The PDGF-BB-SOX7 axis-modulated IL-33 in pericytes and stromal cells promotes metastasis through tumour-associated macrophages

Nat Commun. 2016 May 6:7:11385. doi: 10.1038/ncomms11385.

Abstract

Signalling molecules and pathways that mediate crosstalk between various tumour cellular compartments in cancer metastasis remain largely unknown. We report a mechanism of the interaction between perivascular cells and tumour-associated macrophages (TAMs) in promoting metastasis through the IL-33-ST2-dependent pathway in xenograft mouse models of cancer. IL-33 is the highest upregulated gene through activation of SOX7 transcription factor in PDGF-BB-stimulated pericytes. Gain- and loss-of-function experiments validate that IL-33 promotes metastasis through recruitment of TAMs. Pharmacological inhibition of the IL-33-ST2 signalling by a soluble ST2 significantly inhibits TAMs and metastasis. Genetic deletion of host IL-33 in mice also blocks PDGF-BB-induced TAM recruitment and metastasis. These findings shed light on the role of tumour stroma in promoting metastasis and have therapeutic implications for cancer therapy.

Publication types

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

MeSH terms

  • Animals
  • Becaplermin
  • Cell Line, Tumor
  • Female
  • Humans
  • Interleukin-33 / genetics
  • Interleukin-33 / metabolism*
  • Macrophages / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Metastasis
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Pericytes / metabolism*
  • Proto-Oncogene Proteins c-sis / metabolism*
  • SOXF Transcription Factors / genetics
  • SOXF Transcription Factors / metabolism*
  • Stromal Cells / metabolism*

Substances

  • Interleukin-33
  • Proto-Oncogene Proteins c-sis
  • SOX7 protein, human
  • SOXF Transcription Factors
  • Becaplermin