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

Proc Natl Acad Sci U S A. 2017 Jan 3;114(1):E85-E94. doi: 10.1073/pnas.1606909114. Epub 2016 Dec 16.

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.

Keywords: CXCL12; CXCR4; CXCR7; Schwann cells; pancreatic cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Pancreatic Ductal / pathology*
  • Cell Line, Tumor
  • Chemokine CXCL12 / metabolism*
  • Chemotaxis / physiology*
  • Mice
  • Mice, Transgenic
  • Pain / prevention & control*
  • Pancreatic Neoplasms / pathology*
  • Receptors, CXCR / metabolism*
  • Receptors, CXCR4 / metabolism*
  • Schwann Cells / physiology*

Substances

  • CXCR4 protein, mouse
  • Chemokine CXCL12
  • Cmkor1 protein, mouse
  • Cxcl12 protein, mouse
  • Receptors, CXCR
  • Receptors, CXCR4