Flow Induces Epithelial-mesenchymal Transition, Cellular Heterogeneity And Biomarker Modulation In 3D Ovarian Cancer Nodules
Imran Rizvi, Umut A. Gurkan, Savas Tasoglu, Nermina Alagic, Jonathan P. Celli, Lawrence B Mensah, Zhiming Jim Mai, Utkan Demirci, Tayyaba Hasan
Published 2013 · Biology, Medicine
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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.
This paper references
Selective removal of ovarian cancer cells from human ascites fluid using magnetic nanoparticles.
Kenneth E. Scarberry (2010)
Integrated genomic and proteomic analyses of a systematically perturbed metabolic network.
Trey Ideker (2001)
Intraperitoneal cancer dissemination: Mechanisms of the patterns of spread
C. Pablo Carmignani (2004)
BPD-MA-mediated photosensitization in vitro and in vivo: cellular adhesion and β1 integrin expression in ovarian cancer cells
Judith M. Runnels (1999)
Autologous chemotaxis as a mechanism of tumor cell homing to lymphatics via interstitial flow and autocrine CCR7 signaling.
Jacqueline D. Shields (2007)
Integrin Inhibitors as a Therapeutic Agent for Ovarian Cancer
Kenjiro Sawada (2012)
MMP-2 functions as an early response protein in ovarian cancer metastasis
Hilary A Kenny (2009)
A three-dimensional in vitro ovarian cancer coculture model using a high-throughput cell patterning platform.
Feng Xu (2011)
Gene expression profiling: monitoring transcription and translation products using DNA microarrays and proteomics.
J. E. Celis (2000)
Matrix metalloproteinase 9 is a mediator of epidermal growth factor-dependent e-cadherin loss in ovarian carcinoma cells.
Karen D Cowden Dahl (2008)
Epithelial-mesenchymal interconversions in normal ovarian surface epithelium and ovarian carcinomas: an exception to the norm.
Nuzhat Ahmed (2007)
Modeling tissue-specific signaling and organ function in three dimensions
Karen L. Schmeichel (2003)
Effect of Epidermal Growth Factor Receptor Expression Level on Survival in Patients with Epithelial Ovarian Cancer
Amanda K. Psyrri (2005)
Intraperitoneal photodynamic therapy.
Keith A Cengel (2007)
Isolation and characterization of stromal progenitor cells from ascites of patients with epithelial ovarian adenocarcinoma
Chih-Ming Ho (2011)
The role of apoptosis in creating and maintaining luminal space within normal and oncogene - expressing mammary acini
J Debnath (2002)
EGF-Induced EMT and Invasiveness in Serous Borderline Ovarian Tumor Cells: A Possible Step in the Transition to Low-Grade Serous Carcinoma Cells?
Jung-Chien Cheng (2012)
Synergism of epidermal growth factor receptor-targeted immunotherapy with photodynamic treatment of ovarian cancer in vivo.
Marcela Guadalupe del Carmen (2005)
A phase II study of ixabepilone (BMS-247550) in metastatic renal-cell carcinoma
Edwin M Posadas (2006)
EMT transcription factors snail and slug directly contribute to cisplatin resistance in ovarian cancer
Alexandria Haslehurst (2011)
Adriamycin accumulation and metabolism in adriamycin-sensitive and -resistant human ovarian cancer cell lines.
Karen G. Louie (1986)
PuraMatrix Encapsulation of Cancer Cells
Adnan O. Abu-Yousif (2009)
Regulation of the cytoskeleton: an oncogenic function for cdk inhibitors?
Arnaud Besson (2004)
Early Edition | 9 of 10 APPLIED BIOLOGICAL SCIENCES 30 The morphological and molecular features of the epithelial-to-mesenchymal transition
Quantitative analysis of complex protein mixtures using isotope-coded affinity tags
Steven P. Gygi (1999)
Enumeration of CD4+ T-Cells Using a Portable Microchip Count Platform in Tanzanian HIV-Infected Patients
Sangjun Moon (2011)
Fractals in pathology.
Simon S. Cross (1997)
A Perspective on Cancer Cell Metastasis
Christine L Chaffer (2011)
The Dermatan Sulfate Proteoglycan Decorin Modulates α2β1 Integrin and the Vimentin Intermediate Filament System during Collagen Synthesis
Oliver Jungmann (2012)
Loss of E-cadherin promotes ovarian cancer metastasis via alpha 5-integrin, which is a therapeutic target.
