title: Modulating Three-Dimensional Microenvironment with Hyaluronan of Different Molecular Weights Alters Breast Cancer Cell Invasion Behavior.
abstract: Hyaluronan (HA), a polymer with various molecular weights (MW) found in tumor microenvironments, is associated with malignant progression of breast cancer. Reducing the amount of high-MW HA in the microenvironment by hyaluronidase is a promising approach for breast cancer treatment. However, whether the generation of HA fragments negatively affects breast cancer cells remains to be determined. Furthermore, HA forms three-dimensional (3D) networks by cross-linking with other extracellular molecules to function. Therefore, a model mimicking the cross-linked HA network is required to determine the effect of HA fragments on breast cancer cells. To clarify the differential roles of low (HA35) versus high (HA117) MW HA on cancer cell phenotype, a 3D culture system was set up by covalently cross-linking HA with alginate and investigating the behavior of 4T-1 and SKBR3 breast cancer cells alongside a two-dimensional (2D) control. The results show the invasion and migration abilities of 4T-1 and SKBR3 cells are significantly enhanced by the presence of HA35 but inhibited by HA117 in both 2D monolayers and 3D spheroids. The differential effects of HA35 and HA117 on cancer cell epithelial-mesenchymal transition (EMT) phenotype were further confirmed in terms of differential regulation of E-cadherin and vimentin as important EMT markers at both the cellular and mRNA levels. Additional experiments show the CD44-Twist signaling pathway might be involved in the differential effects of HA35 and HA117. These results have important implications with respect to understanding the role of HA in breast cancer development and for the design of therapeutic approaches based on the eradication of HA with hyaluronidase.
authors.affiliation: School of Life Science and Technology, Harbin Institute of Technology , Harbin 150080, P. R. China.
authors.forename: Yu-Fang
authors.initials: YF
authors.lastname: Zhao
authors.affiliation: School of Life Science and Technology, Harbin Institute of Technology , Harbin 150080, P. R. China.
authors.forename: Shu-Pei
authors.initials: SP
authors.lastname: Qiao
authors.affiliation: School of Life Science and Technology, Harbin Institute of Technology , Harbin 150080, P. R. China.
authors.forename: Shu-Liang
authors.initials: SL
authors.lastname: Shi
authors.affiliation: Department of Neurology (National Clinical Key Specialty), The First Affiliated Hospital of Harbin Medical University , Harbin, Heilongjiang Province 150080, P. R. China.
authors.forename: Li-Fen
authors.initials: LF
authors.lastname: Yao
authors.affiliation: School of Life Science and Technology, Harbin Institute of Technology , Harbin 150080, P. R. China.
authors.forename: Xiao-Lu
authors.initials: XL
authors.lastname: Hou
authors.affiliation: School of Life Science and Technology, Harbin Institute of Technology , Harbin 150080, P. R. China.
authors.forename: Chun-Feng
authors.initials: CF
authors.lastname: Li
authors.affiliation: Division of Biomedical Engineering and Nanomedicine Research, National Health Research Institutes , Miaoli 360, Taiwan, ROC.|Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University , Taipei 222, Taiwan, ROC.
authors.forename: Feng-Huei
authors.initials: FH
authors.lastname: Lin
authors.affiliation: School of Life Science and Technology, Harbin Institute of Technology , Harbin 150080, P. R. China.
authors.forename: Kai
authors.initials: K
authors.lastname: Guo
authors.affiliation: School of Life Science and Technology, Harbin Institute of Technology , Harbin 150080, P. R. China.
authors.forename: Alaka
authors.initials: A
authors.lastname: Acharya
authors.affiliation: Department of Mechanical Engineering, University of Saskatchewan , Saskatoon, Saskatchewan S7N 5A2, Canada.
authors.forename: Xiong-Biao
authors.initials: XB
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, The Fourth Military Medical University , Xi'an, Shaanxi 710032, P. R. China.
authors.forename: Yongzhan
authors.initials: Y
authors.lastname: Nie
authors.affiliation: School of Life Science and Technology, Harbin Institute of Technology , Harbin 150080, P. R. China.
authors.forename: Wei-Ming
authors.identifier: http://orcid.org/0000-0003-2816-1204
authors.initials: WM
authors.lastname: Tian
mesh_terms: D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D002465:Cell Movement; D006801:Humans; D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid / Q000737:chemistry*; D006821:Hyaluronoglucosaminidase; D008970:Molecular Weight; D009363:Neoplasm Proteins; D059016:Tumor Microenvironment
chemical_list: C586650:HA117 protein, human; D018960:Hyaluronan Receptors; D009363:Neoplasm Proteins; D006820:Hyaluronic Acid; D006821:Hyaluronoglucosaminidase
keywords: breast cancer cell; hyaluronan; invasion; molecular weight; three-dimensional microenvironment