CXCL12 chemokine expression suppresses human pancreatic cancer growth and metastasis

PLoS One. 2014 Mar 4;9(3):e90400. doi: 10.1371/journal.pone.0090400. eCollection 2014.

Abstract

Pancreatic ductal adenocarcinoma is an unsolved health problem with nearly 75% of patients diagnosed with advanced disease and an overall 5-year survival rate near 5%. Despite the strong link between mortality and malignancy, the mechanisms behind pancreatic cancer dissemination and metastasis are poorly understood. Correlative pathological and cell culture analyses suggest the chemokine receptor CXCR4 plays a biological role in pancreatic cancer progression. In vivo roles for the CXCR4 ligand CXCL12 in pancreatic cancer malignancy were investigated. CXCR4 and CXCR7 were consistently expressed in normal and cancerous pancreatic ductal epithelium, established cell lines, and patient-derived primary cancer cells. Relative to healthy exocrine ducts, CXCL12 expression was pathologically repressed in pancreatic cancer tissue specimens and patient-derived cell lines. To test the functional consequences of CXCL12 silencing, pancreatic cancer cell lines stably expressingthe chemokine were engineered. Consistent with a role for CXCL12 as a tumor suppressor, cells producing the chemokine wereincreasingly adherent and migration deficient in vitro and poorly metastatic in vivo, compared to control cells. Further, CXCL12 reintroduction significantly reduced tumor growth in vitro, with significantly smaller tumors in vivo, leading to a pronounced survival advantage in a preclinical model. Together, these data demonstrate a functional tumor suppressive role for the normal expression of CXCL12 in pancreatic ducts, regulating both tumor growth andcellulardissemination to metastatic sites.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anoikis / drug effects
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Adhesion / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chemokine CXCL12 / metabolism*
  • Chemokine CXCL12 / pharmacology
  • Chemotaxis / drug effects
  • Disease Models, Animal
  • Epigenesis, Genetic / drug effects
  • Epithelium / drug effects
  • Epithelium / metabolism
  • Epithelium / pathology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Ligands
  • Mice, SCID
  • Neoplasm Metastasis
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology*
  • Receptors, CXCR / metabolism
  • Receptors, CXCR4 / metabolism
  • Survival Analysis
  • Transfection
  • Xenograft Model Antitumor Assays

Substances

  • ACKR3 protein, human
  • CXCL12 protein, human
  • Chemokine CXCL12
  • Ligands
  • Receptors, CXCR
  • Receptors, CXCR4

Supplementary concepts

  • Pancreatic Carcinoma

Grant support

This work was supported in part by grants from the A Healthier Wisconsin and the MCW Cancer Center. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.