Kenjiro Sawada (2008)
Feedback regulation of EGFR signalling: decision making by early and delayed loops
Roi Avraham (2011)
Epithelial-mesenchymal-transition induced by EGFR activation interferes with cell migration and response to irradiation and cetuximab in head and neck cancer cells.
Carmen Holz (2011)
The role of lymphatic obstruction in the formation of ascites in a murine ovarian carcinoma.
George B. Feldman (1972)
Oncogenic Ras and Akt signaling contribute to glioblastoma formation by differential recruitment of existing mRNAs to polysomes.
Vinagolu K. Rajasekhar (2003)
Translational control in stress and apoptosis
Martin Holcik (2005)
The epidermal growth factor receptor as a therapeutic target in epithelial ovarian cancer.
Ting Gui (2012)
Tumor cell cycle arrest induced by shear stress: Roles of integrins and Smad
Shun-Fu Chang (2008)
Three-dimensional culture models of normal and malignant breast epithelial cells
Genee Y. Lee (2007)
Pathogenesis of ascites in peritoneal carcinomatosis.
P Holm-Nielsen (1953)
GINECO Group (2004) Lack of relationship between EGFR-1 immunohistochemical expression and prognosis in a multicentre clinical trial of 93 patients with advanced primary ovarian epithelial cancer
C Elie (2004)
Lack of relationship between EGFR-1 immunohistochemical expression and prognosis in a multicentre clinical trial of 93 patients with advanced primary ovarian epithelial cancer (GINECO group)
Caroline Elie (2004)
Disaggregation and invasion of ovarian carcinoma ascites spheroids
Kathryn M. Burleson (2005)
Integrin-mediated adhesion and signalling in ovarian cancer cells.
J A Buczek-Thomas (1998)
Integrins as therapeutic targets: lessons and opportunities
Dermot Cox (2010)
A phase II and pharmacodynamic study of ge fi tinib in patients with refractory or recurrent epithelial ovarian
EM Posadas (2007)
Combination of photodynamic therapy with anti-cancer agents.
M-F Zuluaga (2008)
Microenvironmental regulation of metastasis
Johanna A. Joyce (2009)
Human ovarian cancer stem/progenitor cells are stimulated by doxorubicin but inhibited by Mullerian inhibiting substance
Kátia Meirelles (2012)
Multi-step microfluidic device for studying cancer metastasis.
Kuan Chun Chaw (2007)
Tumor Metastasis: Molecular Insights and Evolving Paradigms
Scott Valastyan (2011)
Rab-coupling protein coordinates recycling of α5β1 integrin and EGFR1 to promote cell migration in 3D microenvironments
Patrick T. Caswell (2008)
Tissue structure, nuclear organization, and gene expression in normal and malignant breast.
Mina J. Bissell (1999)
Standardization of epidermal growth factor receptor (EGFR) measurement by quantitative immunofluorescence and impact on antibody-based mutation detection in non-small cell lung cancer.
Anastasios T Dimou (2011)
The physics of cancer: the role of physical interactions and mechanical forces in metastasis
Denis Wirtz (2011)
Epithelial mesenchymal transition and cancer stem cell-like phenotypes facilitate chemoresistance in recurrent ovarian cancer.
Nuzhat Ahmed (2010)
Molecular pathways regulating EGF-induced epithelio-mesenchymal transition in human ovarian surface epithelium.
Nuzhat Ahmed (2006)
Manipulating biological agents and cells in micro-scale volumes for applications in medicine.
Savas Tasoglu (2013)
ErbB2, but not ErbB1, reinitiates proliferation and induces luminal repopulation in epithelial acini
Senthil K. Muthuswamy (2001)
Epidermal growth factor receptor signaling and the invasive phenotype of ovarian carcinoma cells.
Alper O (2001)
Phase II Trial of Debulking Surgery and Photodynamic Therapy for Disseminated Intraperitoneal Tumors
Samantha K. Hendren (2001)
A phase II and pharmacodynamic study of gefitinib in patients with refractory or recurrent epithelial ovarian cancer.
Edwin M Posadas (2007)
The morphologies of breast cancer cell lines in three-dimensional assays correlate with their profiles of gene expression.
Paraic A. Kenny (2007)
Imaging and photodynamic therapy: mechanisms, monitoring, and optimization.
Jonathan P. Celli (2010)
Observations concerning cancer spread within the peritoneal cavity and concepts supporting an ordered pathophysiology.
Paul H Sugarbaker (1996)
Interaction with basement membrane serves to rapidly distinguish growth and differentiation pattern of normal and malignant human breast epithelial cells.
