Diabetic concentrations of metformin inhibit platelet-mediated ovarian cancer cell progression
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Rafaela Erices1,2, Sofía Cubillos2, Raúl Aravena2,3, Felice Santoro2, Monica Marquez2, Renan Orellana1,15, Carolina Ramírez2, Pamela González2,4, Patricia Fuenzalida2, María Loreto Bravo2,4,5, Bárbara Oliva2,4, Sumie Kato1, Carolina Ibañez5,6,7, Jorge Brañes1, Erasmo Bravo8, Catalina Alonso8, Karen García7,9, Clemente Arab10, Vicente A. Torres11,16, Alejandro S. Godoy2,12, Jaime Pereira6, Galdo Bustos13, Julio Cesar Cardenas13,14, Mauricio A. Cuello1, Gareth I. Owen2,4,5,7,16
1Division of Obstetrics and Gynecology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
2Department of Physiological Sciences, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile
3Universidad Santo Tomás, Santiago, Chile
4Biomedical Research Consortium of Chile, Santiago, Chile
5Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile
6Hematology and Oncology Department, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
7Center UC Investigation in Oncology, Pontificia Universidad Católica de Chile, Santiago, Chile
8Hospital Gustavo Fricke, Viña de Mar, Santiago, Chile
9Hospital Sotero del Rio, Santiago, Chile
10Hospital Luis Tisne, Santiago, Chile
11Institute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Santiago, Chile
12Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, USA
13Anatomy and Developmental Biology, Institute of Biomedical Science, Geroscience Center for Brain Health and Metabolism, University of Chile, Santiago, Chile
14Buck Institute for Research on Aging, Novato, CA, USA
15Universidad Bernardo OHiggins, Facultad de Salud, Departamento de Ciencias Químicas y Biológicas, General Gana, Santiago, Chile
16Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago, Chile
Gareth I. Owen, email: [email protected]
Keywords: thrombocytosis, hemostasis, EA.hy926, SKOV3, UCI101
Received: July 27, 2016 Accepted: January 27, 2017 Published: February 15, 2017
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.
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