The role of bone morphogenetic protein 4 signalling in human ovarian cancer cell behaviour.
Date
2007
Authors
Theriault, Brigitte L.
Journal Title
Journal ISSN
Volume Title
Publisher
Dalhousie University
Abstract
Description
Ovarian cancer (OvCa) is the most lethal of the gynecological malignancies, and its mechanisms of carcinogenesis are poorly understood. Most OvCas are thought to arise from the ovarian surface epithelium (OSE). An autocrine bone morphogenetic protein 4 (BMP4) signalling pathway in primary human normal OSE and OvCa cells has been identified in our laboratory, and this study investigated the behavioural consequences of BMP4 signalling in OSE and OvCa cells. BMP4 treatment of OvCa cells produced morphological alterations and increased cellular adhesion, motility and invasion. The BMP4 inhibitor Noggin blocked the BMP4-induced phenotype, and decreased autocrine BMP4-mediated OvCa cell motility and adherence. Exogenous BMP4 upregulated the epithelial-mesenchymal transition (EMT) markers Snail and Slug while E-cadherin was downregulated, and the network of alpha smooth muscle actin (alphaSMA) changed to resemble a mesenchymal cell. Levels of activated Rho-GTPases in OvCa cells were changed, suggesting that the BMP4-induced cellular behaviours are likely mediated through the activation of these molecules. Treatment of OSE cells with BMP4 or Noggin failed to alter cell motility, providing evidence that OSE and OvCa cells possess distinct capacities to respond to BMP4. The BMP4-induced changes in morphology and motility were shown to be Smad-dependent through the RNA-mediated targeting of Smad expression. These studies suggest a link between autocrine BMP signalling mediated through Smad-dependent signalling, the Rho-GTPases, and Snail/Slug-induced EMT that may collectively contribute to aggressive OvCa behaviour.
Transforming growth factor beta (TGFbeta) and Activin signalling pathways were also found to be intact in OSE and OvCa cells, where exogenous ligand stimulated Smad phosphorylation and target gene upregulation. BMP6, TGFbeta1 and ActivinA also induced morphologic changes characterized by cell spreading. Interestingly, TGFbeta1 and ActivinA induced inhibition of OvCa growth and motility, while BMP4 and BMP6 increased cellular motility, having no proliferative effect. TGFbeta and Activin inhibitors increased cellular growth and motility to above control levels, indicating that autocrine TGFbeta/Activin signalling also exerts control over OvCa behaviours. Taken together, these results suggest that a balance exists between BMP and TGFbeta/Activin signalling within OSE and/or OvCa cells, and that this balance is altered to favor BMP signalling during OvCa metastatic progression.
Thesis (Ph.D.)--Dalhousie University (Canada), 2007.
Transforming growth factor beta (TGFbeta) and Activin signalling pathways were also found to be intact in OSE and OvCa cells, where exogenous ligand stimulated Smad phosphorylation and target gene upregulation. BMP6, TGFbeta1 and ActivinA also induced morphologic changes characterized by cell spreading. Interestingly, TGFbeta1 and ActivinA induced inhibition of OvCa growth and motility, while BMP4 and BMP6 increased cellular motility, having no proliferative effect. TGFbeta and Activin inhibitors increased cellular growth and motility to above control levels, indicating that autocrine TGFbeta/Activin signalling also exerts control over OvCa behaviours. Taken together, these results suggest that a balance exists between BMP and TGFbeta/Activin signalling within OSE and/or OvCa cells, and that this balance is altered to favor BMP signalling during OvCa metastatic progression.
Thesis (Ph.D.)--Dalhousie University (Canada), 2007.
Keywords
Health Sciences, Pharmacology., Health Sciences, Oncology.