title: Paracrine factors of human fetal MSCs inhibit liver cancer growth through reduced activation of IGF-1R/PI3K/Akt signaling.
abstract: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death in the world. The multikinase inhibitor sorafenib only demonstrated marginal improvement in overall survival for advanced disease prompted the search for alternative treatment options. Human mesenchymal stem cells (MSCs) have the ability to home to tumor cells. However, its functional roles on the tumor microenvironment remain controversial. Herein, we showed that conditioned media derived from human fetal MSC (CM-hfMSCs) expressed high level of the insulin growth factor binding proteins IGFBPs and can sequester free insulin-like growth factors (IGFs) to inhibit HCC cell proliferation. The inhibitory effect of IGFBPs on IGF signaling was further evident from the reduction of activated IGF-1R and PI3K/Akt, leading eventually to the induction of cell cycle arrest. We also demonstrated that CM-hfMSCs could enhance the therapeutic efficacy of sorafenib and sunitinib. To the best of our knowledge, this is the first report to show that CM-hfMSCs has a tumor-specific, antiproliferative effect that is not observed with normal human hepatocyte cells and patient-derived matched normal tissues. Our results thus suggest that CM-hfMSCs can provide a useful tool to design alternative/adjuvant treatment strategies for HCC, especially in related function to potentiate the effects of chemotherapeutic drugs.
authors.affiliation: Division of Cellular and Molecular Research, National Cancer Centre, Singapore.
authors.forename: Yulyana
authors.initials: Y
authors.lastname: Yulyana
authors.affiliation: Division of Cellular and Molecular Research, National Cancer Centre, Singapore.
authors.forename: Ivy A W
authors.initials: IA
authors.lastname: Ho
authors.affiliation: Division of Cellular and Molecular Research, National Cancer Centre, Singapore.
authors.forename: Kian Chuan
authors.initials: KC
authors.lastname: Sia
authors.affiliation: Division of Cellular and Molecular Research, National Cancer Centre, Singapore.
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Newman
authors.affiliation: Division of Cellular and Molecular Research, National Cancer Centre, Singapore.
authors.forename: Xin Yi
authors.initials: XY
authors.lastname: Toh
authors.affiliation: Griffith University, Griffith Health Institute, School of Medical Science, Southport, Australia.
authors.forename: Berwini B
authors.initials: BB
authors.lastname: Endaya
authors.affiliation: 1] Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore [2] Department of Reproductive Medicine, KK Women's and Children's Hospital, Singapore [3] Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore.
authors.forename: Jerry K Y
authors.initials: JK
authors.lastname: Chan
authors.affiliation: 1] Department of Cardiothoracic and Vascular Sciences - Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy [2] Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Italy [3] Department of Medicine, University of Cape Town, South Africa.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Gnecchi
authors.affiliation: Division of Cellular and Molecular Research, National Cancer Centre, Singapore.
authors.forename: Hung
authors.initials: H
authors.lastname: Huynh
authors.affiliation: Department of General Surgery, Singapore General Hospital, Singapore.
authors.forename: Alexander Y F
authors.initials: AY
authors.lastname: Chung
authors.affiliation: Department of Pathology, Singapore General Hospital, Singapore.
authors.forename: Kiat Hon
authors.initials: KH
authors.lastname: Lim
authors.affiliation: Division of Medical Sciences, National Cancer Centre, Singapore.
authors.forename: Hui Sun
authors.initials: HS
authors.lastname: Leong
authors.affiliation: Division of Medical Sciences, National Cancer Centre, Singapore.
authors.forename: Narayanan Gopalakrishna
authors.initials: NG
authors.lastname: Iyer
authors.affiliation: 1] Division of Cellular and Molecular Research, National Cancer Centre, Singapore [2] Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore [3] Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore [4] Institute of Molecular and Cell Biology, A*STAR, Proteos, Singapore.
authors.forename: Kam Man
authors.initials: KM
authors.lastname: Hui
authors.affiliation: 1] Division of Cellular and Molecular Research, National Cancer Centre, Singapore [2] Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore [3] Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Paula Y P
authors.initials: PY
authors.lastname: Lam
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology*; D049109:Cell Proliferation; D017077:Culture Media, Conditioned; D005333:Fetus / Q000166:cytology*; D055785:Gene Knockdown Techniques; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D009536:Niacinamide / Q000031:analogs & derivatives / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011758:Pyrroles / Q000627:therapeutic use; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000077157:Sorafenib; D000077210:Sunitinib
chemical_list: D017077:Culture Media, Conditioned; D007211:Indoles; D010671:Phenylurea Compounds; D011758:Pyrroles; D009536:Niacinamide; D000077157:Sorafenib; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D000077210:Sunitinib