Human splenic TER cells: A relevant prognostic factor acting via the artemin-GFRα3-ERK pathway in pancreatic ductal adenocarcinoma

Int J Cancer. 2021 Apr 1;148(7):1756-1767. doi: 10.1002/ijc.33410. Epub 2020 Dec 6.

Abstract

Splenectomy is routinely performed during distal or total pancreatectomy (DP or TP) for pancreatic ductal adenocarcinoma (PDAC), but information about its oncological value is limited. TER cells, nonimmune cells discovered in the spleens of tumour-bearing mice, are elicited by tumours and promote tumour progression, while their role in the clinical outcomes of patients with PDAC remains unclear. In our study, postoperative specimens from 622 patients who underwent DP or TP with splenectomy were analysed by flow cytometry or immunofluorescence, and the relationship between splenic TER cell count and clinical parameters was calculated. We also purified human TER cells for functional experiments and mechanistic studies. We found that TER cell numbers were increased only in the spleens of patients with PDAC but not in PDAC tissue and adjacent pancreatic tissue. High splenic TER cell counts independently predicted poor prognosis (P < .001) and indicated large tumour size, lymph node metastasis, advanced 8th AJCC/mAJCC stage and high CA19-9 classification (all P < .050) in patients with PDAC. Mechanistic analysis showed that TER cells express artemin, which facilitates the proliferation and invasion of PDAC cells by activating GFRα3-ERK signalling. Our study reveals that TER cell count is an indicator of poor prognosis of PDAC, while splenectomy during pancreatic surgery might provide oncological benefits in addition to ensuring the radical resection of PDAC.

Keywords: PDAC; TER cell; artemin; prognosis; splenectomy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Pancreatic Ductal / metabolism*
  • Carcinoma, Pancreatic Ductal / mortality
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Cohort Studies
  • Female
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Glial Cell Line-Derived Neurotrophic Factor Receptors / metabolism*
  • Humans
  • Lymphatic Metastasis
  • MAP Kinase Signaling System
  • Male
  • Middle Aged
  • Nerve Tissue Proteins / metabolism
  • Nerve Tissue Proteins / pharmacology*
  • Pancreatectomy
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Prognosis
  • Recombinant Proteins
  • Spleen / cytology*
  • Spleen / metabolism*
  • Spleen / pathology
  • Splenectomy

Substances

  • ARTN protein, human
  • GFRA3 protein, human
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Nerve Tissue Proteins
  • Recombinant Proteins