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      SPARCL1 suppresses osteosarcoma metastasis and recruits macrophages by activation of canonical WNT/β-catenin signaling through stabilization of the WNT–receptor complex

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          Abstract

          Metastasis significantly reduces the survival rate of osteosarcoma (OS) patients. Therefore, identification of novel targets remains extremely important to prevent metastasis and treat OS. In this report, we show that SPARCL1 is downregulated in OS by epigenetic methylation of promoter DNA. In vitro and in vivo experiments revealed that SPARCL1 inhibits OS metastasis. We further demonstrated that SPARCL1-activated WNT/β-catenin signaling by physical interaction with various frizzled receptors and lipoprotein receptor-related protein 5/6, leading to WNT–receptor complex stabilization. Activation of WNT/β-catenin signaling contributes to the SPARCL1-mediated inhibitory effects on OS metastasis. Furthermore, we uncovered a paracrine effect of SPARCL1 on macrophage recruitment through activated WNT/β-catenin signaling-mediated secretion of chemokine ligand5 from OS cells. These findings suggest that the targeting of SPARCL1 as a new anti-metastatic strategy for OS patients.

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          Macrophage regulation of tumor responses to anticancer therapies.

          Michele De Palma, Claire Lewis (2013)
          Tumor-associated macrophages (TAMs) promote key processes in tumor progression, like angiogenesis, immunosuppression, invasion, and metastasis. Increasing studies have also shown that TAMs can either enhance or antagonize the antitumor efficacy of cytotoxic chemotherapy, cancer-cell targeting antibodies, and immunotherapeutic agents--depending on the type of treatment and tumor model. TAMs also drive reparative mechanisms in tumors after radiotherapy or treatment with vascular-targeting agents. Here, we discuss the biological significance and clinical implications of these findings, with an emphasis on novel approaches that effectively target TAMs to increase the efficacy of such therapies. Copyright © 2013 Elsevier Inc. All rights reserved.
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            Macrophages in Tumor Microenvironments and the Progression of Tumors

            Zhiren Zhang, Ning-Bo Hao, Mu-Han Lü … (2012)
            Macrophages are widely distributed innate immune cells that play indispensable roles in the innate and adaptive immune response to pathogens and in-tissue homeostasis. Macrophages can be activated by a variety of stimuli and polarized to functionally different phenotypes. Two distinct subsets of macrophages have been proposed, including classically activated (M1) and alternatively activated (M2) macrophages. M1 macrophages express a series of proinflammatory cytokines, chemokines, and effector molecules, such as IL-12, IL-23, TNF- α , iNOS and MHCI/II. In contrast, M2 macrophages express a wide array of anti-inflammatory molecules, such as IL-10, TGF- β , and arginase1. In most tumors, the infiltrated macrophages are considered to be of the M2 phenotype, which provides an immunosuppressive microenvironment for tumor growth. Furthermore, tumor-associated macrophages secrete many cytokines, chemokines, and proteases, which promote tumor angiogenesis, growth, metastasis, and immunosuppression. Recently, it was also found that tumor-associated macrophages interact with cancer stem cells. This interaction leads to tumorigenesis, metastasis, and drug resistance. So mediating macrophage to resist tumors is considered to be potential therapy.
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              LDL-receptor-related proteins in Wnt signal transduction.

              K. Tamai, M. Semenov, Y Kato … (2000)
              The Wnt family of secreted signalling molecules are essential in embryo development and tumour formation. The Frizzled (Fz) family of serpentine receptors function as Wnt receptors, but how Fz proteins transduce signalling is not understood. In Drosophila, arrow phenocopies the wingless (DWnt-1) phenotype, and encodes a transmembrane protein that is homologous to two members of the mammalian low-density lipoprotein receptor (LDLR)-related protein (LRP) family, LRP5 and LRP6 (refs 12-15). Here we report that LRP6 functions as a co-receptor for Wnt signal transduction. In Xenopus embryos, LRP6 activated Wnt-Fz signalling, and induced Wnt responsive genes, dorsal axis duplication and neural crest formation. An LRP6 mutant lacking the carboxyl intracellular domain blocked signalling by Wnt or Wnt-Fz, but not by Dishevelled or beta-catenin, and inhibited neural crest development. The extracellular domain of LRP6 bound Wnt-1 and associated with Fz in a Wnt-dependent manner. Our results indicate that LRP6 may be a component of the Wnt receptor complex.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Oncogene
                Journal ID (iso-abbrev): Oncogene
                Title: Oncogene
                Publisher: Nature Publishing Group
                ISSN (Print): 0950-9232
                ISSN (Electronic): 1476-5594
                Publication date (Print): 22 February 2018
                Publication date (Electronic): 30 October 2017
                Volume: 37
                Issue: 8
                Pages: 1049-1061
                Affiliations
                [1 ]Department of Orthopedics, the Affiliated Hospital of Nanjing Medical University, Changzhou No.2 People’s Hospital , Changzhou, Jiangsu, China
                [2 ]State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai, China
                [3 ]Department of Obstetrics and Gynecology, Fengxian Hospital, Southern Medical University , Shanghai, China
                [4 ]Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital , Shanghai, China
                Author notes
                [* ]Department of Orthopedics, the Affiliated Hospital of Nanjing Medical University, Changzhou No.2 People’s Hospital , Changzhou, Jiangsu 213003, China. E-mail: zhoudong1012@ 123456hotmail.com or zzhang@ 123456shsci.org
                [5]

                These authors contributed equally to this work.

                Article
                Publisher Item ID: onc2017403
                DOI: 10.1038/onc.2017.403
                PMC ID: 5851113
                PubMed ID: 29084211
                SO-VID: 4432c21e-5563-40c4-97c6-92ab9c29923e
                Copyright © Copyright © 2018 The Author(s)
                License:

                This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/

                History
                Date received : 25 January 2017
                Date revision received : 09 August 2017
                Date accepted : 15 September 2017
                Categories
                Subject: Original Article

                ScienceOpen disciplines: Oncology & Radiotherapy
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy

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