title: Antitumor effects of hyaluronan inhibition in desmoid tumors.
abstract: Desmoid tumors (DTs) are rare, mesenchymal tumors that exhibit features of an abundant wound healing process. Previously, we showed that mesenchymal stem cells (MSCs) are constituents of DTs and may contribute to desmoid tumorigenesis via activities associated with wound healing. Hyaluronan (HA) is a long-charged chain of repeating glucuronate and N-acetylglucosamine disaccharides that is synthesized by HA synthases (HAS) and degraded by hyaluronidases (HYAL). HA is secreted into the extracellular matrix by injured stroma and is important for normal tissue repair and neoplastic progression. Here, we investigated the presence of HA in DTs and the antitumor effects of the HA inhibitor, 4-methylumbelliferone (4-MU), on DT-derived mesenchymal cells. By immunohistochemistry and enzyme-linked immunosorbent assay, we found abundant expression of HA in 29/30 DTs as well as >5-fold increased HA levels in DT-derived cell lines relative to controls. Immunohistochemistry also demonstrated high expression of HAS2 in DTs, and quantitative PCR analysis showed increased HAS2 upregulation in frozen DTs and DT-derived cells. 4-MU treatment of DT-derived cells significantly decreased proliferation as well as HA and HAS2 levels. Fluorescent immunohistochemistry showed that MSCs in DTs coexpressed HA, HAS2, HYAL2, as well as the major HA receptor CD44 and HA coreceptor TLR4. Taken together, our results suggest that paracrine regulation of HA signaling in DTs may contribute to MSC recruitment and tumor proliferation. Future studies investigating the role of HA in tumor-stroma crosstalk and inhibition of HA-MSC interactions as a novel therapeutic target in DTs and other solid tumors are warranted.
authors.affiliation: Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA and Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Briggs
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Rosenberg
authors.affiliation: Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA and Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Justin D
authors.initials: JD
authors.lastname: Buie
authors.affiliation: Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA and Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Hira
authors.initials: H
authors.lastname: Rizvi
authors.affiliation: Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA and Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Monica M
authors.initials: MM
authors.lastname: Bertagnolli
authors.affiliation: Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA and Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA nlcho@partners.org.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Cho
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D005260:Female; D018222:Desmoid Tumors / Q000188:drug therapy* / Q000473:pathology*; D058851:GPI-Linked Proteins / Q000096:biosynthesis; D014453:Glucuronosyltransferase / Q000096:biosynthesis; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D006821:Hyaluronoglucosaminidase / Q000096:biosynthesis; D006923:Hymecromone / Q000494:pharmacology*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects*; D008875:Middle Aged; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D014945:Wound Healing
chemical_list: D000970:Antineoplastic Agents; C497483:CD44 protein, human; D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; D018960:Hyaluronan Receptors; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D006923:Hymecromone; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C101754:HAS2 protein, human; D000076002:Hyaluronan Synthases; C473096:Hyal2 protein, human; D006821:Hyaluronoglucosaminidase