Research Papers:

Diabetic concentrations of metformin inhibit platelet-mediated ovarian cancer cell progression

Rafaela Erices, Sofía Cubillos, Raúl Aravena, Felice Santoro, Monica Marquez, Renan Orellana, Carolina Ramírez, Pamela González, Patricia Fuenzalida, María Loreto Bravo, Bárbara Oliva, Sumie Kato, Carolina Ibañez, Jorge Brañes, Erasmo Bravo, Catalina Alonso, Karen García, Clemente Arab, Vicente A. Torres, Alejandro S. Godoy, Jaime Pereira, Galdo Bustos, Julio Cesar Cardenas, Mauricio A. Cuello and Gareth I. Owen _

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Oncotarget. 2017; 8:20865-20880. https://doi.org/10.18632/oncotarget.15348

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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

Correspondence to:

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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