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  • Oncogenomics
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Gene expression profiling of advanced ovarian cancer: characterization of a molecular signature involving fibroblast growth factor 2

Oncogene volume 23, pages 8171–8183 (2004)Cite this article

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.

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Acknowledgements

Support for this project was provided to INT (Istituto Nazionale Tumori) – LNCIB (Laboratorio Nazionale CIB) by AIRC (Associazione Italiana Ricerca sul Cancro) Coordinated Project at IFOM (FIRC Institute for Molecular oncology) ‘Detection of cancer gene mutation and expression profiling by nanotechnology’ and by CNR/MIUR ‘Progetto strategico Oncologia’ (contract no. 02.00385.ST97 to MA Pierotti and no. 02.00386.ST97 to C Schneider) and grants to S Canevari from AIRC-FIRC and Special Project of Health Ministry.

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Author notes

  1. James F Reid

    Present address: IFOM FIRC Institute for Molecular Oncology, 20139, Milan, Italy

  2. Loris De Cecco and Luigi Marchionni: These junior authors contributed equally to this work.

  3. Silvana Canevari and Claudio Schneider: These senior authors contributed equally to this work.

Authors and Affiliations

  1. Laboratorio Nazionale CIB, Area Science Park, Padriciano 99, Trieste, 34012, Italy

    Loris De Cecco, Luigi Marchionni, James F Reid & Claudio Schneider

  2. Department of Experimental Oncology, Istituto Nazionale Tumori, via G Venezian 1, Milan, 20133, Italy

    Loris De Cecco, Manuela Gariboldi, M Stefania Lagonigro, Stefano Caramuta, Cristina Ferrario, Erica Bussani, Delia Mezzanzanica, Fabio Turatti, Domenico Delia, Maria G Daidone, Marco A Pierotti & Silvana Canevari

  3. IFOM FIRC Institute for Molecular Oncology, via Adamello 16, Milan, 20139, Italy

    Loris De Cecco, Manuela Gariboldi, M Stefania Lagonigro, Stefano Caramuta, Cristina Ferrario, Erica Bussani & Marco A Pierotti

  4. Department of Pathology, Istituto Nazionale Tumori, via G Venezian 1, Milan, 20133, Italy

    Maria Oggionni, Norma Bertuletti & Silvana Pilotti

  5. Department of Surgical Oncology, Istituto Nazionale Tumori, via G. Venezian 1, Milan, 20133, Italy

    Antonino Ditto & Francesco Raspagliesi

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  1. Loris De Cecco
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Correspondence to Marco A Pierotti or Claudio Schneider.

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Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc).

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Cecco, L., Marchionni, L., Gariboldi, M. et al. Gene expression profiling of advanced ovarian cancer: characterization of a molecular signature involving fibroblast growth factor 2. Oncogene 23, 8171–8183 (2004). https://doi.org/10.1038/sj.onc.1207979

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