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Edited by David Kessel, Wayne State University School of Medicine, Detroit, MI, and accepted by the Editorial Board March 26, 2013 (received for review October 2, 2012)
Abstract
Seventy-five percent of patients with epithelial ovarian cancer present with advanced-stage disease that is extensively disseminated intraperitoneally and prognosticates the poorest outcomes. Primarily metastatic within the abdominal cavity, ovarian carcinomas initially spread to adjacent organs by direct extension and then disseminate via the transcoelomic route to distant sites. Natural fluidic streams of malignant ascites triggered by physiological factors, including gravity and negative subdiaphragmatic pressure, carry metastatic cells throughout the peritoneum. We investigated the role of fluidic forces as modulators of metastatic cancer biology in a customizable microfluidic platform using 3D ovarian cancer nodules. Changes in the morphological, genetic, and protein profiles of biomarkers associated with aggressive disease were evaluated in the 3D cultures grown under controlled and continuous laminar flow. A modulation of biomarker expression and tumor morphology consistent with increased epithelial–mesenchymal transition, a critical step in metastatic progression and an indicator of aggressive disease, is observed because of hydrodynamic forces. The increase in epithelial–mesenchymal transition is driven in part by a posttranslational up-regulation of epidermal growth factor receptor (EGFR) expression and activation, which is associated with the worst prognosis in ovarian cancer. A flow-induced, transcriptionally regulated decrease in E-cadherin protein expression and a simultaneous increase in vimentin is observed, indicating increased metastatic potential. These findings demonstrate that fluidic streams induce a motile and aggressive tumor phenotype. The microfluidic platform developed here potentially provides a flow-informed framework complementary to conventional mechanism-based therapeutic strategies, with broad applicability to other lethal malignancies.
Footnotes
↵1Present address: Case Biomanufacturing and Microfabrication Laboratory, Mechanical and Aerospace Engineering, Case Western Reserve University, Advanced Platform Technology Center, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH 44106.
- ↵2To whom correspondence may be addressed. E-mail: thasan{at}mgh.harvard.edu or udemirci{at}rics.bwh.harvard.edu.
Author contributions: I.R., U.A.G., U.D., and T.H. designed research; I.R., U.A.G., S.T., N.A., J.P.C., L.B.M., and Z.M. performed research; I.R., U.A.G., S.T., J.P.C., L.B.M., and U.D. contributed new reagents/analytic tools; I.R., U.A.G., S.T., N.A., J.P.C., L.B.M., Z.M., and U.D. analyzed data; and I.R., U.A.G., S.T., N.A., J.P.C., U.D., and T.H. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission. D.K. is a guest editor invited by the Editorial Board.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1216989110/-/DCSupplemental.
Flow-induced increase in EMT in 3D ovarian tumors
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