Molecular profiling and epigenetic alterations in pancreatic cancer and associated stromal cells.

摘要

Pancreatic cancer is one of the most highly invasive of the solid cancers and is characterized by an extensive desmoplastic stromal response. Mounting evidence suggests that cancer associated fibroblasts (CAFs), the predominant stromal cell type, actively communicate with and stimulate tumor cells, thereby contributing to tumor development and progression. CAFs adopt an activated phenotype during tumorigenesis, undergoing morphologic, functional, and gene expression changes relative to normal fibroblasts. These activated CAFs are characterized by enhanced contractile and secretory ability, and increased synthesis of collagens, extracellular matrix proteins and growth factors. Through these and other signals, CAFs interact intimately with tumor cells to promote their growth, and therefore CAFs are of considerable interest as a therapeutic target. Athough are the important role of CAFs in tumor growth and development is increasingly recognized, the molecular mechanisms underlying the CAF phenotype are not well understood. To better characterize pancreatic CAFs at the molecular level, we established primary cultures of cancer associated fibroblasts (CAFs) and control fibroblasts from human pancreatic adenocarcinomas and control tissues. We performed global genetic, epigenetic, and gene expression profiling of these pancreatic CAFs. We find that human pancreatic CAFs display normal allelotypes with no evidence of widespread genetic alteraltions. Epigenetic profiling reveals that pancreatic CAFs and control pancreatic fibroblasts are less responsive than cancer cells to 5-aza-dC-mediated gene reactivation, suggesting that DNA methylation is not the primary mechanism regulating gene expression changes in CAFs. Finally, we identify the Hedgehog receptor SMO as overexpressed in human pancreatic CAFs and present evidence of Hedgehog pathway activity in stromal cells derived from primary pancreatic adenocarcinomas. Taken together, these studies provide insight into the mechanisms regulating gene expression changes in CAFs and their contribution to pancreatic tumor growth. Further, they provide a resource for future studies of tumor-stromal interactions in pancreatic cancer.