Selectins mediate small cell lung cancer systemic metastasis

PLoS One. 2014 Apr 3;9(4):e92327. doi: 10.1371/journal.pone.0092327. eCollection 2014.

Abstract

Metastasis formation is the major reason for the extremely poor prognosis in small cell lung cancer (SCLC) patients. The molecular interaction partners regulating metastasis formation in SCLC are largely unidentified, however, from other tumor entities it is known that tumor cells use the adhesion molecules of the leukocyte adhesion cascade to attach to the endothelium at the site of the future metastasis. Using the human OH-1 SCLC line as a model, we found that these cells expressed E- and P-selectin binding sites, which could be in part attributed to the selectin binding carbohydrate motif sialyl Lewis A. In addition, protein backbones known to carry these glycotopes in other cell lines including PSGL-1, CD44 and CEA could be detected in in vitro and in vivo grown OH1 SCLC cells. By intravital microscopy of murine mesenterial vasculature we could capture SCLC cells while rolling along vessel walls demonstrating that SCLC cells mimic leukocyte rolling behavior in terms of selectin and selectin ligand interaction in vivo indicating that this mechanism might indeed be important for SCLC cells to seed distant metastases. Accordingly, formation of spontaneous distant metastases was reduced by 50% when OH-1 cells were xenografted into E-/P-selectin-deficient mice compared with wild type mice (p = 0.0181). However, as metastasis formation was not completely abrogated in selectin deficient mice, we concluded that this adhesion cascade is redundant and that other molecules of this cascade mediate metastasis formation as well. Using several of these adhesion molecules as interaction partners presumably make SCLC cells so highly metastatic.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • CA-19-9 Antigen
  • E-Selectin / metabolism*
  • Female
  • Flow Cytometry
  • Humans
  • Immunoenzyme Techniques
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology*
  • Male
  • Mice
  • Mice, Knockout
  • Mice, SCID
  • Middle Aged
  • Neoplasm Metastasis
  • Neoplasm Staging
  • Oligosaccharides / metabolism
  • P-Selectin / metabolism*
  • Prognosis
  • Small Cell Lung Carcinoma / metabolism
  • Small Cell Lung Carcinoma / mortality
  • Small Cell Lung Carcinoma / secondary*
  • Survival Rate
  • Tissue Array Analysis
  • Tumor Cells, Cultured

Substances

  • CA-19-9 Antigen
  • E-Selectin
  • Oligosaccharides
  • P-Selectin

Grant support

This work was supported by the Bundesministerium für Bildung und Forschung (TOMCAT, grant number 01EZ0824; http://www.bmbf.de/) and Landesexzellenzinitiative Hamburg (Nanotechnology in Medicine – NAME). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.