Autocrine CCL5 signaling promotes invasion and migration of CD133+ ovarian cancer stem-like cells via NF-κB-mediated MMP-9 upregulation

Stem Cells. 2012 Oct;30(10):2309-19. doi: 10.1002/stem.1194.

Abstract

The concept of cancer stem cells (CSCs) proposes that solely CSCs are capable of generating tumor metastases. However, how CSCs maintain their invasion and migration abilities, the most important properties of metastatic cells, still remains elusive. Here we used CD133 to mark a specific population from human ovarian cancer cell line and ovarian cancer tissue and determined its hyperactivity in migration and invasion. Therefore, we labeled this population as cancer stem-like cells (CSLCs). In comparison to CD133- non-CSLCs, chemokine CCL5 and its receptors, CCR1, CCR3, and CCR5, were consistently upregulated in CSLCs, and most importantly, blocking of CCL5, CCR1, or CCR3 effectively inhibits the invasive capacity of CSLCs. Mechanistically, we identified that this enhanced invasiveness is mediated through nuclear factor κB (NF-κB) activation and the consequently elevated MMP9 secretion. Our results suggested that the autocrine activation of CCR1 and CCR3 by CCL5 represents one of major mechanisms underlying the metastatic property of ovarian CSLCs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AC133 Antigen
  • Antigens, CD / genetics
  • Antigens, CD / metabolism
  • Biomarkers, Tumor
  • Cell Line, Tumor
  • Cell Movement
  • Chemokine CCL5 / antagonists & inhibitors
  • Chemokine CCL5 / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Glycoproteins / genetics
  • Glycoproteins / metabolism
  • Humans
  • Matrix Metalloproteinase 9 / genetics*
  • Matrix Metalloproteinase 9 / metabolism
  • NF-kappa B / genetics*
  • NF-kappa B / metabolism
  • Neoplasm Invasiveness / genetics
  • Neoplastic Stem Cells / physiology*
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology*
  • Ovary / metabolism
  • Ovary / pathology*
  • Peptides / genetics
  • Peptides / metabolism
  • Primary Cell Culture
  • Receptors, CCR1 / antagonists & inhibitors
  • Receptors, CCR1 / genetics
  • Receptors, CCR3 / antagonists & inhibitors
  • Receptors, CCR3 / genetics
  • Receptors, CCR5 / genetics
  • Receptors, CCR5 / metabolism
  • Signal Transduction

Substances

  • AC133 Antigen
  • Antigens, CD
  • Biomarkers, Tumor
  • CCL5 protein, human
  • CCR1 protein, human
  • CCR3 protein, human
  • Chemokine CCL5
  • Glycoproteins
  • NF-kappa B
  • PROM1 protein, human
  • Peptides
  • Receptors, CCR1
  • Receptors, CCR3
  • Receptors, CCR5
  • Matrix Metalloproteinase 9