Briggs Alexandra, Rosenberg Laura, Buie Justin D, Rizvi Hira, Bertagnolli Monica M, Cho Nancy L
Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA and Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
Carcinogenesis. 2015 Feb;36(2):272-9. doi: 10.1093/carcin/bgu324. Epub 2015 Jan 2.
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.
硬纤维瘤（DTs）是一种罕见的间充质肿瘤，具有丰富的伤口愈合过程特征。此前，我们发现间充质干细胞（MSCs）是DTs的组成部分，并可能通过与伤口愈合相关的活动促进硬纤维瘤的发生。透明质酸（HA）是由重复的葡萄糖醛酸和N - 乙酰葡糖胺二糖组成的长链带电荷分子，由透明质酸合酶（HAS）合成，并由透明质酸酶（HYAL）降解。HA由受损的基质分泌到细胞外基质中，对正常组织修复和肿瘤进展很重要。在此，我们研究了HA在DTs中的存在情况以及HA抑制剂4 - 甲基伞形酮（4 - MU）对DTs来源的间充质细胞的抗肿瘤作用。通过免疫组织化学和酶联免疫吸附测定，我们发现29/30例DTs中HA表达丰富，并且相对于对照组，DTs来源的细胞系中HA水平增加了5倍以上。免疫组织化学还显示DTs中HAS2高表达，定量PCR分析表明冷冻的DTs和DTs来源的细胞中HAS2上调增加。用4 - MU处理DTs来源的细胞显著降低了细胞增殖以及HA和HAS2水平。荧光免疫组织化学显示DTs中的MSCs共表达HA、HAS2、HYAL2以及主要的HA受体CD44和HA共受体TLR4。综上所述，我们的结果表明DTs中HA信号的旁分泌调节可能有助于MSC募集和肿瘤增殖。有必要开展进一步研究，探讨HA在肿瘤 - 基质相互作用中的作用以及抑制HA - MSC相互作用作为DTs和其他实体瘤的新型治疗靶点。
