title: Hyaluronan synthase HAS2 promotes tumor progression in bone by stimulating the interaction of breast cancer stem-like cells with macrophages and stromal cells.
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.
authors: Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois 62794, USA.
authors: Hiroshi
authors: H
authors: Okuda
authors: Aya
authors: A
authors: Kobayashi
authors: Bo
authors: B
authors: Xia
authors: Misako
authors: M
authors: Watabe
authors: Sudha K
authors: SK
authors: Pai
authors: Shigeru
authors: S
authors: Hirota
authors: Fei
authors: F
authors: Xing
authors: Wen
authors: W
authors: Liu
authors: Puspa R
authors: PR
authors: Pandey
authors: Koji
authors: K
authors: Fukuda
authors: Vishnu
authors: V
authors: Modur
authors: Arnab
authors: A
authors: Ghosh
authors: Andrew
authors: A
authors: Wilber
authors: Kounosuke
authors: K
authors: Watabe
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000556:secondary; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D000076002:Hyaluronan Synthases; D006923:Hymecromone / Q000031:analogs & derivatives / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000201:enzymology / Q000473:pathology*; D017154:Stromal Cells / Q000201:enzymology / Q000473:pathology*; D015854:Up-Regulation
chemical_list: D006923:Hymecromone; D014453:Glucuronosyltransferase; C101754:HAS2 protein, human; D000076002:Hyaluronan Synthases