Autocrine bone morphogenetic protein-9 signals through activin receptor-like kinase-2/Smad1/Smad4 to promote ovarian cancer cell proliferation.
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 beta/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 approximately 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.
Herrera
Blanca
B
Growth Factor Signalling Laboratory, The Beatson Institute for Cancer Research, Glasgow, United Kingdom.
van Dinther
Maarten
M
Ten Dijke
Peter
P
Inman
Gareth J
GJ
D030201:Activin Receptors, Type I / Q000378:metabolism*; D030301:Activin Receptors, Type II / Q000378:metabolism; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D005260:Female; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors / Q000096:biosynthesis / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D051898:Smad1 Protein / Q000378:metabolism*; D051901:Smad4 Protein / Q000378:metabolism*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
C525887:GDF2 protein, human; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C497399:SMAD1 protein, human; C497796:SMAD4 protein, human; D051898:Smad1 Protein; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II; C425585:activin receptor type II-A