Leptin stimulates migration and invasion and maintains cancer stem-like properties in ovarian cancer cells: an explanation for poor outcomes in obese women

// Sumie Kato 1 , Lorena Abarzua-Catalan 1 , Cesar Trigo 1 , Ana Delpiano 1 , Cristobal Sanhueza 2 , Karen Garcia 1 , Carolina Ibanez 2 , Katherine Hormazabal 1 , Daniela Diaz 1 , Jorge Branes 1 , Enrique Castellon 4 , Erasmo Bravo 5 , Gareth Owen 3 and Mauricio A. Cuello 1 1 Division of Obstetrics and Gynecology, Faculty of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile 2 Department Hematology and Oncology, Pontificia Universidad Catolica de Chile, Santiago, Chile 3 Department of Physiological Sciences, Faculty of Biological Sciences, Pontificia Universidad Catolica de Chile, Santiago, Chile 4 Faculty of Medicine, University of Chile, Santiago, Chile 5 Gynecologic Oncology Unit, Hospital Gustavo Fricke, Vina del Mar, Chile Correspondence to: Mauricio A. Cuello, email: // Keywords : leptin, ovary, neoplasia, metastasis, obesity Received : March 10, 2015 Accepted : May 13, 2015 Published : May 22, 2015 Abstract The evidence linking obesity with ovarian cancer remains controversial. Leptin is expressed at higher levels in obese women and stimulates cell migration in other epithelial cancers. Here, we explored the clinical impact of overweight/obesity on patient prognosis and leptin’s effects on the metastatic potential of ovarian cancer cells. We assessed clinical outcomes in 70 ovarian cancer patients (33 healthy weight and 37 overweight) that were validated with an external cohort from The Cancer Genome Atlas (TCGA) database. Progression-free and overall survival rates were significantly decreased in overweight patients. Similarly, a worse overall survival rate was found in TCGA patients expressing higher leptin/OB-Rb levels. We explored serum and ascites leptin levels and OB-Rb expression in our cohort. Serum and ascites leptin levels were higher in overweight patients experiencing worse survival. OB-Rb was more highly expressed in ascites and metastases than in primary tumors. Leptin exposure increased cancer cell migration/invasion through leptin-mediated activation of JAK/STAT3, PI3/AKT and RhoA/ROCK and promoted new lamellipodial, stress-fiber and focal adhesion formation. Leptin also contributed to the maintenance of stemness and the mesenchymal phenotype in ovarian cancer cells. Our findings demonstrate that leptin stimulated ovarian cancer cell migration and invasion, offering a potential explanation for the poor prognosis among obese women.