title: Mesenchymal stem cells regulate epithelial-mesenchymal transition and tumor progression of pancreatic cancer cells.
abstract: Cancer-associated fibroblasts contribute to cancer progression that is caused by epithelial-mesenchymal transition (EMT). Recently, mesenchymal stem cells (MSCs) were found to be the major candidate involved in the development of tumor-promoting cancer stroma. Here we report that α-smooth muscle actin-positive myofibroblast-like cells originating from MSCs contribute to inducing EMT in side population cells of pancreatic cancer. More importantly, MSC-derived myofibroblasts function to maintain tumor-initiating stem cell-like characteristics, including augmenting expression levels of various stemness-associated genes, enhancing sphere- forming activity, promoting tumor formation in a mouse xenograft model, and showing resistance to anticancer drugs. Furthermore, both γ-secretase inhibitor and siRNA directed against Jagged-1 attenuated MSC-associated E-cadherin suppression and sphere formation in pancreatic cancer side population cells. Thus, our results suggest that MSC-derived myofibroblasts play important roles in regulating EMT and tumor-initiating stem cell-like properties of pancreatic cancer cells through an intermediating Notch signal.
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Ayano
authors.initials: A
authors.lastname: Kabashima-Niibe
authors.forename: Hajime
authors.initials: H
authors.lastname: Higuchi
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Takaishi
authors.forename: Yohei
authors.initials: Y
authors.lastname: Masugi
authors.forename: Yumi
authors.initials: Y
authors.lastname: Matsuzaki
authors.forename: Yo
authors.initials: Y
authors.lastname: Mabuchi
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Funakoshi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Adachi
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Hamamoto
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Kawachi
authors.forename: Koichi
authors.initials: K
authors.lastname: Aiura
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kitagawa
authors.forename: Michiie
authors.initials: M
authors.lastname: Sakamoto
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Hibi
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D016212:Transforming Growth Factor beta; D053829:Amyloid Precursor Protein Secretases