Transforming Growth Factor-β Limits Secretion of Lumican by Activated Stellate Cells within Primary Pancreatic Adenocarcinoma Tumors.

Purpose:Pancreatic ductal adenocarcinoma (PDAC) is lethal cancer whose primary tumor is characterized by dense composition of cancer cells, stromal cells and extracellular matrix (ECM) composed largely of collagen. Within the PDAC tumor microenvironment, activated pancreatic stellate cells (PSC) are the dominant stromal cell type and responsible for collagen deposition. Lumican is a secreted proteoglycan that regulates collagen fibril assembly. We have previously identified that the presence of lumican in the ECM surrounding PDAC cells is associated with improved patient outcome after multimodal therapy and surgical removal of localized PDAC. Experimental Design: Lumican expression in PDAC from 27 patients was determined by IHC and quantitatively analyzed for co-localization with PSC. In vitro studies examined the molecular mechanisms of lumican transcription and secretion from PSC (HPSC, HPaSteC), and cell adhesion and migration assays examined the effect of lumican on PSC in a collagen-rich environment. Results: Here we identify PSC as a significant source of extracellular lumican production through quantitative IHC analysis. We demonstrate that the cytokine, transforming growth factor-β (TGF-β), negatively regulates lumican gene transcription within HPSC through its canonical signaling pathway and binding of SMAD4 to novel SBEs identified within the promoter region. Additionally, we found that the ability of HPSC to produce and secrete extracellular lumican significantly enhances HPSC adhesion and mobility on collagen. Conclusions: Our results demonstrate that activated pancreatic stellate cells within PDAC secrete lumican under the negative control of TGF-β; once secreted, the extracellular lumican enhances stellate cell adhesion and mobility in a collagen rich environment.