Ole William Petersen (1992)
Malignant ascites: past, present, and future.
Rony A. Adam (2004)
Cancer Metastasis: Building a Framework
Gaorav P. Gupta (2006)
Synergistic enhancement of carboplatin efficacy with photodynamic therapy in a three-dimensional model for micrometastatic ovarian cancer.
Imran Rizvi (2010)
Adhesion molecule signalling: not always a sticky business
Ugo Cavallaro (2011)
Blockade of tumor cell transforming growth factor-betas enhances cell cycle progression and sensitizes human breast carcinoma cells to cytotoxic chemotherapy.
Tohru Ohmori (1998)
Hallmarks of Cancer: The Next Generation
Douglas Hanahan (2011)
Integrins in cancer: biological implications and therapeutic opportunities
Jay S. Desgrosellier (2010)
Ovarian carcinoma ascites spheroids adhere to extracellular matrix components and mesothelial cell monolayers.
Kathryn M. Burleson (2004)
Loss of E-cadherin mediated cell-cell adhesion as an early trigger of apoptosis induced by photodynamic treatment.
Sergio Galaz (2005)
Cytology, immunopathology and flow cytometry in the diagnosis of pleural and peritoneal effusions.
A M Croonen (1988)
Proteomic profiling of the NCI-60 cancer cell lines using new high-density reverse-phase lysate microarrays
Satoshi S. Nishizuka (2003)
Integration of intra- and extravasation in one cell-based microfluidic chip for the study of cancer metastasis.
Min Kyeong Shin (2011)
Quantitative imaging reveals heterogeneous growth dynamics and treatment-dependent residual tumor distributions in a three-dimensional ovarian cancer model.
Jonathan P. Celli (2010)
Of extracellular matrix, scaffolds, and signaling: tissue architecture regulates development, homeostasis, and cancer.
Celeste M. Nelson (2006)
Diffusion coefficients for hydrogen sulfide, carbon dioxide, and nitrous oxide in water over the temperature range 293--368 K
Abdelrahman Tamimi (1994)
The Role of Apoptosis in Creating and Maintaining Luminal Space within Normal and Oncogene-Expressing Mammary Acini
Jayanta Debnath (2002)
Dissemination of intraperitoneal ovarian cancer: Discussion of mechanisms and demonstration of lymphatic spreading in ovarian cancer model.
Anis Feki (2009)
Ovarian cancer development and metastasis.
Ernst Lengyel (2010)
The morphological and molecular features of the epithelial-to-mesenchymal transition
Gema Moreno-Bueno (2009)
Use of a novel 3D culture model to elucidate the role of mesothelial cells, fibroblasts and extra-cellular matrices on adhesion and invasion of ovarian cancer cells to the omentum.
Hilary A Kenny (2007)
Vimentin contributes to human mammary epithelial cell migration.
Christine Gilles (1999)
Metastasis: from dissemination to organ-specific colonization
Don Nguyen (2009)
Mechanisms of transcoelomic metastasis in ovarian cancer.
David Sp Tan (2006)
Epithelial-mesenchymal transition in cancer development and its clinical significance.
Masaaki Iwatsuki (2010)
Ovarian Cancer Metastasis: Integrating insights from disparate model organisms
Honami Naora (2005)
Targeting the EGF Receptor for Ovarian Cancer Therapy
Reema Zeineldin (2010)
Integrating cancer genomics and proteomics in the post-genome era.
Samir M. Hanash (2002)
Postgenomic global analysis of translational control induced by oncogenic signaling
Vinagolu K. Rajasekhar (2004)
A phase II trial of EMD72000 (matuzumab), a humanized anti-EGFR monoclonal antibody, in patients with platinum-resistant ovarian and primary peritoneal malignancies.
Michael V. Seiden (2007)
Ki-67 as a molecular target for therapy in an in vitro three-dimensional model for ovarian cancer.
Ramtin Rahmanzadeh (2010)
Epithelial to mesenchymal transition is a determinant of sensitivity of non-small-cell lung carcinoma cell lines and xenografts to epidermal growth factor receptor inhibition.
Stuart Thomson (2005)
Metastasis: Dissemination and growth of cancer cells in metastatic sites
Ann F. Chambers (2002)
Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures.
