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      SPARC mediates metastatic cooperation between CSC and non-CSC prostate cancer cell subpopulations

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          Abstract

          Background

          Tumor cell subpopulations can either compete with each other for nutrients and physical space within the tumor niche, or co-operate for enhanced survival, or replicative or metastatic capacities. Recently, we have described co-operative interactions between two clonal subpopulations derived from the PC-3 prostate cancer cell line, in which the invasiveness of a cancer stem cell (CSC)-enriched subpopulation (PC-3M, or M) is enhanced by a non-CSC subpopulation (PC-3S, or S), resulting in their accelerated metastatic dissemination.

          Methods

          M and S secretomes were compared by SILAC (Stable Isotope Labeling by Aminoacids in Cell Culture). Invasive potential in vitro of M cells was analyzed by Transwell-Matrigel assays. M cells were co-injected with S cells in the dorsal prostate of immunodeficient mice and monitored by bioluminescence for tumor growth and metastatic dissemination. SPARC levels were determined by immunohistochemistry and real-time RT-PCR in tumors and by ELISA in plasma from patients with metastatic or non-metastatic prostate cancer.

          Results

          Comparative secretome analysis yielded 213 proteins differentially secreted between M and S cells. Of these, the protein most abundantly secreted in S relative to M cells was SPARC. Immunodepletion of SPARC inhibited the enhanced invasiveness of M induced by S conditioned medium. Knock down of SPARC in S cells abrogated the capacity of its conditioned medium to enhance the in vitro invasiveness of M cells and compromised their potential to boost the metastatic behavior of M cells in vivo. In most primary human prostate cancer samples, SPARC was expressed in the epithelial tumoral compartment of metastatic cases.

          Conclusions

          The matricellular protein SPARC, secreted by a prostate cancer clonal tumor cell subpopulation displaying non-CSC properties, is a critical mediator of paracrine effects exerted on a distinct tumor cell subpopulation enriched in CSC. This paracrine interaction results in an enhanced metastatic behavior of the CSC-enriched tumor subpopulation. SPARC is expressed in the neoplastic cells of primary prostate cancer samples from metastatic cases, and could thus constitute a tumor progression biomarker and a therapeutic target in advanced prostate cancer.

          Electronic supplementary material

          The online version of this article (doi:10.1186/1476-4598-13-237) contains supplementary material, which is available to authorized users.

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          Most cited references48

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          Epithelial-mesenchymal transition can suppress major attributes of human epithelial tumor-initiating cells.

          Malignant progression in cancer requires populations of tumor-initiating cells (TICs) endowed with unlimited self renewal, survival under stress, and establishment of distant metastases. Additionally, the acquisition of invasive properties driven by epithelial-mesenchymal transition (EMT) is critical for the evolution of neoplastic cells into fully metastatic populations. Here, we characterize 2 human cellular models derived from prostate and bladder cancer cell lines to better understand the relationship between TIC and EMT programs in local invasiveness and distant metastasis. The model tumor subpopulations that expressed a strong epithelial gene program were enriched in highly metastatic TICs, while a second subpopulation with stable mesenchymal traits was impoverished in TICs. Constitutive overexpression of the transcription factor Snai1 in the epithelial/TIC-enriched populations engaged a mesenchymal gene program and suppressed their self renewal and metastatic phenotypes. Conversely, knockdown of EMT factors in the mesenchymal-like prostate cancer cell subpopulation caused a gain in epithelial features and properties of TICs. Both tumor cell subpopulations cooperated so that the nonmetastatic mesenchymal-like prostate cancer subpopulation enhanced the in vitro invasiveness of the metastatic epithelial subpopulation and, in vivo, promoted the escape of the latter from primary implantation sites and accelerated their metastatic colonization. Our models provide new insights into how dynamic interactions among epithelial, self-renewal, and mesenchymal gene programs determine the plasticity of epithelial TICs.
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            The urokinase-type plasminogen activator system in cancer metastasis: a review.

