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Open AccessArticle

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

1
Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
2
Department of Physics, College of Science and Mathematics, University of Massachusetts at Boston, Boston, MA 02125, USA
3
Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC and North Carolina State University, Raleigh, NC 27599, USA
4
School for Engineering of Matter, Transport and Energy, Ira A. Fulton Schools of Engineering, Arizona State University, Tempe, AZ 85287, USA
5
Department of Urology, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
6
Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA
7
Bio-Acoustic MEMS in Medicine (BAMM) Laboratory, Canary Center at Stanford for Cancer Early Detection, Department of Radiology School of Medicine Stanford University, Palo Alto, CA 94304, USA
8
Division of Gynecologic Oncology, Vincent Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
9
Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA
10
Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
*
Author to whom correspondence should be addressed.
Equal contribution.
J. Clin. Med. 2020, 9(4), 924; https://doi.org/10.3390/jcm9040924
Received: 4 February 2020 / Revised: 20 March 2020 / Accepted: 23 March 2020 / Published: 28 March 2020
(This article belongs to the Special Issue The Past, Present and Future of Photodynamic Therapy for Cancers)
A key reason for the persistently grim statistics associated with metastatic ovarian cancer is resistance to conventional agents, including platinum-based chemotherapies. A major source of treatment failure is the high degree of genetic and molecular heterogeneity, which results from significant underlying genomic instability, as well as stromal and physical cues in the microenvironment. Ovarian cancer commonly disseminates via transcoelomic routes to distant sites, which is associated with the frequent production of malignant ascites, as well as the poorest prognosis. In addition to providing a cell and protein-rich environment for cancer growth and progression, ascitic fluid also confers physical stress on tumors. An understudied area in ovarian cancer research is the impact of fluid shear stress on treatment failure. Here, we investigate the effect of fluid shear stress on response to platinum-based chemotherapy and the modulation of molecular pathways associated with aggressive disease in a perfusion model for adherent 3D ovarian cancer nodules. Resistance to carboplatin is observed under flow with a concomitant increase in the expression and activation of the epidermal growth factor receptor (EGFR) as well as downstream signaling members mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) and extracellular signal-regulated kinase (ERK). The uptake of platinum by the 3D ovarian cancer nodules was significantly higher in flow cultures compared to static cultures. A downregulation of phospho-focal adhesion kinase (p-FAK), vinculin, and phospho-paxillin was observed following carboplatin treatment in both flow and static cultures. Interestingly, low-dose anti-EGFR photoimmunotherapy (PIT), a targeted photochemical modality, was found to be equally effective in ovarian tumors grown under flow and static conditions. These findings highlight the need to further develop PIT-based combinations that target the EGFR, and sensitize ovarian cancers to chemotherapy in the context of flow-induced shear stress. View Full-Text
Keywords: ovarian cancer; epidermal growth factor receptor (EGFR); mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK); extracellular signal-regulated kinase (ERK); chemoresistance; fluid shear stress; ascites; perfusion model; photoimmunotherapy (PIT); photodynamic therapy (PDT); carboplatin ovarian cancer; epidermal growth factor receptor (EGFR); mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK); extracellular signal-regulated kinase (ERK); chemoresistance; fluid shear stress; ascites; perfusion model; photoimmunotherapy (PIT); photodynamic therapy (PDT); carboplatin
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MDPI and ACS Style

Nath, S.; Pigula, M.; Khan, A.P.; Hanna, W.; Ruhi, M.K.; Dehkordy, F.M.; Pushpavanam, K.; Rege, K.; Moore, K.; Tsujita, Y.; Conrad, C.; Inci, F.; del Carmen, M.G.; Franco, W.; Celli, J.P.; Demirci, U.; Hasan, T.; Huang, H.-C.; Rizvi, I. 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. J. Clin. Med. 2020, 9, 924. https://doi.org/10.3390/jcm9040924

AMA Style

Nath S, Pigula M, Khan AP, Hanna W, Ruhi MK, Dehkordy FM, Pushpavanam K, Rege K, Moore K, Tsujita Y, Conrad C, Inci F, del Carmen MG, Franco W, Celli JP, Demirci U, Hasan T, Huang H-C, Rizvi I. 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. Journal of Clinical Medicine. 2020; 9(4):924. https://doi.org/10.3390/jcm9040924

Chicago/Turabian Style

Nath, Shubhankar; Pigula, Michael; Khan, Amjad P.; Hanna, William; Ruhi, Mustafa K.; Dehkordy, Farzaneh M.; Pushpavanam, Karthik; Rege, Kaushal; Moore, Kaitlin; Tsujita, Yujiro; Conrad, Christina; Inci, Fatih; del Carmen, Marcela G.; Franco, Walfre; Celli, Jonathan P.; Demirci, Utkan; Hasan, Tayyaba; Huang, Huang-Chiao; Rizvi, Imran. 2020. "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" J. Clin. Med. 9, no. 4: 924. https://doi.org/10.3390/jcm9040924

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