S1PR1-STAT3 signaling is crucial for myeloid cell colonization at future metastatic sites

Cancer Cell. 2012 May 15;21(5):642-54. doi: 10.1016/j.ccr.2012.03.039.

Abstract

Recent studies underscore the importance of myeloid cells in rendering distant organs hospitable for disseminating tumor cells to colonize. However, what enables myeloid cells to have an apparently superior capacity to colonize distant organs is unclear. Here, we show that S1PR1-STAT3 upregulation in tumor cells induces factors that activate S1PR1-STAT3 in various cells in premetastatic sites, leading to premetastatic niche formation. Targeting either S1PR1 or STAT3 in myeloid cells disrupts existing premetastatic niches. S1PR1-STAT3 pathway enables myeloid cells to intravasate, prime the distant organ microenvironment and mediate sustained proliferation and survival of their own and other stromal cells at future metastatic sites. Analyzing tumor-free lymph nodes from cancer patients shows elevated myeloid infiltrates, STAT3 activity, and increased survival signal.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Cell Survival
  • CpG Islands
  • Humans
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary
  • Lymph Nodes / metabolism
  • Lymph Nodes / pathology
  • Lymphatic Metastasis
  • Male
  • Melanoma / metabolism
  • Melanoma / secondary
  • Mice
  • Mice, Knockout
  • Myeloid Cells / metabolism*
  • Myeloid Cells / pathology
  • Neoplasm Invasiveness
  • Neoplasms / metabolism*
  • Neoplasms / pathology*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • RNA Interference
  • Receptors, Lysosphingolipid / deficiency
  • Receptors, Lysosphingolipid / genetics
  • Receptors, Lysosphingolipid / metabolism*
  • STAT3 Transcription Factor / deficiency
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction*
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology
  • Sphingosine-1-Phosphate Receptors
  • Time Factors
  • Transduction, Genetic
  • Tumor Microenvironment*
  • Urinary Bladder Neoplasms / metabolism
  • Urinary Bladder Neoplasms / pathology

Substances

  • Receptors, Lysosphingolipid
  • S1PR1 protein, human
  • S1pr1 protein, mouse
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Sphingosine-1-Phosphate Receptors
  • Stat3 protein, mouse