Up-regulation of L1CAM in Pancreatic Duct Cells Is Transforming Growth Factor β1– and Slug-Dependent: Role in Malignant Transformation of Pancreatic Cancer

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-B1 (TGF-B1)-dependent up-regulation of L1CAM expression. Similarly, L1CAM expression increased in monocultured H6c7 cells after administration of exogenous TGF-B1. Both TGF-B1-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-B1-and PMF-induced L1CAM expression. As a result of L1CAM expression, H6c7 cells acquired a chemoresistant and migratory phenotype. This mechanism of TGF-B1-induced L1CAM expression and the resulting phenotype could be verified in the TGF-B1-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. [Cancer Res 2009;69(10):4517-26]

L1CAM–integrin interaction induces constitutive NF-κB activation in pancreatic adenocarcinoma cells by enhancing IL-1β expression

“…Furthermore, L1CAM was detected in tumour-associated endothelium (Issa et al, 2009;Maddaluno et al, 2009). Expression of L1CAM was also described in pancreatic ductal adenocarcinomas (PDACs) (Sebens Muerkoster et al, 2007Geismann et al, 2009). Accumulating evidence suggests an important role of L1CAM in the malignancy of this tumour (Sebens Muerkoster et al, 2007Geismann et al, 2009).…”

“…Expression of L1CAM was also described in pancreatic ductal adenocarcinomas (PDACs) (Sebens Muerkoster et al, 2007Geismann et al, 2009). Accumulating evidence suggests an important role of L1CAM in the malignancy of this tumour (Sebens Muerkoster et al, 2007Geismann et al, 2009). The mechanism of L1CAM-mediated tumour progression is not clearly established.…”

Binding of the transcription factor Slug to the L1CAM promoter is essential for transforming growth factor-β1 (TGF-β)-induced L1CAM expression in human pancreatic ductal adenocarcinoma cells

“…In support of this assumption, the strong L1CAM expression in the PDAC cell line Panc1 which is TGF-ß1 responsive in an autocrine fashion and which exhibits a pronounced mesenchymal phenotype (e.g. significant migratory potential, strong vimentin and reduced E-cadherin expression) was shown to be also dependent on Slug (16).…”

“…Recently, it was demonstrated that TGF-ß1 induces the expression of the promigratory molecule L1CAM (L1/CD171) in human pancreatic ductal epithelial cells (16). L1CAM is a 200-220-kD glycoprotein and a member of the immunoglobulin superfamily.…”

The Adhesion Molecule L1CAM as a Novel Therapeutic Target for Treatment of Pancreatic Cancer Patients?

“…On the other hand, numerous in vitro and in vivo studies provide compelling evidence for the role of L1CAM in cell migration of various tumor entities such as ovarian cancer (Arlt et al, 2006;Gast et al, 2005;Zecchini et al, 2008), colon cancer (Gavert et al, 2005;Gavert et al, 2011), melanoma (Meier et al, 2006), glioma (Yang et al, 2009;Yang et al, 2011), glioblastoma stem cells , breast cancer (Li & Galileo, 2010) and PDAC (Chen et al, 2010;Geismann et al, 2009). Cleavage of L1CAM seemed to be a prequisite for promoting the adhesion and migration of breast cancer cells (Li & Galileo, 2010) as well as for the motility of glioma (Yang et al, 2009), ovarian cancer (Mechtersheimer et al 2001) and colon cancer cells (Gavert et al, 2005).…”