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      Tumor Microenvironment on a Chip: The Progress and Future Perspective

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          Abstract

          Tumors develop in intricate microenvironments required for their sustained growth, invasion, and metastasis. The tumor microenvironment plays a critical role in the malignant or drug resistant nature of tumors, becoming a promising therapeutic target. Microengineered physiological systems capable of mimicking tumor environments are one emerging platform that allows for quantitative and reproducible characterization of tumor responses with pathophysiological relevance. This review highlights the recent advancements of engineered tumor microenvironment systems that enable the unprecedented mechanistic examination of cancer progression and metastasis. We discuss the progress and future perspective of these microengineered biomimetic approaches for anticancer drug prescreening applications.

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          Tensional homeostasis and the malignant phenotype.

          Matthew J. Paszek, Nastaran Zahir, Kandice R. Johnson … (2005)
          Tumors are stiffer than normal tissue, and tumors have altered integrins. Because integrins are mechanotransducers that regulate cell fate, we asked whether tissue stiffness could promote malignant behavior by modulating integrins. We found that tumors are rigid because they have a stiff stroma and elevated Rho-dependent cytoskeletal tension that drives focal adhesions, disrupts adherens junctions, perturbs tissue polarity, enhances growth, and hinders lumen formation. Matrix stiffness perturbs epithelial morphogenesis by clustering integrins to enhance ERK activation and increase ROCK-generated contractility and focal adhesions. Contractile, EGF-transformed epithelia with elevated ERK and Rho activity could be phenotypically reverted to tissues lacking focal adhesions if Rho-generated contractility or ERK activity was decreased. Thus, ERK and Rho constitute part of an integrated mechanoregulatory circuit linking matrix stiffness to cytoskeletal tension through integrins to regulate tissue phenotype.
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            Drug resistance and the solid tumor microenvironment.

            Olivier Trédan, Carlos M. Galmarini, Krupa Patel … (2007)
            Resistance of human tumors to anticancer drugs is most often ascribed to gene mutations, gene amplification, or epigenetic changes that influence the uptake, metabolism, or export of drugs from single cells. Another important yet little-appreciated cause of anticancer drug resistance is the limited ability of drugs to penetrate tumor tissue and to reach all of the tumor cells in a potentially lethal concentration. To reach all viable cells in the tumor, anticancer drugs must be delivered efficiently through the tumor vasculature, cross the vessel wall, and traverse the tumor tissue. In addition, heterogeneity within the tumor microenvironment leads to marked gradients in the rate of cell proliferation and to regions of hypoxia and acidity, all of which can influence the sensitivity of the tumor cells to drug treatment. In this review, we describe how the tumor microenvironment may be involved in the resistance of solid tumors to chemotherapy and discuss potential strategies to improve the effectiveness of drug treatment by modifying factors relating to the tumor microenvironment.
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              Nanomedicine in cancer therapy: challenges, opportunities, and clinical applications.

              Andreas Wicki, Dominik Witzigmann, Vimalkumar Balasubramanian … (2015)
              Cancer is a leading cause of death worldwide. Currently available therapies are inadequate and spur demand for improved technologies. Rapid growth in nanotechnology towards the development of nanomedicine products holds great promise to improve therapeutic strategies against cancer. Nanomedicine products represent an opportunity to achieve sophisticated targeting strategies and multi-functionality. They can improve the pharmacokinetic and pharmacodynamic profiles of conventional therapeutics and may thus optimize the efficacy of existing anti-cancer compounds. In this review, we discuss state-of-the-art nanoparticles and targeted systems that have been investigated in clinical studies. We emphasize the challenges faced in using nanomedicine products and translating them from a preclinical level to the clinical setting. Additionally, we cover aspects of nanocarrier engineering that may open up new opportunities for nanomedicine products in the clinic.
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                Author and article information

                Contributors
                Hyun Jung Kim: Role: Academic Editor
                Journal
                Journal ID (nlm-ta): Bioengineering (Basel)
                Journal ID (iso-abbrev): Bioengineering (Basel)
                Journal ID (publisher-id): bioengineering
                Title: Bioengineering
                Publisher: MDPI
                ISSN (Electronic): 2306-5354
                Publication date (Electronic): 21 July 2017
                Publication date Collection: September 2017
                Volume: 4
                Issue: 3
                Electronic Location Identifier: 64
                Affiliations
                [1 ]George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA; ahnjungho0513@ 123456gmail.com (J.A.); yoshi.john@ 123456gmail.com (Y.J.S.)
                [2 ]School of Mechanical and Aerospace Engineering, Seoul National University, Seoul 151-744, Korea; njeon@ 123456snu.ac.kr
                [3 ]Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA
                [4 ]Institute for Electronics and Nanotechnology, Georgia Institute of Technology, Atlanta, GA 30332, USA
                [5 ]Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA
                Author notes
                [* ]Correspondence: ytkim@ 123456gatech.edu ; Tel.: +1-404-385-1478
                Article
                Publisher ID: bioengineering-04-00064
                DOI: 10.3390/bioengineering4030064
                PMC ID: 5615310
                PubMed ID: 28952543
                SO-VID: 39761f0d-2f71-4ae7-9a55-9e99af7e1bdf
                Copyright © © 2017 by the authors.
                License:

                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
                Date received : 27 May 2017
                Date accepted : 19 July 2017
                Categories
                Subject: Review

                Keywords: organ-on-a-chip,microfluidics,in vitro disease models,tumor microenvironment,drug screening,nanomedicine
                Data availability:
                Keywords: organ-on-a-chip, microfluidics, in vitro disease models, tumor microenvironment, drug screening, nanomedicine

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