Abstract
Pancreatic ductal adenocarcinoma (PDAC) is thought to originate from ductal structures, exhibiting strong desmoplastic reaction with stromal pancreatic myofibroblasts (PMF), which are supposed to drive PDAC tumorigenesis. Previously, we observed high expression of the adhesion molecule L1CAM (CD171) in PDAC cells accounting for chemoresistance. Thus, this study aimed to investigate whether PMFs are involved in the induction of tumoral L1CAM and whether this contributes to malignant transformation of pancreatic ductal cells and PDAC tumorigenesis. Immunohistochemistry of tissues from chronic pancreatitis specimens revealed considerable L1CAM expression in ductal structures surrounded by dense fibrotic tissue, whereas no L1CAM staining was seen in normal pancreatic tissues. Using the human pancreatic duct cell line H6c7, we show that coculture with PMFs led to a transforming growth factor-beta1 (TGF-beta1)-dependent up-regulation of L1CAM expression. Similarly, L1CAM expression increased in monocultured H6c7 cells after administration of exogenous TGF-beta1. Both TGF-beta1- and PMF-induced L1CAM expression were independent of Smad proteins but required c-Jun NH(2)-terminal kinase activation leading to the induction of the transcription factor Slug. Moreover, Slug interacted with the L1CAM promoter, and its knockdown abrogated the TGF-beta1- and PMF-induced L1CAM expression. As a result of L1CAM expression, H6c7 cells acquired a chemoresistant and migratory phenotype. This mechanism of TGF-beta1-induced L1CAM expression and the resulting phenotype could be verified in the TGF-beta1-responsive PDAC cell lines Colo357 and Panc1. Our data provide new insights into the mechanisms of tumoral L1CAM induction and how PMFs contribute to malignant transformation of pancreatic duct cells early in PDAC tumorigenesis.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly malignant phenotype associated with early metastasis and profound chemoresistance
Tumorigenesis and progression is thought to be driven by epithelial-mesenchymal transition (EMT) of epithelial/carcinoma cells, a process involving the alteration of cell morphology, the loss of the epithelial specific surface molecule E-cadherin, and an up-regulation of mesenchymal marker proteins such as vimentin and N-cadherin [8, 9]
Because L1CAM expression could be detected in carcinoma cells of PDAC primaries [21] as well as in lymph nodes and liver metastases,8 L1CAM seems to play a role in pancreatic tumorigenesis and progression
Summary
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly malignant phenotype associated with early metastasis and profound chemoresistance. Tumorigenesis and progression is thought to be driven by epithelial-mesenchymal transition (EMT) of epithelial/carcinoma cells, a process involving the alteration of cell morphology, the loss of the epithelial specific surface molecule E-cadherin, and an up-regulation of mesenchymal marker proteins such as vimentin and N-cadherin [8, 9]. One important regulator of PDAC tumorigenesis is transforming growth factor h1 (TGF-h1), which acts both as a tumor suppressor and as a tumor promoter. TGF-h1 is able to inhibit tumor cell proliferation during the early stages of tumorigenesis thereby exhibiting a net tumor-suppressive effect, it later promotes tumor progression by boosting EMT, neovascularization, and tumor metastasis [10,11,12]. ALK5 is a specific type I receptor for TGF-hs whereas ALK4 and ALK7 function as type I receptors for activins that are often expressed in tumor cells [13].
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