Jayanta Debnath (2003)
Interstitial flow influences direction of tumor cell migration through competing mechanisms
William J. Polacheck (2011)
The biology of ovarian cancer: new opportunities for translation
Robert C. Bast (2009)
The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy
Isabel M. Chu (2008)
PATHOGENESIS OF ASCITES IN PERITONEAL CARCINOMATOSIS1
Povl Holm-Nielsen (2009)
Rethinking ovarian cancer: recommendations for improving outcomes
Sebastian Vaughan (2011)
This paper is referenced by
3-D geometry and irregular connectivity dictate neuronal firing in frequency domain and synchronization.
Tanchen Ren (2019)
Complex Determinants of Epithelial: Mesenchymal Phenotypic Plasticity in Ovarian Cancer
Yuliya Klymenko (2017)
Cell migration in microengineered tumor environments.
Eujin Um (2017)
The Role of Cancer Stem Cells and Mechanical Forces in Ovarian Cancer Metastasis
Michael E. Bregenzer (2019)
Plug-and-Play In Vitro Metastasis System toward Recapitulating the Metastatic Cascade
Bing-Syuan Ni (2019)
Towards artificial tissue models: past, present, and future of 3D bioprinting.
Ahu Arslan-Yildiz (2016)
Open Fluidics: A Cell Culture Flow System Developed Over Wettability Contrast‐Based Chips
Nuno M Oliveira (2017)
Density Based Characterization of Mechanical Cues on Cancer Cells Using Magnetic Levitation.
Murat Baday (2019)
Fluids and their mechanics in tumour transit: shaping metastasis
Gautier Follain (2019)
Using Integrated Cancer-on-Chip Platforms to Emulate and Probe Various Cancer Models
Ziqiu Tong (2019)
Advancing cancer research using bioprinting for tumor-on-a-chip platforms
Stephanie Knowlton (2016)
Inhibition of the JAK2/STAT3 pathway in ovarian cancer results in the loss of cancer stem cell-like characteristics and a reduced tumor burden
Khalid Abubaker (2013)
基于三维培养下的肿瘤细胞恶性研究 Study of Cancer Cell Malignancy Based on Three-Dimensional Cell Culture Technology
Two-dimensional numerical study of flow dynamics of a nucleated cell tethered under shear flow
Zhengyuan Luo (2014)
Simulation-assisted design of microfluidic sample traps for optimal trapping and culture of non-adherent single cells, tissues, and spheroids
Nassim Rousset (2017)
Mechanical Characterization of 3D Ovarian Cancer Nodules Using Brillouin Confocal Microscopy
Christina Conrad (2019)
3-D Microwell Array System for Culturing Virus Infected Tumor Cells
Rami El Assal (2016)
Tumor spheroids under perfusion within a 3D microfluidic platform reveal critical roles of cell-cell adhesion in tumor invasion
Yu ling Huang (2020)
Micro and Nano-Scale Technologies for Cell Mechanics
Mustafa Unal (2014)
Deformation of a single mouse oocyte in a constricted microfluidic channel
Zhengyuan Luo (2015)
Flow-induced Shear Stress Confers Resistance to Carboplatin in an Adherent Three-Dimensional Model for Ovarian Cancer: A Role for EGFR-Targeted Photoimmunotherapy Informed by Physical Stress
Shubhankar Nath (2020)
The lipid kinase PI3Kα is required for aggregation and survival of intraperitoneal cancer cells
Adrien Thole (2019)
Microfluidics for sperm research.
Stephanie Knowlton (2015)
Flow-induced stress on adherent cells in microfluidic devices.
Jonathan Shemesh (2015)
Two-dimensional numerical study of fl ow dynamics of a nucleated cell
Zheng Yuan Luo (2014)
Layer‐by‐layer nanoparticles for novel delivery of cisplatin and PARP inhibitors for platinum‐based drug resistance therapy in ovarian cancer
Lawrence B Mensah (2019)
A Complex Systems Analysis of Cancer Networks
Abicumaran Uthamacumaran (2019)
Continuous flow micro-bioreactors for the production of biopharmaceuticals: the effect of geometry, surface texture, and flow rate.
Lucía D. Garza-García (2014)
Three-dimensional modeling of ovarian cancer.
Erin A. White (2014)
Migration and vascular lumen formation of endothelial cells in cancer cell spheroids of various sizes.
Bishnubrata Patra (2014)
A Microfluidic Perfusion Platform for In Vitro Analysis of Drug Pharmacokinetic-Pharmacodynamic (PK-PD) Relationships
Yadir A Guerrero (2020)
Biophysical analysis of fluid shear stress induced cellular deformation in a microfluidic device.
Grant M Landwehr (2018)See more