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      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

      research-article
      1 , 1 , 1 , 2 , 1 , 3 , 1 , 4 , 4 , 1 , 1 , 5 , 6 , 7 , 8 , 1 , 2 , 7 , 1 , 6 , 9 , 1 , 3 , 10 , *
      Journal of Clinical Medicine
      MDPI
      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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          Abstract

          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.

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          Most cited references126

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          Cancer Cell-Selective In Vivo Near Infrared Photoimmunotherapy Targeting Specific Membrane Molecules

          Three major modes of cancer therapies, surgery, radiation and chemotherapy, have been the mainstay of modern oncologic therapy. To minimize side effects, molecular targeted cancer therapies including armed antibody therapy have been developed with limited success. In this study, we developed a new type of molecular targeted cancer therapy, photoimmunotherapy (PIT), employing a target-specific photosensitizer based on a near infrared (NIR) phthalocyanine dye, IR700, conjugated to monoclonal antibodies (MAb) targeting epidermal growth factor receptors (EGFR). Cell death was induced immediately only upon irradiating, MAb-IR700 bound, target cells with NIR light. In vivo tumor shrinkage after irradiation with NIR light was observed only in target EGFR-expressing cells. The MAb-IR700 conjugates were most effective when bound to the cell membrane, producing no phototoxicity when not bound, suggesting a different mechanism for PIT compared with conventional photodynamic therapies. Target selective PIT enables treatment of cancer based on MAb binding on the cell membrane.
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            • Article: not found

            How ERK1/2 activation controls cell proliferation and cell death: Is subcellular localization the answer?

            Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) are members of the mitogen-activated protein kinase super family that can mediate cell proliferation and apoptosis. The Ras-Raf-MEK-ERK signaling cascade controlling cell proliferation has been well studied but the mechanisms involved in ERK1/2-mediated cell death are largely unknown. This review focuses on recent papers that define ERK1/2 translocation to the nucleus and the proteins involved in the cytosolic retention of activated ERK1/2. Cytosolic retention of ERK1/2 denies access to the transcription factor substrates that are responsible for the mitogenic response. In addition, cytosolic ERK1/2, besides inhibiting survival and proliferative signals in the nucleus, potentiates the catalytic activity of some proapoptotic proteins such as DAP kinase in the cytoplasm. Studies that further define the function of cytosolic ERK1/2 and its cytosolic substrates that enhance cell death will be essential to harness this pathway for developing effective treatments for cancer and chronic inflammatory diseases.
              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              Getting to Know Ovarian Cancer Ascites: Opportunities for Targeted Therapy-Based Translational Research

              More than one third of ovarian cancer patients present with ascites at diagnosis, and almost all have ascites at recurrence. The presence of ascites correlates with the peritoneal spread of ovarian cancer and is associated with poor disease prognosis. Malignant ascites acts as a reservoir of a complex mixture of soluble factors and cellular components which provide a pro-inflammatory and tumor-promoting microenvironment for the tumor cells. Subpopulations of these tumor cells exhibit cancer stem-like phenotypes, possess enhanced resistance to therapies and the capacity for distal metastatic spread and recurrent disease. Thus, ascites-derived malignant cells and the ascites microenvironment represent a major source of morbidity and mortality for ovarian cancer patients. This review focuses on recent advances in our understanding of the molecular, cellular, and functional characteristics of the cellular populations within ascites and discusses their contributions to ovarian cancer metastasis, chemoresistance, and recurrence. We highlight in particular recent translational findings which have used primary ascites-derived tumor cells as a tool to understand the pathogenesis of the disease, yielding new insights and targets for therapeutic manipulation.

                Author and article information

                Journal
                J Clin Med
                J Clin Med
                jcm
                Journal of Clinical Medicine
                MDPI
                2077-0383
                28 March 2020
                April 2020
                : 9
                : 4
                : 924
                Affiliations
                [1 ]Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; snath.vet2000@ 123456gmail.com (S.N.); m.pigula94@ 123456gmail.com (M.P.); APKHAN@ 123456mgh.harvard.edu (A.P.K.); mkruhi@ 123456email.unc.edu (M.K.R.); FMahmoodpoorDehkordy@ 123456mgh.harvard.edu (F.M.D.); kmoore31@ 123456mgh.harvard.edu (K.M.); yujirotsujita@ 123456gmail.com (Y.T.); wfranco@ 123456mgh.harvard.edu (W.F.); thasan@ 123456mgh.harvard.edu (T.H.)
                [2 ]Department of Physics, College of Science and Mathematics, University of Massachusetts at Boston, Boston, MA 02125, USA; william.hanna001@ 123456gmail.com (W.H.); jonathan.celli@ 123456umb.edu (J.P.C.)
                [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; kpsubram@ 123456asu.edu (K.P.); Kaushal.Rege@ 123456asu.edu (K.R.)
                [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; cconrad8@ 123456terpmail.umd.edu (C.C.); hchuang@ 123456umd.edu (H.-C.H.)
                [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; finci@ 123456stanford.edu (F.I.); utkan@ 123456stanford.edu (U.D.)
                [8 ]Division of Gynecologic Oncology, Vincent Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; mdelcarmen@ 123456mgh.harvard.edu
                [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 notes
                [* ]Correspondence: imran.rizvi@ 123456unc.edu
                [†]

                Equal contribution.

                Author information
                https://orcid.org/0000-0001-5778-7615
                https://orcid.org/0000-0002-6854-291X
                https://orcid.org/0000-0001-6312-2572
                https://orcid.org/0000-0001-8688-2523
                https://orcid.org/0000-0002-5406-0733
                https://orcid.org/0000-0001-9673-4700
                Article
                jcm-09-00924
                10.3390/jcm9040924
                7230263
                32231055
                4893f25a-7b5a-4d64-99d6-9b3dd5db4643
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 04 February 2020
                : 23 March 2020
                Categories
                Article

                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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