authors.initials: MA
authors.lastname: Pierotti
authors.forename: Silvana
authors.initials: S
authors.lastname: Canevari
authors.forename: Claudio
authors.initials: C
authors.lastname: Schneider
mesh_terms: D045744:Cell Line, Tumor; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000502:physiology*; D020869:Gene Expression Profiling; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000235:genetics*; D016133:Polymerase Chain Reaction; D017468:Receptors, Fibroblast Growth Factor / Q000502:physiology
chemical_list: D016326:Extracellular Matrix Proteins; D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2