Data from Autocrine Bone Morphogenetic Protein-9 Signals through Activin Receptor-like Kinase-2/Smad1/Smad4 to Promote Ovarian Cancer Cell Proliferation

Abstract

Abstract Bone morphogenetic proteins (BMPs) act as central regulators of ovarian physiology and may be involved in ovarian cancer development. In an effort to understand these processes, we characterized transforming growth factor β/BMP receptor and Smad expression in immortalized ovarian surface epithelial cells and a panel of ovarian cancer cell lines. These studies prompted us to evaluate the potential role of BMP9 signaling in ovarian cancer. Using small interfering RNA, ligand trap, inhibitor, and ligand stimulation approaches, we show that BMP9 acts as a proliferative factor for immortalized ovarian surface epithelial cells and ovarian cancer cell lines, signaling predominantly through an ALK2/Smad1/Smad4 pathway rather than through ALK1, the major BMP9 receptor in endothelial cells. Importantly, we find that some ovarian cancer cell lines have gained autocrine BMP9 signaling that is required for proliferation. Furthermore, immunohistochemistry analysis of an ovarian cancer tissue microarray reveals that ∼25% of epithelial ovarian cancers express BMP9, whereas normal human ovarian surface epithelial specimens do not. Our data indicate that BMP9 signaling through ALK2 may be a novel therapeutic target in ovarian cancer. [Cancer Res 2009;69(24):9254–62]

Authors 4

1. Blanca M. Herrera

   Cancer Research UK Scotland Institute

   Affiliation as printed

   Growth Factor Signalling Laboratory, The Beatson Institute for Cancer Research, Glasgow, United Kingdom and

2. Maarten van Dinther Aachen Department of Molecular Cell Biology and Center for Biomedical Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Molecular Cell Biology and Center for Biomedical Genetics, Leiden University Medical Center, Leiden, the Netherlands

3. Peter ten Dijke Aachen Department of Molecular Cell Biology and Center for Biomedical Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Molecular Cell Biology and Center for Biomedical Genetics, Leiden University Medical Center, Leiden, the Netherlands

4. Gareth J. Inman corresponding

   Cancer Research UK Scotland Institute

   Affiliation as printed

   Growth Factor Signalling Laboratory, The Beatson Institute for Cancer Research, Glasgow, United Kingdom and