Genomic profiling of tumor initiating prostatospheres
1 Cancer Stem Cell Section. Laboratory of Cancer Prevention. National Cancer Institute at Frederick, 1050 Boyles Street, Frederick, MD 21702, USA
2 Laboratorio de Interacciones Moleculares. Departamento de BiologÍa Molecular y Celular. Facultad de Ciencias. Universidad de la República, Iguá 4225, Montevideo 11400, Uruguay
3 Departamento de Genética. Facultad de Medicina. Universidad de la República, General Flores 2125, Montevideo 11800, Uruguay
4 Laboratory of Molecular Technology. Advanced Technology Program, SAIC-Frederick, Inc. National Cancer Institute at Frederick, 915 Toll House Avenue, Frederick, MD 21702, USA
5 Facultad de Ciencias. Universidad de la República, Iguá 4225, Montevideo 11400, Uruguay
6 Departamento de NeurobiologÍa Molecular y Celular. Instituto de Investigaciones Biológicas Clemente Estable, Avenida Italia 3318, Montevideo 11600, Uruguay
BMC Genomics 2010, 11:324 doi:10.1186/1471-2164-11-324Published: 25 May 2010
The cancer stem cell (CSC) hypothesis proposes that a population of tumor cells bearing stem cell properties is responsible for the origin and maintenance of tumors. Normal and cancer stem cells possess the ability to grow in vitro as self-renewing spheres, but the molecular basis of this phenotype remains largely unknown. We intended to establish a comprehensive culture system to grow prostatospheres (PSs) from both cancer cell lines and patient tumors. We then used gene expression microarrays to gain insight on the molecular pathways that sustain the PS tumor initiating cell (TIC) phenotype.
Traditional stem cell medium (SCM) supplemented with Knockout™SR (KO) allows the propagation of monoclonal PSs from cell lines and primary cells. PSs display gene expression and tumorigenicity hallmarks of TICs. Gene expression analysis defined a gene signature composed of 66 genes that characterize LNCaP and patient PSs. This set includes novel prostate TIC growth factors (NRP1, GDF1, JAG1), proteins implicated in cell adhesion and cytoskeletal maintenance, transcriptional regulators (MYCBP, MYBL1, ID1, ID3, FOS, ELF3, ELF4, KLF2, KLF5) and factors involved in protein biosynthesis and metabolism. Meta-analysis in Oncomine reveals that some of these genes correlate with prostate cancer status and/or progression. Reporter genes and inhibitors indicate that the Notch pathway contributes to prostatosphere growth.
We have developed a model for the culture of PSs, and provide a genomic profile that support CSCs identity. This signature identifies novel markers and pathways that are predicted to correlate with prostate cancer evolution.