Data from Hyaluronan Synthase HAS2 Promotes Tumor Progression in Bone by Stimulating the Interaction of Breast Cancer Stem–Like Cells with Macrophages and Stromal Cells

Abstract

<div>Abstract<p>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<sup>+</sup>/CD24<sup>−</sup>/ESA<sup>+</sup> 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 <i>in vitro</i> or <i>in vivo</i>, 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. <i>Cancer Res; 72(2); 537–47. ©2011 AACR</i>.</p></div>