Dr. Weeks’ Comment: Cancer STEM cells, as opposed to cancer TUMOR cells are the dangerous cancer cell. Now we know that the epigenetics and the paracrine interactions are what drive metastasis. Stop being distracted by cancer TUMOR cells (only these are killed by chemo and radiation) and focus on the lethal cancer STEM cells.
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, orM) 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.
Author: Francesca MateoÃ“scar Meca-CortÃ©sToni CeliÃ -TerrassaYolanda FernÃ¡ndezIbane AbasoloLourdes SÃ¡nchez-CidRaquel BermudoAmaia SagastaLeonardo RodrÃguez-CarunchioMÃ²nica PonsVerÃ³nica CÃ¡novasMercedes MarÃn-AguileraLourdes MengualAntonio AlcarazSi