Z Gastroenterol 2018; 56(08): e323
DOI: 10.1055/s-0038-1668980
Kurzvorträge
Gastroenterologische Onkologie
Pankreaskarzinom: Molekulare und zellbiologische Grundlagen – Donnerstag, 13. September 2018, 12:15 – 13:35, 21a
Georg Thieme Verlag KG Stuttgart · New York

Parasympathetic signaling via Chrm1directly suppresses pancreatic carcinogenesis and cancer stemness through inhibition of EGFR/MAPK and PI3K/AKT pathway

BW Renz
1   Klinikum der Universität München, Klinik für Allgemeine, Viszeral-, Transplantations-, und Gefäßchirurgie, München, Deutschland
,
T Tanaka
2   Columbia University Medical Center, Division of Digestive and Liver Diseases, New York, Vereinigte Staaten von Amerika
,
M Macchini
2   Columbia University Medical Center, Division of Digestive and Liver Diseases, New York, Vereinigte Staaten von Amerika
,
Y Hayakawa
2   Columbia University Medical Center, Division of Digestive and Liver Diseases, New York, Vereinigte Staaten von Amerika
,
M Ilmer
1   Klinikum der Universität München, Klinik für Allgemeine, Viszeral-, Transplantations-, und Gefäßchirurgie, München, Deutschland
,
CB Westphalen
3   Klinikum der Universität München, Medizinische Klinik und Poliklinik III, München, Deutschland
,
PE Oberstein
2   Columbia University Medical Center, Division of Digestive and Liver Diseases, New York, Vereinigte Staaten von Amerika
,
AC Iuga
2   Columbia University Medical Center, Division of Digestive and Liver Diseases, New York, Vereinigte Staaten von Amerika
,
RA Friedmann
2   Columbia University Medical Center, Division of Digestive and Liver Diseases, New York, Vereinigte Staaten von Amerika
,
J Werner
1   Klinikum der Universität München, Klinik für Allgemeine, Viszeral-, Transplantations-, und Gefäßchirurgie, München, Deutschland
,
KP Olive
2   Columbia University Medical Center, Division of Digestive and Liver Diseases, New York, Vereinigte Staaten von Amerika
,
TC Wang
2   Columbia University Medical Center, Division of Digestive and Liver Diseases, New York, Vereinigte Staaten von Amerika
› Author Affiliations
Further Information

Publication History

Publication Date:
13 August 2018 (online)

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    Fragestellung:

    In many solid tumors, parasympathetic input is provided by the vagus nerve, which has been shown to modulate growth through effects on both tumor and stroma. Whether parasympathetic signaling directly regulates progression of pancreatic cancer (PDAC) has not been defined.

    Methodik:

    KC mice were vagotomized and kept on regular water or water supplemented with a muscarinic agonist. Pancreatic tissue was collected and analyzed by IHC and RT-PCR; cells were isolated and assayed for colony and sphere forming assays. Different human and murine PDAC cell lines were subjected to cholinergic and anti-cholinergic drugs and assayed by RT-PCR, Western blot and flow cytometry. CHRM1 was deleted in Pdx1-Cre/KRas G12D(KC) and Pdx1-Cre/KRasG12D/Trp53 R172 H(KPC) mice. A syngeneic model of metastatic PDAC was also utilized.

    Ergebnis:

    In organoid cultures derived from pancreata harboring an oncogenic KRas mutation, cholinergic agonists suppressed sphere formation significantly. Pharmacological inhibition or genetic knockout of the CHRM1abolished this effect in vitro. When Panc-1 cells pretreated with direct parasympathetic agonists were assayed in a xenograft model, they formed less and smaller tumors than controls. Surgical vagotomy accelerated tumor development in KC, while treatment with the muscarinic agonist bethanechol rescued the phenotype. An effect also seen in KC-CHRM1 KO mice. In KPC mice, bethanechol significantly extended survival. While KO of the CHRM1 (KPM) shortened overall survival. These effects appeared to be mediated through the CHRM1, which inhibited the downstream MAPK/EGFR and PI3K/AKT pathways. Reduced cholinergic signaling led to an increase of pancreatic CSC, and accelerated metastatic growth in the liver.

    Schlussfolgerung:

    Taken together, these data suggest that parasympathetic signaling directly suppresses the growth of PDAC cells and therapies directed at stimulating muscarinic receptors may be useful in inhibiting the progression of PDAC.


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