            The urokinase-type plasminogen activator (u-PA) system consists of the serine proteinases plasmin and u-PA; the serpin inhibitors alpha2-anti-plasmin, PAI-1 and PAI-2; and the u-PA receptor (u-PAR). Two lines of evidence have strongly suggested an important and apparently causal role for the u-PA system in cancer metastasis: results from experimental model systems with animal tumor metastasis and the finding that high levels of u-PA, PAI-1 and u-PAR in many tumor types predict poor patient prognosis. We discuss here recent observations related to the molecular and cellular mechanisms underlying this role of the u-PA system. Many findings suggest that the system does not support tumor metastasis by the unrestricted enzyme activity of u-PA and plasmin. Rather, pericellular molecular and functional interactions between u-PA, u-PAR, PAI-1, extracellular matrix proteins, integrins, endocytosis receptors and growth factors appear to allow temporal and spatial re-organizations of the system during cell migration and a selective degradation of extracellular matrix proteins during invasion. Differential expression of components of the system by cancer and non-cancer cells, regulated by paracrine mechanisms, appear to determine the involvement of the system in cancer cell-directed tissue remodeling. A detailed knowledge of these processes is necessary for utilization of the therapeutic potential of interfering with the action of the system in cancers.
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              Epithelial-mesenchymal transition and cell cooperativity in metastasis.

              The role of epithelial-mesenchymal transition (EMT) in metastasis remains controversial. EMT has been postulated as an absolute requirement for tumor invasion and metastasis. Three different models including incomplete EMT, mesenchymal-epithelial transition (MET), and collective migration have been proposed for the role of EMT in cancer invasion and metastasis. However, skepticism remains about whether EMT truly occurs during cancer progression, and if it does, whether it plays an indispensible role in metastasis. Our recent findings suggest that EMT cells are responsible for degrading the surrounding matrix to enable invasion and intravasation of both EMT and non-EMT cells. Only non-EMT cells that have entered the blood stream are able to re-establish colonies in the secondary sites. Here, we discuss an alternative model for the role of EMT in cancer metastasis in which EMT and non-EMT cells cooperate to complete the entire process of spontaneous metastasis.
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                Author and article information

                Contributors
                fmgbmc@ibmb.csic.es
                omcbmc@ibmb.csic.es
                acelia@princeton.edu
                yolanda.fernandez.amurgo@vhir.org
                ibane.abasolo@vhir.org
                MLSANCHE@clinic.ub.es
                raquel.bermudo@idibaps.org
                ASAGASTA@clinic.ub.es
                lerodrig@clinic.ub.es
                mppbmc@ibmb.csic.es
                veronica.canovas@vhir.org
                MMARIN1@clinic.ub.es
                lmengual@ub.edu
                aalcaraz@clinic.ub.es
                simo.schwartz@vhir.org
                bmellado@clinic.ub.es
                kristina.aguilera@utsouthwestern.edu
                Rolf.Brekken@utsouthwestern.edu
                plfernan@clinic.ub.es
                rosanna.paciucci@vhir.org
                titbmc@ibmb.csic.es
                Journal
                Mol Cancer
                Mol. Cancer
                Molecular Cancer
                BioMed Central (London )
                1476-4598
                21 October 2014
                21 October 2014
                2014
                : 13
                : 1
                : 237
                Affiliations
                [ ]Department of Cell Biology, Molecular Biology Institute of Barcelona, National Research Council (CSIC), c. Baldiri Reixac 15-21, Barcelona, 08028 Spain
                [ ]Networking Research Centre for Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, Zaragoza, 50018 Spain
                [ ]Functional Validation and Preclinical Research, CIBBIM-Nanomedicine, Vall d’Hebron Research Institute, Barcelona, 08035 Spain
                [ ]Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, 08034 Spain
                [ ]Department of Pathology, Hospital Clínic, Barcelona, 08034 Spain
                [ ]Biomedical Research and Translational Oncology Unit, Vall d’Hebron Research Institute, Barcelona, 08035 Spain
                [ ]Department of Oncology, Hospital Clínic, Barcelona, 08034 Spain
                [ ]Laboratory and Department of Urology, Hospital Clínic, Barcelona, 08034 Spain
                [ ]Division of Surgical Oncology, Department of Surgery, Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX 75229 USA
                [ ]Universitat de Barcelona, Barcelona, 08034 Spain
                [ ]Department of Molecular Biology, Princeton University, Princeton, NJ 08544-1014 USA
                Article
                1437
                10.1186/1476-4598-13-237
                4210604
                25331979
                e2935155-cc01-4192-b62b-0bf5caa07573
                © Mateo et al.; licensee BioMed Central Ltd. 2014

                This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 10 February 2014
                : 8 October 2014
                Categories
                Research
                Custom metadata
                © The Author(s) 2014

                Oncology & Radiotherapy
                sparc,tumor heterogeneity,cell cooperation,metastasis
                Oncology & Radiotherapy
                sparc, tumor heterogeneity, cell cooperation, metastasis

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