title: Excessive hyaluronan production promotes acquisition of cancer stem cell signatures through the coordinated regulation of Twist and the transforming growth factor β (TGF-β)-Snail signaling axis.
abstract: The cancer stem cell (CSC) model suggests that a small subpopulation of cancer cells possesses the ability to self-renew and give rise to malignant progeny that drive cancer progression. Recent reports have also proposed the existence of certain extra- or intracellular signals that allow cancer progenitors to dynamically revert to a stem cell state. However, the mechanisms underlying cancer cell plasticity and CSC expansion are not entirely clear. Our previous studies using a hyaluronan synthase 2 (Has2) transgenic mouse model demonstrated that hyaluronan overproduction caused rapid development of aggressive breast carcinoma at a high incidence. Thus, we hypothesize that hyaluronan overproduction may accelerate cancer progression by expanding CSC subpopulations during cancer development. Primary cancer cells were established from mammary tumors developed in the transgenic mice and subjected to the Hoechst 33342 dye exclusion assay to sort side population (SP) from non-side population (non-SP) cells. Flow cytometric analysis demonstrated the enrichment of CD44(high)/CD24(low) CSC-like cells in the SP fraction of hyaluronan-overproducing cancer cells. This subpopulation exhibited several characteristics that were similar to CSCs, including cancer-initiating and mammosphere-forming abilities. Excess hyaluronan production drove the epithelial-to-mesenchymal transition process defined as the loss of epithelial phenotypes, up-regulation of transforming growth factor β (TGF-β), and induction of the epithelial-to-mesenchymal transition-related transcriptional factors Snail and Twist. Inhibition of TGF-β-Snail signaling or silencing of Twist expression abrogated the entrance into a stem cell state. Taken together, our findings suggest that hyaluronan overproduction allows plastic cancer cell populations to revert to stem cell states via Twist and the TGF-β-Snail signaling axis.
authors: Institute of Advanced Technology, Kyoto Sangyo University, Kita-ku, Kyoto 603-8555, Japan.
authors: Theerawut
authors: T
authors: Chanmee
authors: Division of Engineering (Biotechnology), Graduate School of Engineering, and Kyoto Sangyo University, Kita-ku, Kyoto 603-8555, Japan.
authors: Pawared
authors: P
authors: Ontong
authors: Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Kita-ku, Kyoto 603-8555, Japan.
authors: Nobutoshi
authors: N
authors: Mochizuki
authors: Thailand Excellence Center for Tissue Engineering and Stem Cells, Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand, and.
authors: Prachya
authors: P
authors: Kongtawelert
authors: Department of Animal Medical Sciences, Faculty of Life Sciences, Kyoto Sangyo University, Kita-ku, Kyoto 603-8555, Japan. Electronic address: kkonno@cc.kyoto-su.ac.jp.
authors: Kenjiro
authors: K
authors: Konno
authors: Institute of Advanced Technology, Kyoto Sangyo University, Kita-ku, Kyoto 603-8555, Japan; Division of Engineering (Biotechnology), Graduate School of Engineering, and Kyoto Sangyo University, Kita-ku, Kyoto 603-8555, Japan; Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Kita-ku, Kyoto 603-8555, Japan,. Electronic address: itanon@cc.kyoto-su.ac.jp.
authors: Naoki
authors: N
authors: Itano
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D004790:Enzyme Induction; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015870:Gene Expression; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000096:biosynthesis*; D020935:MAP Kinase Signaling System; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014407:Tumor Cells, Cultured; D051879:Twist-Related Protein 1 / Q000378:metabolism*
chemical_list: D009687:Nuclear Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D051879:Twist-Related Protein 1; C067250:Twist1 protein, mouse; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C491099:Has2 protein, mouse; D000076002:Hyaluronan Synthases
keywords: Cancer Biology; Cancer Stem Cells; Epithelial-Mesenchymal Transition (EMT); Extracellular Matrix; Glycobiology; Glycosyltransferase; Hyaluronan; Snail; Transforming Growth Factor β (TGF-β); Twist