title: SPARC mediates metastatic cooperation between CSC and non-CSC prostate cancer cell subpopulations.
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.
authors.forename: Francesca
authors.initials: F
authors.lastname: Mateo
authors.forename: Oscar
authors.initials: O
authors.lastname: Meca-Cortés
authors.forename: Toni
authors.initials: T
authors.lastname: Celià-Terrassa
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Fernández
authors.forename: Ibane
authors.initials: I
authors.lastname: Abasolo
authors.forename: Lourdes
authors.initials: L
authors.lastname: Sánchez-Cid
authors.forename: Raquel
authors.initials: R
authors.lastname: Bermudo
authors.forename: Amaia
authors.initials: A
authors.lastname: Sagasta
authors.forename: Leonardo
authors.initials: L
authors.lastname: Rodríguez-Carunchio
authors.forename: Mònica
authors.initials: M
authors.lastname: Pons
authors.forename: Verónica
authors.initials: V
authors.lastname: Cánovas
authors.forename: Mercedes
authors.initials: M
authors.lastname: Marín-Aguilera
authors.forename: Lourdes
authors.initials: L
authors.lastname: Mengual
authors.forename: Antonio
authors.initials: A
authors.lastname: Alcaraz
authors.forename: Simó
authors.initials: S
authors.lastname: Schwartz
authors.forename: Begoña
authors.initials: B
authors.lastname: Mellado
authors.forename: Kristina Y
authors.initials: KY
authors.lastname: Aguilera
authors.forename: Rolf
authors.initials: R
authors.lastname: Brekken
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Fernández
authors.forename: Rosanna
authors.initials: R
authors.lastname: Paciucci
authors.affiliation: Department of Cell Biology, Molecular Biology Institute of Barcelona, National Research Council (CSIC), c, Baldiri Reixac 15-21, Barcelona 08028, Spain. titbmc@ibmb.csic.es.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Thomson
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004848:Epithelium / Q000187:drug effects / Q000473:pathology; D005110:Extracellular Space / Q000378:metabolism; D006801:Humans; D008207:Lymphatic Metastasis / Q000473:pathology*; D008297:Male; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D015676:Osteonectin / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*
chemical_list: D017077:Culture Media, Conditioned; D015676:Osteonectin