title: Diabetic concentrations of metformin inhibit platelet-mediated ovarian cancer cell progression.
abstract: Clinical studies have suggested a survival benefit in ovarian cancer patients with type 2 diabetes mellitus taking metformin, however the mechanism by which diabetic concentrations of metformin could deliver this effect is still poorly understood. Platelets not only represent an important reservoir of growth factors and angiogenic regulators, they are also known to participate in the tumor microenvironment implicated in tumor growth and dissemination. Herein, we investigated if diabetic concentrations of metformin could impinge upon the previously reported observation that platelet induces an increase in the tube forming capacity of endothelial cells (angiogenesis) and upon ovarian cancer cell aggressiveness. We demonstrate that metformin inhibits the increase in angiogenesis brought about by platelets in a mechanism that did not alter endothelial cell migration. In ovarian cancer cell lines and primary cultured cancer cells isolated from the ascitic fluid of ovarian cancer patients, we assessed the effect of combinations of platelets and metformin upon angiogenesis, migration, invasion and cancer sphere formation. The enhancement of each of these parameters by platelets was abrogated by the present of metformin in the vast majority of cancer cell cultures tested. Neither metformin nor platelets altered proliferation; however, metformin inhibited the increase in phosphorylation of focal adhesion kinase induced by platelets. We present the first evidence suggesting that concentrations of metformin present in diabetic patients may reduce the actions of platelets upon both endothelial cells and cancer cell survival and dissemination.
authors.affiliation: Division of Obstetrics and Gynecology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.|Department of Physiological Sciences, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Rafaela
authors.initials: R
authors.lastname: Erices
authors.affiliation: Department of Physiological Sciences, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Sofía
authors.initials: S
authors.lastname: Cubillos
authors.affiliation: Department of Physiological Sciences, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.|Universidad Santo Tomás, Santiago, Chile.
authors.forename: Raúl
authors.initials: R
authors.lastname: Aravena
authors.affiliation: Department of Physiological Sciences, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Felice
authors.initials: F
authors.lastname: Santoro
authors.affiliation: Department of Physiological Sciences, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Monica
authors.initials: M
authors.lastname: Marquez
authors.affiliation: Division of Obstetrics and Gynecology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.|Universidad Bernardo OHiggins, Facultad de Salud, Departamento de Ciencias Químicas y Biológicas, General Gana, Santiago, Chile.
authors.forename: Renan
authors.initials: R
authors.lastname: Orellana
authors.affiliation: Department of Physiological Sciences, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Carolina
authors.initials: C
authors.lastname: Ramírez
authors.affiliation: Department of Physiological Sciences, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.|Biomedical Research Consortium of Chile, Santiago, Chile.
authors.forename: Pamela
authors.initials: P
authors.lastname: González
authors.affiliation: Department of Physiological Sciences, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Patricia
authors.initials: P
authors.lastname: Fuenzalida
authors.affiliation: Department of Physiological Sciences, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.|Biomedical Research Consortium of Chile, Santiago, Chile.|Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: María Loreto
authors.initials: ML
authors.lastname: Bravo
authors.affiliation: Department of Physiological Sciences, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.|Biomedical Research Consortium of Chile, Santiago, Chile.
authors.forename: Bárbara
authors.initials: B
authors.lastname: Oliva
authors.affiliation: Division of Obstetrics and Gynecology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Sumie
authors.initials: S
authors.lastname: Kato
authors.affiliation: Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile.|Hematology and Oncology Department, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.|Center UC Investigation in Oncology, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Carolina
authors.initials: C
authors.lastname: Ibañez
authors.affiliation: Division of Obstetrics and Gynecology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Jorge
authors.initials: J
authors.lastname: Brañes
authors.affiliation: Hospital Gustavo Fricke, Viña de Mar, Santiago, Chile.
authors.forename: Erasmo
authors.initials: E
authors.lastname: Bravo
authors.affiliation: Hospital Gustavo Fricke, Viña de Mar, Santiago, Chile.
authors.forename: Catalina
authors.initials: C
authors.lastname: Alonso
authors.affiliation: Center UC Investigation in Oncology, Pontificia Universidad Católica de Chile, Santiago, Chile.|Hospital Sotero del Rio, Santiago, Chile.
authors.forename: Karen
authors.initials: K
authors.lastname: García
authors.affiliation: Hospital Luis Tisne, Santiago, Chile.
authors.forename: Clemente
authors.initials: C
authors.lastname: Arab
authors.affiliation: Institute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Santiago, Chile.|Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago, Chile.
authors.forename: Vicente A
authors.initials: VA
authors.lastname: Torres
authors.affiliation: Department of Physiological Sciences, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.|Roswell Park Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Alejandro S
authors.initials: AS
authors.lastname: Godoy
authors.affiliation: Hematology and Oncology Department, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Jaime
authors.initials: J
authors.lastname: Pereira
authors.affiliation: Anatomy and Developmental Biology, Institute of Biomedical Science, Geroscience Center for Brain Health and Metabolism, University of Chile, Santiago, Chile.
authors.forename: Galdo
authors.initials: G
authors.lastname: Bustos
authors.affiliation: Anatomy and Developmental Biology, Institute of Biomedical Science, Geroscience Center for Brain Health and Metabolism, University of Chile, Santiago, Chile.|Buck Institute for Research on Aging, Novato, CA, USA.
authors.forename: Julio Cesar
authors.initials: JC
authors.lastname: Cardenas
authors.affiliation: Division of Obstetrics and Gynecology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Mauricio A
authors.initials: MA
authors.lastname: Cuello
authors.affiliation: Department of Physiological Sciences, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.|Biomedical Research Consortium of Chile, Santiago, Chile.|Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile.|Center UC Investigation in Oncology, Pontificia Universidad Católica de Chile, Santiago, Chile.|Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago, Chile.
authors.forename: Gareth I
authors.initials: GI
authors.lastname: Owen
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001792:Blood Platelets; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D018450:Disease Progression; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008687:Metformin / Q000627:therapeutic use*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D007004:Hypoglycemic Agents; D008687:Metformin
keywords: EA.hy926; SKOV3; UCI101; hemostasis; thrombocytosis