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

Sebens, Susanne; Schäfer, Heiner

doi:10.5772/30146

Cited by 1 publication

(1 citation statement)

References 72 publications

(99 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Further studies are planned to investigate whether treatment with anti-L1CAM antibodies will reduce growth or metastasis of our 5-FU-resistant pancreatic cancer cell lines in vivo . The finding that pancreatic cancer cells with acquired resistance to 5-FU show increased expression of L1CAM, in addition to the distinction of L1CAM presence in cancerous vs. normal tissues [ 52 ], makes us hopeful that targeting of L1CAM with therapeutic antibodies and/or in combination with 5-FU could potentially benefit selected patients with refractory pancreatic tumors. Our findings provide further insight into the molecular mechanisms leading to a chemoresistant and migratory phenotype in pancreatic cancer cells and highlight the importance of addressing Slug-induced L1CAM expression in recurrent pancreatic cancer.…”

Section: Discussionmentioning

confidence: 99%

Slug-Dependent Upregulation of L1CAM Is Responsible for the Increased Invasion Potential of Pancreatic Cancer Cells following Long-Term 5-FU Treatment

Lund¹,

Dembinski

Solberg³

et al. 2015

PLoS ONE

View full text Add to dashboard Cite

BackgroundPancreatic adenocarcinoma is a lethal disease with 5-year survival of less than 5%. 5-fluorouracil (5-FU) is a principal first-line therapy, but treatment only extends survival modestly and is seldom curative. Drug resistance and disease recurrence is typical and there is a pressing need to overcome this. To investigate acquired 5-FU resistance in pancreatic adenocarcinoma, we established chemoresistant monoclonal cell lines from the Panc 03.27 cell line by long-term exposure to increasing doses of 5-FU.Results5-FU-resistant cell lines exhibited increased expression of markers associated with multidrug resistance explaining their reduced sensitivity to 5-FU. In addition, 5-FU-resistant cell lines showed alterations typical for an epithelial-to-mesenchymal transition (EMT), including upregulation of mesenchymal markers and increased invasiveness. Microarray analysis revealed the L1CAM pathway as one of the most upregulated pathways in the chemoresistant clones, and a significant upregulation of L1CAM was seen on the RNA and protein level. In pancreatic cancer, expression of L1CAM is associated with a chemoresistant and migratory phenotype. Using esiRNA targeting L1CAM, or by blocking the extracellular part of L1CAM with antibodies, we show that the increased invasiveness observed in the chemoresistant cells functionally depends on L1CAM. Using esiRNA targeting β-catenin and/or Slug, we demonstrate that in the chemoresistant cell lines, L1CAM expression depends on Slug rather than β-catenin.ConclusionOur findings establish Slug-induced L1CAM expression as a mediator of a chemoresistant and migratory phenotype in pancreatic adenocarcinoma cells.

show abstract

Section: Discussionmentioning

confidence: 99%