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      Interactions in the (Pre)metastatic Niche Support Metastasis Formation

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          Abstract

          Metastasis formation is the leading cause of death in cancer patients. Thus, understanding and targeting this process is an unmet need. Crucial steps during the establishment of metastases include the (pre)metastatic niche formation. This process relies on the interaction of the primary tumor with the environment of distant organs (premetastatic niche) and the interaction of cancer cells with their environment when arriving in a distant organ (metastatic niche). Here, we summarize the current knowledge on the interactions in the tumor environment that result in (pre)metastatic niche formation, specifically in the context of tumor secreted factors, extracellular matrix, immune as well as stromal cells, and nutrient availability. We further highlight strategies to disrupt these interactions as therapeutic interventions against metastases.

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          Most cited references47

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          The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis.

          Recent pre-clinical and clinical research has provided evidence that cancer progression is driven not only by a tumour's underlying genetic alterations and paracrine interactions within the tumour microenvironment, but also by complex systemic processes. We review these emerging paradigms of cancer pathophysiology and discuss how a clearer understanding of systemic regulation of cancer progression could guide development of new therapeutic modalities and efforts to prevent disease relapse following initial diagnosis and treatment.
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            Control of Metastasis by NK Cells.

            The metastatic spread of malignant cells to distant anatomical locations is a prominent cause of cancer-related death. Metastasis is governed by cancer-cell-intrinsic mechanisms that enable neoplastic cells to invade the local microenvironment, reach the circulation, and colonize distant sites, including the so-called epithelial-to-mesenchymal transition. Moreover, metastasis is regulated by microenvironmental and systemic processes, such as immunosurveillance. Here, we outline the cancer-cell-intrinsic and -extrinsic factors that regulate metastasis, discuss the key role of natural killer (NK) cells in the control of metastatic dissemination, and present potential therapeutic approaches to prevent or target metastatic disease by harnessing NK cells.
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              Patrolling monocytes control tumor metastasis to the lung.

              The immune system plays an important role in regulating tumor growth and metastasis. Classical monocytes promote tumorigenesis and cancer metastasis, but how nonclassical "patrolling" monocytes (PMo) interact with tumors is unknown. Here we show that PMo are enriched in the microvasculature of the lung and reduce tumor metastasis to lung in multiple mouse metastatic tumor models. Nr4a1-deficient mice, which specifically lack PMo, showed increased lung metastasis in vivo. Transfer of Nr4a1-proficient PMo into Nr4a1-deficient mice prevented tumor invasion in the lung. PMo established early interactions with metastasizing tumor cells, scavenged tumor material from the lung vasculature, and promoted natural killer cell recruitment and activation. Thus, PMo contribute to cancer immunosurveillance and may be targets for cancer immunotherapy.
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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                24 April 2019
                2019
                : 9
                : 219
                Affiliations
                [1] 1Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB , Leuven, Belgium
                [2] 2Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute , Leuven, Belgium
                Author notes

                Edited by: Andreas Pircher, Innsbruck Medical University, Austria

                Reviewed by: Michael P. Lisanti, University of Salford, United Kingdom; Ubaldo Emilio Martinez-Outschoorn, Thomas Jefferson University, United States

                *Correspondence: Sarah-Maria Fendt sarah-maria.fendt@ 123456kuleuven.vib.be

                This article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Oncology

                †These authors have contributed equally to this work

                Article
                10.3389/fonc.2019.00219
                6491570
                31069166
                cdfcc743-ada0-4e6f-b1d8-5027f78c0fca
                Copyright © 2019 Doglioni, Parik and Fendt.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 09 December 2018
                : 12 March 2019
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 88, Pages: 7, Words: 6041
                Categories
                Oncology
                Mini Review

                Oncology & Radiotherapy
                metastatic niche,premetastatic niche,tumor environment,immune cells,stromal cells,extracellular matrix,nutrient environment,tumor secreted factors

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