title: Leptin stimulates migration and invasion and maintains cancer stem-like properties in ovarian cancer cells: an explanation for poor outcomes in obese women.
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.
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: Division of Obstetrics and Gynecology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Lorena
authors.initials: L
authors.lastname: Abarzua-Catalan
authors.affiliation: Division of Obstetrics and Gynecology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: César
authors.initials: C
authors.lastname: Trigo
authors.affiliation: Division of Obstetrics and Gynecology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Ana
authors.initials: A
authors.lastname: Delpiano
authors.affiliation: Department Hematology and Oncology, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Cristobal
authors.initials: C
authors.lastname: Sanhueza
authors.affiliation: Division of Obstetrics and Gynecology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Karen
authors.initials: K
authors.lastname: García
authors.affiliation: Department Hematology and 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: Katherine
authors.initials: K
authors.lastname: Hormazábal
authors.affiliation: Division of Obstetrics and Gynecology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Daniela
authors.initials: D
authors.lastname: Diaz
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: Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: Enrique
authors.initials: E
authors.lastname: Castellón
authors.affiliation: Gynecologic Oncology Unit, Hospital Gustavo Fricke, Viña del Mar, Chile.
authors.forename: Erasmo
authors.initials: E
authors.lastname: Bravo
authors.affiliation: Department of Physiological Sciences, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Gareth
authors.initials: G
authors.lastname: Owen
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
mesh_terms: D000368:Aged; D001201:Ascites / Q000097:blood; D045744:Cell Line, Tumor; D002465:Cell Movement; D015331:Cohort Studies; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D006801:Humans; D020738:Leptin / Q000097:blood / Q000378:metabolism*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000166:cytology*; D009765:Obesity / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000150:complications* / Q000378:metabolism* / Q000401:mortality; D050177:Overweight; D011379:Prognosis; D011994:Recombinant Proteins / Q000737:chemistry; D012008:Recurrence; D016896:Treatment Outcome
chemical_list: D020738:Leptin; D011994:Recombinant Proteins
keywords: leptin; metastasis; neoplasia; obesity; ovary