Abstract
BackgroundProstate cancer is characterized by heterogeneity in the clinical course that often does not correlate with morphologic features of the tumor. Metastasis reflects the most adverse outcome of prostate cancer, and to date there are no reliable morphologic features or serum biomarkers that can reliably predict which patients are at higher risk of developing metastatic disease. Understanding the differences in the biology of metastatic and organ confined primary tumors is essential for developing new prognostic markers and therapeutic targets.MethodsUsing Affymetrix oligonucleotide arrays, we analyzed gene expression profiles of 24 androgen-ablation resistant metastatic samples obtained from 4 patients and a previously published dataset of 64 primary prostate tumor samples. Differential gene expression was analyzed after removing potentially uninformative stromal genes, addressing the differences in cellular content between primary and metastatic tumors.ResultsThe metastatic samples are highly heterogenous in expression; however, differential expression analysis shows that 415 genes are upregulated and 364 genes are downregulated at least 2 fold in every patient with metastasis. The expression profile of metastatic samples reveals changes in expression of a unique set of genes representing both the androgen ablation related pathways and other metastasis related gene networks such as cell adhesion, bone remodelling and cell cycle. The differentially expressed genes include metabolic enzymes, transcription factors such as Forkhead Box M1 (FoxM1) and cell adhesion molecules such as Osteopontin (SPP1).ConclusionWe hypothesize that these genes have a role in the biology of metastatic disease and that they represent potential therapeutic targets for prostate cancer.
Highlights
Prostate cancer is characterized by heterogeneity in the clinical course that often does not correlate with morphologic features of the tumor
Since only the epithelial component of prostate cancer is present in metastatic tumors, this result most likely reflects the lack of stroma in metastases, and not a true down-regulation of these genes in the metastatic epithelial cells
Our study shows that a number of biological processes including cell adhesion, cell cycle and transcription regulation are altered in metastatic disease when compared to primary tumors, and point to specific transcripts that participate in the metastatic process
Summary
Prostate cancer is characterized by heterogeneity in the clinical course that often does not correlate with morphologic features of the tumor. Metastasis reflects the most adverse outcome of prostate cancer, and to date there are no reliable morphologic features or serum biomarkers that can reliably predict which patients are at higher risk of developing metastatic disease. Disruption of a complex set of biological processes must occur in order for tumor cells to leave the prostate and establish themselves in a different environment. Their altered interaction with the prostate microenvironment, including the stroma and extracellular matrix, their ability to migrate into the vasculature and establish themselves in secondary organs with recruitment of vascular supply represent disruption of normal cellular processes [3]. Understanding the molecular events involved in the development of metastatic prostate cancer has the potential to identify biological determinants that can aid in prognosis and development of more effective therapies
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