Early pancreatic cancer lesions suppress pain through CXCL12-mediated chemoattraction of Schwann cells


Demir I. E. , Kujundzic K., Pfitzinger P. L. , Saricaoglu O. C. , Teller S., Kehl T., ...More

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol.114, no.1, 2017 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 114 Issue: 1
  • Publication Date: 2017
  • Doi Number: 10.1073/pnas.1606909114
  • Journal Name: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED)
  • Keywords: Schwann cells, pancreatic cancer, CXCL12, CXCR4, CXCR7, CHEMOKINE RECEPTOR CXCR4, NEUROPATHIC PAIN, NEURONAL PLASTICITY, CXCL12/CXCR4 AXIS, NEURAL PLASTICITY, FACTOR-I, EXPRESSION, SURVIVAL, INVASION, SDF-1
  • Acibadem Mehmet Ali Aydinlar University Affiliated: No

Abstract

Pancreatic ductal adenocarcinoma (PDAC) cells (PCC) have an exceptional propensity to metastasize early into intratumoral, chemokine-secreting nerves. However, we hypothesized the opposite process, that precancerous pancreatic cells secrete chemokines that chemoattract Schwann cells (SC) of nerves and thus induce ready-to-use routes of dissemination in early carcinogenesis. Here we show a peculiar role for the chemokine CXCL12 secreted in early PDAC and for its receptors CXCR4/CXCR7 on SC in the initiation of neural invasion in the cancer precursor stage and the resulting delay in the onset of PDAC-associated pain. SC exhibited cancer-or hypoxia-induced CXCR4/CXCR7 expression in vivo and in vitro and migrated toward CXCL12-expressing PCC. Glia-specific depletion of CXCR4/CXCR7 in mice abrogated the chemoattraction of SC to PCC. PDAC mice with pancreas-specific CXCL12 depletion exhibited diminished SC chemoattraction to pancreatic intraepithelial neoplasia and increased abdominal hypersensitivity caused by augmented spinal astroglial and microglial activity. In PDAC patients, reduced CXCR4/CXCR7 expression in nerves correlated with increased pain. Mechanistically, upon CXCL12 exposure, SC down-regulated the expression of several pain-associated targets. Therefore, PDAC-derived CXCL12 seems to induce tumor infiltration by SC during early carcinogenesis and to attenuate pain, possibly resulting in delayed diagnosis in PDAC.