Abstract
BackgroundThe ability to selectively detect and target cancer cells that have undergone an epithelial-mesenchymal transition (EMT) may lead to improved methods to treat cancers such as pancreatic cancer. The remodeling of cellular glycosylation previously has been associated with cell differentiation and may represent a valuable class of molecular targets for EMT.Methodology/Principal FindingsAs a first step toward investigating the nature of glycosylation alterations in EMT, we characterized the expression of glycan-related genes in three in-vitro model systems that each represented a complementary aspect of pancreatic cancer EMT. These models included: 1) TGFβ-induced EMT, which provided a look at the active transition between states; 2) a panel of 22 pancreatic cancer cell lines, which represented terminal differentiation states of either epithelial-like or mesenchymal-like; and 3) actively-migrating and stationary cells, which provided a look at the mechanism of migration. We analyzed expression data from a list of 587 genes involved in glycosylation (biosynthesis, sugar transport, glycan-binding, etc.) or EMT. Glycogenes were altered at a higher prevalence than all other genes in the first two models (p<0.05 and <0.005, respectively) but not in the migration model. Several functional themes were shared between the induced-EMT model and the cell line panel, including alterations to matrix components and proteoglycans, the sulfation of glycosaminoglycans; mannose receptor family members; initiation of O-glycosylation; and certain forms of sialylation. Protein-level changes were confirmed by Western blot for the mannose receptor MRC2 and the O-glycosylation enzyme GALNT3, and cell-surface sulfation changes were confirmed using Alcian Blue staining.Conclusions/SignificanceAlterations to glycogenes are a major component of cancer EMT and are characterized by changes to matrix components, the sulfation of GAGs, mannose receptors, O-glycosylation, and specific sialylated structures. These results provide leads for targeting aggressive and drug resistant forms of pancreatic cancer cells.
Highlights
Pancreatic cancer has one of the poorest survival rates of any major cancer [1]
Early-stage and pre-malignant states are thought to consist of dysplastic cells within pancreatic ducts [5], and the progression to ductal adenocarcinoma is characterized by proliferating epithelial cancer cells assembled in tube-like ductal structures surrounded by fibrotic stroma
Glycogene expression in TGFb-induced epithelial-mesenchymal transition (EMT) The first model system in which we examined glycogene expression changes was TGFb induction of EMT in the cell lines Panc-1 and A549
Summary
Pancreatic cancer has one of the poorest survival rates of any major cancer [1]. The extreme lethality of pancreatic cancer is related to its tendency to disseminate at early stages prior to diagnosis [2,3] and its resistance to chemotherapeutics [2,4]. Early-stage and pre-malignant states are thought to consist of dysplastic cells within pancreatic ducts [5], and the progression to ductal adenocarcinoma is characterized by proliferating epithelial cancer cells assembled in tube-like ductal structures surrounded by fibrotic stroma. The metastatic dissemination of pancreatic cancer requires cells to break away from the epithelial ductal structures and take on characteristics of migratory, mesenchymal cells. This transition involves enormous remodeling of the cell and is likely driven by genetic aberrations, extracellular signals, and the activation of differentiation programs in the cancer cells. Characterizing the molecular alterations associated with the phenotypic switch in pancreatic cancer cells from epithelial-like to mesenchymal-like traits will provide insights into avenues for detecting and targeting this conversion.
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