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      Is Open Access

      Chemoresistance of Cancer Cells: Requirements of Tumor Microenvironment-mimicking In Vitro Models in Anti-Cancer Drug Development

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          Abstract

          For decades, scientists have been using two-dimensional cell culture platforms for high-throughput drug screening of anticancer drugs. Growing evidence indicates that the results of anti-cancer drug screening vary with the cell culture microenvironment, and this variation has been proposed as a reason for the high failure rate of clinical trials. Since the culture condition-dependent drug sensitivity of anti-cancer drugs may negatively impact the identification of clinically effective drug candidates, more reliable in vitro cancer platforms are urgently needed. In this review article, we provide an overview of how cell culture conditions can alter drug efficacy and highlight the importance of developing more reliable cancer drug testing platforms for use in the drug discovery process. The environmental factors that can alter drug delivery and efficacy are reviewed. Based on these observations of chemoresistant tumor physiology, we summarize the recent advances in the fabrication of in vitro cancer models and the model-dependent cytotoxicity of anti-cancer drugs, with a particular focus on engineered environmental factors in these platforms. It is believed that more physiologically relevant cancer models can revolutionize the drug discovery process.

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          Most cited references131

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          On the origin of cancer cells.

          O WARBURG (1956)
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            Tensional homeostasis and the malignant phenotype.

            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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              Hypoxia in cancer: significance and impact on clinical outcome.

              Hypoxia, a characteristic feature of locally advanced solid tumors, has emerged as a pivotal factor of the tumor (patho-)physiome since it can promote tumor progression and resistance to therapy. Hypoxia represents a "Janus face" in tumor biology because (a) it is associated with restrained proliferation, differentiation, necrosis or apoptosis, and (b) it can also lead to the development of an aggressive phenotype. Independent of standard prognostic factors, such as tumor stage and nodal status, hypoxia has been suggested as an adverse prognostic factor for patient outcome. Studies of tumor hypoxia involving the direct assessment of the oxygenation status have suggested worse disease-free survival for patients with hypoxic cervical cancers or soft tissue sarcomas. In head & neck cancers the studies suggest that hypoxia is prognostic for survival and local control. Technical limitations of the direct O(2) sensing technique have prompted the use of surrogate markers for tumor hypoxia, such as hypoxia-related endogenous proteins (e.g., HIF-1alpha, GLUT-1, CA IX) or exogenous bioreductive drugs. In many - albeit not in all - studies endogenous markers showed prognostic significance for patient outcome. The prognostic relevance of exogenous markers, however, appears to be limited. Noninvasive assessment of hypoxia using imaging techniques can be achieved with PET or SPECT detection of radiolabeled tracers or with MRI techniques (e.g., BOLD). Clinical experience with these methods regarding patient prognosis is so far only limited. In the clinical studies performed up until now, the lack of standardized treatment protocols, inconsistencies of the endpoints characterizing the oxygenation status and methodological differences (e.g., different immunohistochemical staining procedures) may compromise the power of the prognostic parameter used.
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                Author and article information

                Journal
                Theranostics
                Theranostics
                thno
                Theranostics
                Ivyspring International Publisher (Sydney )
                1838-7640
                2018
                22 October 2018
                : 8
                : 19
                : 5259-5275
                Affiliations
                [1 ]School of Integrative Engineering, Chung-Ang University, Seoul 06974, Republic of Korea
                [2 ]Center for BioMicrosystems, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
                [3 ]Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea
                [4 ]Division of Bioengineering, Incheon National University, Incheon, Republic of Korea
                [5 ]Department of Chemical and Biomolecular Engineering, Seoul National University of Science and Technology, Seoul, Republic of Korea
                Author notes
                ✉ Corresponding authors: Dr. Hong Nam Kim, Email: hongnam.kim@ 123456kist.re.kr ; Prof. Jonghoon Choi, Email: nanomed@ 123456cau.ac.kr

                Conflict of Interest: The authors declare no conflict of interest.

                Article
                thnov08p5259
                10.7150/thno.29098
                6276092
                30555545
                e05eb41c-7792-4d01-a83f-6590a3d6a7df
                © Ivyspring International Publisher

                This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.

                History
                : 8 August 2018
                : 4 October 2018
                Categories
                Review

                Molecular medicine
                chemoresistance,tumor microenvironment,cancer cell,biomimetic,efficacy
                Molecular medicine
                chemoresistance, tumor microenvironment, cancer cell, biomimetic, efficacy

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