1. SPARC mediates metastatic cooperation between CSC and non-CSC prostate cancer cell subpopulations
- Author
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Pedro L. Fernández, Begoña Mellado, Mònica Pons, Lourdes Mengual, Kristina Y. Aguilera, Timothy M. Thomson, Lourdes Sánchez-Cid, Francesca Mateo, Verónica Cánovas, Amaia Sagasta, Leonardo Rodriguez-Carunchio, Raquel Bermudo, Simó Schwartz, Toni Celià-Terrassa, Rosanna Paciucci, Yolanda Fernández, Ibane Abasolo, Rolf A. Brekken, Óscar Meca-Cortés, Mercedes Marín-Aguilera, Antonio Alcaraz, Universitat de Barcelona, Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), Institut d'Investigacions Biomèdiques August Pi i Sunyer, Ministerio de Ciencia e Innovación (España), Generalitat de Catalunya, and CSIC - Unidad de Recursos de Información Científica para la Investigación (URICI)
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Tumor heterogeneity ,Cancer Research ,Epithelium ,Metastasis ,Prostate cancer ,Paracrine signalling ,Metàstasi ,Cancer stem cell ,Cell Line, Tumor ,medicine ,Humans ,Neoplasm Invasiveness ,Osteonectin ,Cell Proliferation ,Cell cooperation ,biology ,Càncer de pròstata ,Cell growth ,Research ,Marcadors tumorals ,Prostatic Neoplasms ,Cancer ,SPARC ,medicine.disease ,Oncology ,Tumor progression ,Culture Media, Conditioned ,Lymphatic Metastasis ,Tumor markers ,Neoplastic Stem Cells ,biology.protein ,Cancer research ,Molecular Medicine ,Extracellular Space - Abstract
Francesca Mateo et al., [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. © 2014 Mateo et al.; licensee BioMed Central Ltd., FM is a Juan de la Cierva Investigator, OM is a FPU Fellow from the Spanish Ministries of Science and Innovation (MICINN) and Economy and Competitiveness (MINECO) and LS is the recipient of a IDIBAPS fellowship. This work was supported by grants to TMT from MICINN (SAF2011-24686) and MINECO (SAF2012-40017-C02-01), Catalan Agència d’Ajuts Universitaris i de Recerca (AGAUR; 2009SGR1482), and Xarxa de Referència en Biotecnologia; to RP from Instituto de Salud Carlos III (ISCIII; RETICS RD06-0020/0058) and MICINN (SAF2011-30496); to IA from MINECO (PI11/079 and IPT-090000-2010-001; the latter cofinanced by the European Regional Development Fund) and AGAUR (SGR157); and to PLF from MICINN (FIS-PI080274) and MINECO (SAF2012-40017-C02-02). The Hospital Clínic-IDIBAPS Biobank is part of the Xarxa de Bancs de Tumors de Catalunya (XBTC), financed by the Pla Director d’Oncologia de Catalunya, and the Red Nacional de Biobancos (RNBB, ReTBioH), financed by the ISCIII (RETICS RD09-0076/0038), We acknowledge support by the CSIC Open Access Publication Initiative through its Unit of Information Resources for Research (URICI)
- Published
- 2014