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      Revisiting ovarian cancer microenvironment: a friend or a foe?

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          Abstract

          Development of ovarian cancer involves the co-evolution of neoplastic cells together with the adjacent microenvironment. Steps of malignant progression including primary tumor outgrowth, therapeutic resistance, and distant metastasis are not determined solely by genetic alterations in ovarian cancer cells, but considerably shaped by the fitness advantage conferred by benign components in the ovarian stroma. As the dynamic cancer topography varies drastically during disease progression, heterologous cell types within the tumor microenvironment (TME) can actively determine the pathological track of ovarian cancer. Resembling many other solid tumor types, ovarian malignancy is nurtured by a TME whose dark side may have been overlooked, rather than overestimated. Further, harnessing breakthrough and targeting cures in human ovarian cancer requires insightful understanding of the merits and drawbacks of current treatment modalities, which mainly target transformed cells. Thus, designing novel and precise strategies that both eliminate cancer cells and manipulate the TME is increasingly recognized as a rational avenue to improve therapeutic outcome and prevent disease deterioration of ovarian cancer patients.

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          Most cited references102

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          Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha.

          The stromal microenvironment of tumors, which is a mixture of hematopoietic and mesenchymal cells, suppresses immune control of tumor growth. A stromal cell type that was first identified in human cancers expresses fibroblast activation protein-α (FAP). We created a transgenic mouse in which FAP-expressing cells can be ablated. Depletion of FAP-expressing cells, which made up only 2% of all tumor cells in established Lewis lung carcinomas, caused rapid hypoxic necrosis of both cancer and stromal cells in immunogenic tumors by a process involving interferon-γ and tumor necrosis factor-α. Depleting FAP-expressing cells in a subcutaneous model of pancreatic ductal adenocarcinoma also permitted immunological control of growth. Therefore, FAP-expressing cells are a nonredundant, immune-suppressive component of the tumor microenvironment.
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            Extracellular vesicles round off communication in the nervous system.

            Functional neural competence and integrity require interactive exchanges among sensory and motor neurons, interneurons and glial cells. Recent studies have attributed some of the tasks needed for these exchanges to extracellular vesicles (such as exosomes and microvesicles), which are most prominently involved in shuttling reciprocal signals between myelinating glia and neurons, thus promoting neuronal survival, the immune response mediated by microglia, and synapse assembly and plasticity. Such vesicles have also been identified as important factors in the spread of neurodegenerative disorders and brain cancer. These extracellular vesicle functions add a previously unrecognized level of complexity to transcellular interactions within the nervous system.
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              Tumor-associated stromal cells as key contributors to the tumor microenvironment

              The tumor microenvironment is a heterogeneous population of cells consisting of the tumor bulk plus supporting cells. It is becoming increasingly evident that these supporting cells are recruited by cancer cells from nearby endogenous host stroma and promote events such as tumor angiogenesis, proliferation, invasion, and metastasis, as well as mediate mechanisms of therapeutic resistance. In addition, recruited stromal cells range in type and include vascular endothelial cells, pericytes, adipocytes, fibroblasts, and bone-marrow mesenchymal stromal cells. During normal wound healing and inflammatory processes, local stromal cells change their phenotype to become that of reactive stroma. Under certain conditions, however, tumor cells can co-opt these reactive stromal cells and further transition them into tumor-associated stromal cells (TASCs). These TASCs express higher levels of proteins, including alpha-smooth muscle actin, fibroblast activating protein, and matrix metalloproteinases, compared with their normal, non-reactive counterparts. TASCs are also known to secrete many pro-tumorigenic factors, including IL-6, IL-8, stromal-derived factor-1 alpha, vascular endothelial growth factor, tenascin-C, and matrix metalloproteinases, among others, which recruit additional tumor and pro-tumorigenic cells to the developing microenvironment. Here, we review the current literature pertaining to the origins of recruited host stroma, contributions toward tumor progression, tumor-associated stromal cells, and mechanisms of crosstalk between endogenous host stroma and tumor cells.
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                Author and article information

                Contributors
                sunyu@sibs.ac.cn
                Journal
                Protein Cell
                Protein Cell
                Protein & Cell
                Higher Education Press (Beijing )
                1674-800X
                1674-8018
                19 September 2017
                19 September 2017
                August 2018
                : 9
                : 8
                : 674-692
                Affiliations
                [1 ]ISNI 0000 0004 1797 8419, GRID grid.410726.6, Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, , University of Chinese Academy of Sciences, ; Shanghai, 200031 China
                [2 ]ISNI 0000 0004 0368 8293, GRID grid.16821.3c, Institute of Health Sciences, Shanghai Jiao Tong University, School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, ; Shanghai, 200031 China
                [3 ]ISNI 0000000122986657, GRID grid.34477.33, Department of Medicine and VAPSHCS, , University of Washington, ; Seattle, WA 98195 USA
                Author information
                http://orcid.org/0000-0001-7121-9112
                Article
                466
                10.1007/s13238-017-0466-7
                6053350
                28929459
                f3217b8f-70ab-4a60-8f5d-62e057462ad4
                © The Author(s) 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 6 July 2017
                : 21 August 2017
                Categories
                Review
                Custom metadata
                © HEP and Springer-Verlag GmbH Germany, part of Springer Nature 2018

                ovarian cancer,stromal cells,tumor microenvironment,therapeutic resistance,ectopic metastasis,combinational treatment,patient stratification

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