Potential targets in prostate tumor–associated stroma

Abstract

15529 Background: The past 20 years have seen a shift in the paradigm that the stromal compartment in tissues is merely a passive, supporting tissue for epithelial cells. Recent evidence shows that it plays a critical role not only in normal tissue development and homeostasis, but also in the progression of cancer. Further, as the stromal compartment is more readily accessible to vascular-delivered agents, this region might be particularly amenable to clinical intervention. As such, a broad-based study of the carcinoma-associated changes in stromal cells from patient samples could yield a wealth of information on the molecular mechansisms of tumorigenesis, and identify clinically important molecular targets. Methods: Five whole-mount frozen prostatectomy specimens were microdissected in four regions: normal epithelium, tumor epithelium, normal stroma, and tumor-associated stroma. Extracted and amplified mRNA was hybridized to the Human Genome U133 Plus 2.0 GeneChip (Affymetrix). Using the intersection of two statistical analysis packages (GCOS and RMA), we identified differentially expressed genes between the dissection groups. Quantitative RT-PCR was used to validate selected transcripts and immunohistochemistry to evaluate potential stromal molecular targets. Results: Tumor-associated stroma showed a distinctly different expression pattern compared to normal stroma with 675 differentially expressed transcripts, the majority of which were up-regulated. In contrast, tumor epithelium showed more down-regulation in the 829 transcripts that were differentially expressed relative to normal epithelium. Classes of up-regulated genes in the tumor-associated stroma showed a strong linkage to cell adhesion and migration as well as the calcium, MAPK, and TGF-beta signaling pathways. Quantitative RT-PCR was conducted to verify GeneChip findings and revealed over 80% concordance with the original data. Immunohistochemical staining further supported the expression differences. Conclusions: Global mRNA expression analysis of stromal cells within tumors provides insight into prostate cancer progression, and yields novel targets for future diagnostic and therapeutic intervention. No significant financial relationships to disclose.