Pigment epithelium-derived factor associates with neuropathy and fibrosis in pancreatic cancer

Tamar Samkharadze, Mert Erkan, Carolin Reiser-Erkan, Ihsan Ekin Demir, Bo Kong, Güralp O. Ceyhan, Christoph W. Michalski, Irene Esposito, Helmut Friess, Jörg Kleeff

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Objectives: Pigment epithelium-derived factor (PEDF) is a noninhibitory member of the serine protease inhibitor gene family with neuroprotective, neuroproliferative, and anti-angiogenic functions. Its role in pancreatic fibrosis and neuropathy is unknown. Methods: The expression and localization of PEDF were assessed by quantitative real-time (RT)-PCR, immunohistochemistry, and quantitative image analysis and correlated with neural and microvessel densities (MVDs) in the normal pancreas (n20) and pancreatic cancer (n55). Primary human pancreatic stellate cells (PSCs), mouse neuroblastoma, and human Schwann cells were used for functional experiments. The effect of hypoxia on PEDF production in cancer cell lines and immortalized pancreatic ductal epithelial cells was assessed by quantitative RT-PCR and enzyme-linked immunosorbent assay. The effect of recombinant PEDF on PSCs was assessed by immunoblot analysis. Results: PEDF expression was homogeneous in epithelial cells of the normal pancreas where some acinar cells consistently displayed stronger staining. A higher expression was found in tubular complexes, PanIN lesions, and inflammatory cells in pancreatic cancer. Cancer cells expressed various levels of PEDF. In cancer cell lines and in human immortalized pancreatic ductal epithelial cells, hypoxia increased PEDF mRNA up to 132-fold. Higher expression of PEDF in cancer cells was significantly correlated with better patient survival (median survival 21.5 months vs. 17.5 months, P0.043), increased neuropathy (P0.0251), increased PSC activity, and extracellular matrix protein production. Conclusions: PEDF increases PSC activity, thereby contributing to the desmoplasia of pancreatic cancer. PSC overactivation likely leads to periacinar fibrosis and degeneration of fine acinar innervation. Increased focal PEDF expression in cancer cells correlates with neuropathic changes and better patient survival.

Original languageEnglish
Pages (from-to)968-980
Number of pages13
JournalAmerican Journal of Gastroenterology
Volume106
Issue number5
DOIs
StatePublished - May 2011
Externally publishedYes

Fingerprint

Dive into the research topics of 'Pigment epithelium-derived factor associates with neuropathy and fibrosis in pancreatic cancer'. Together they form a unique fingerprint.

Cite this