RESUMO
BACKGROUND: There is a growing body of evidence indicating that epigenetic influences originating from stromal cells in the immediate microenvironment may play a role in carcinogenesis. Determining the molecular mechanisms involved in stromal-stem cell interaction could provide critical insight into prostate development and disease progression, particularly with regard to their relationship to and influence on the putative cancer stem cell. METHODS: Prostate and bladder stromal cells prepared from tissue specimens were co-cultured with the pluripotent embryonal carcinoma cell line NCCIT. Transcriptome analysis was used to characterize NCCIT cell response to prostate or bladder signaling. RESULTS: A systems approach demonstrated that prostate stromal cells were capable of inducing gene expression changes in NCCIT through secreted factors. Induction led to a loss of embryonic stem cell markers, with concurrent up-regulation of many genes characteristic of stromal mesenchyme cells as well as some of epithelial and cancer stem cells. Bladder stromal signaling produced gene expression changes different from those of prostate signaling. CONCLUSIONS: This study indicates that paracrine stromal cell signaling can affect cancer stem cell response in an organ-specific manner and may provide insight for future development of treatment strategies such as differentiation therapy.
Assuntos
Carcinoma Embrionário/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Próstata/metabolismo , Células Estromais/metabolismo , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Carcinoma Embrionário/genética , Carcinoma Embrionário/patologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Perfilação da Expressão Gênica , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Comunicação Parácrina/genética , Próstata/citologia , RNA Mensageiro/metabolismo , Células Estromais/citologia , Bexiga Urinária/citologia , Bexiga Urinária/metabolismoRESUMO
BACKGROUND: Prostate cancer cells in primary tumors have been typed CD10-/CD13-/CD24hi/CD26+/CD38lo/CD44-/CD104-. This CD phenotype suggests a lineage relationship between cancer cells and luminal cells. The Gleason grade of tumors is a descriptive of tumor glandular differentiation. Higher Gleason scores are associated with treatment failure. METHODS: CD26+ cancer cells were isolated from Gleason 3+3 (G3) and Gleason 4+4 (G4) tumors by cell sorting, and their gene expression or transcriptome was determined by Affymetrix DNA array analysis. Dataset analysis was used to determine gene expression similarities and differences between G3 and G4 as well as to prostate cancer cell lines and histologically normal prostate luminal cells. RESULTS: The G3 and G4 transcriptomes were compared to those of prostatic cell types of non-cancer, which included luminal, basal, stromal fibromuscular, and endothelial. A principal components analysis of the various transcriptome datasets indicated a closer relationship between luminal and G3 than luminal and G4. Dataset comparison also showed that the cancer transcriptomes differed substantially from those of prostate cancer cell lines. CONCLUSIONS: Genes differentially expressed in cancer are potential biomarkers for cancer detection, and those differentially expressed between G3 and G4 are potential biomarkers for disease stratification given that G4 cancer is associated with poor outcomes. Differentially expressed genes likely contribute to the prostate cancer phenotype and constitute the signatures of these particular cancer cell types.