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

Abstract

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

Distinctive properties of metastasis-initiating cells

“…ECM proteins, such as SPARC, also serve as messengers of cooperation to enhance invasion and metastasis ( Fig. 5B; Mateo et al 2014). In addition, heterotypic interactions among EMT and non-EMT cells have also been demonstrated to increase metastasis progression of hamster cheek pouch carcinoma cells (Tsuji et al 2008) as well as in xenograft models of prostate cancer metastasis (Celia-Terrassa et al 2012).…”

Fluorescent CSC models evidence that targeted nanomedicines improve treatment sensitivity of breast and colon cancer stem cells

“…Whether this depends on specific cell-to-cell interactions and molecular cross-talk communications, is still to be seen. This possibility however has been recently suggested by data showing that secretion of the matricellular protein SPARC by non-CSC modulates the metastatic capacity of CSC in prostate cancer models(23). Considerations aside, it is clear that preclinical validation of anticancer treatments requires the use of bulk tumor cell line models with stable populations of distinguishable CSC and non-CSC.…”

The secreted protein acidic and rich in cysteine is a critical mediator of cell death program induced by WIN/TRAIL combined treatment in osteosarcoma cells

“…Moreover, its expression is related to the ability to regulate processes such as bone formation, fibrosis and tissue repair (11). SPARC is differentially expressed in various tumors including breast and colorectal cancers, melanoma or glioma (12)(13)(14)(15)(16)(17). Many studies show that in cancer cells SPARC modulates proliferation, apoptosis, invasion and angiogenesis.…”