Hyaluronan synthase HAS2 promotes tumor progression in bone by stimulating the interaction of breast cancer stem-like cells with macrophages and stromal cells

Cancer Res. 2012 Jan 15;72(2):537-47. doi: 10.1158/0008-5472.CAN-11-1678. Epub 2011 Nov 23.

Abstract

The molecular mechanisms that operate within the organ microenvironment to support metastatic progression remain unclear. Here, we report that upregulation of hyaluronan synthase 2 (HAS2) occurs in highly metastatic breast cancer stem-like cells (CSC) defined by CD44(+)/CD24(-)/ESA(+) phenotype, where it plays a critical role in the generation of a prometastatic microenvironment in breast cancer. HAS2 was critical for the interaction of CSCs with tumor-associated macrophages (TAM), leading to enhanced secretion of platelet-derived growth factor-BB from TAMs, which then activated stromal cells and enhanced CSC self-renewal. Loss of HAS2 in CSCs or treatment with 4-methylumbelliferone, an inhibitor of HAS, which blocks hyaluronan production, drastically reduced the incidence and growth of metastatic lesions in vitro or in vivo, respectively. Taken together, our findings show a critical role of HAS2 in the development of a prometastatic microenvironment and suggest that HAS2 inhibitors can act as antimetastatic agents that disrupt a paracrine growth factor loop within this microenvironment.

Publication types

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

MeSH terms

  • Animals
  • Bone Neoplasms / enzymology*
  • Bone Neoplasms / genetics
  • Bone Neoplasms / pathology
  • Bone Neoplasms / secondary
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Cell Adhesion / physiology
  • Cell Movement / physiology
  • Disease Progression
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Glucuronosyltransferase / antagonists & inhibitors
  • Glucuronosyltransferase / metabolism*
  • Humans
  • Hyaluronan Synthases
  • Hymecromone / analogs & derivatives
  • Hymecromone / pharmacology
  • Macrophages / enzymology
  • Macrophages / pathology*
  • Mice
  • Mice, Nude
  • Neoplasm Invasiveness
  • Neoplastic Stem Cells / enzymology
  • Neoplastic Stem Cells / pathology*
  • Stromal Cells / enzymology
  • Stromal Cells / pathology*
  • Up-Regulation

Substances

  • Hymecromone
  • Glucuronosyltransferase
  • HAS2 protein, human
  • Hyaluronan Synthases