TY - JOUR
T1 - SPARC mediates metastatic cooperation between CSC and non-CSC prostate cancer cell subpopulations
AU - Mateo, Francesca
AU - Meca-Cortes, Oscar
AU - Celia-Terrassa, Toni
AU - Fernandez, Yolanda
AU - Abasolo, Ibane
AU - Sanchez-Cid, Lourdes
AU - Bermudo, Raquel
AU - Sagasta, Amaia
AU - Rodriguez-Carunchio, Leonardo
AU - Pons, Monica
AU - Canovas, Veronica
AU - Marin-Aguilera, Mercedes
AU - Mengual, Lourdes
AU - Alcaraz, Antonio
AU - Schwartz, Simo
AU - Mellado, Begona
AU - Aguilera, Kristina Y.
AU - Brekken, Rolf
AU - Fernandez, Pedro L.
AU - Paciucci, Rosanna
AU - Thomson, Timothy M.
PY - 2014/10/21
Y1 - 2014/10/21
N2 - 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.
AB - 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.
KW - SPARC
KW - Tumor heterogeneity
KW - Cell cooperation
KW - Metastasis
KW - EPITHELIAL-MESENCHYMAL TRANSITION
KW - MATRICELLULAR PROTEIN SPARC
KW - PROTEOMIC ANALYSIS
KW - MAMMARY-CARCINOMA
KW - CONDITIONED MEDIA
KW - TARGETING SPARC
KW - CYSTEINE SPARC
KW - TUMOR
KW - EXPRESSION
KW - GROWTH
U2 - 10.1186/1476-4598-13-237
DO - 10.1186/1476-4598-13-237
M3 - Article
SN - 1476-4598
VL - 13
JO - Molecular cancer
JF - Molecular cancer
M1 - 237
ER -
