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ID: 935 (Conflict of Interest: K)

Pankreaskarzinomzellen dringen durch die Nervenscheiden über die Induktion einer Transdifferenzierung der perineuralen Epithelzellen

I. E.Demir, U.Bourquain, S.Teller, E.Krohmer, D.Saur, H.Friess, G. O.Ceyhan
Klinikum Rechts der Isar der TU München, München

Einleitung

Mechanisms of “neural invasion” in pancreatic cancer are widely unclear. Classically, cancer cells are assumed to actively break or mechanically disrupt the perineural barrier to find access into nerves. However, for this hypothesis to be true, the cancer cells would need to exert destructive-toxic effects on the cells that compose the perineural barrier. Here, we hypothesized an alternative mechanism of cancer cell entry into nerves, i.e. the “transdifferentiation” of perineural epithelial cells of the outermost nerve sheath in the cancer micro-environment.

Material und Methoden

Human perineural epithelial cells were cultured within the supernatants of different human pancreatic cancer cell lines and analyzed for markers of epithelial-mesenchymal-transition (EMT). The integrity of the perineural epithelial cell linings was analyzed in human pancreatic cancer tissues by quantitative immunohistochemistry of circumferential perineural GLUT1 staining. Transcriptomic arrays were performed with perineural epithelial cells to decipher the transcriptomic changes in the cancer-induced transdifferentiation process. Levels of different EMT inducers were analysed by ElLISA within pancreatic cancer cell supernatants. Genetically engineered mice with precursors of pancreatic cancer (p48-Cre;LSL-KrasG12D/“KC”) and pancreas-specific TGFbeta1 overexpression (KC;TGFbeta1ov /) were analysed for the perineural integrity.

Ergebnisse

Treatment of human perineural epithelial cells (HPEC) with supernatants of three different human pancreatic cancer cell lines resulted in morphological alterations in the perineural cells that were reminiscent of EMT. Accordingly, cancer-conditioned perineural epithelial cells overexpressed Vimentin and N-Cadherine, and downregulated E-cadherine. The transcriptomic analysis of the cancer-conditioned, perineural epithelial cells revealed expression changes that pointed out towards an EMT signature. Among the different potential mediators of EMT, the only factor that was specifically enriched in the supernatants of human pancreatic cancer cell lines was TGFbeta1. Accordingly, increasing concentrations of TGFbeta1 in the culture medium of human perineural epithelial cells resulted in prominent EMT-like changes in the perineural cells. In human pancreatic cancer tissues, GLUT1-expressing perineural epithelial barrier cells were widely lost as opposed to the intact barrier around nerves in normal pancreas. Moreover, analysis of the perineural integrity in KC;TGFbeta1ov / revealed prominent alterations in perineural integrity when compared to KC mice.

Schlussfolgerung

Cancer cell-induced transdifferentiation of perineural epithelial cells seems to be the initial mechanistic event that enables pancreatic cancer cell access into nerves. In this context, TGFbeta1 signaling seems to be of paramount importance in mediating neural invasion in pancreatic cancer and is thus of potential therapeutic relevance.