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.
Highlights
Epithelial ovarian cancer is the deadliest gynecologic malignancy [1]
To address whether obesity constitutes a risk factor that predisposes a worse outcome in epithelial ovarian cancer, we studied 70 stage III and IV patients that were treated at our institution and stratified the cases by body mass index (BMI)
Olsen et al examined the association between high BMI and ovarian cancer risk through a pooled analysis of 15 case-control studies from the Ovarian Cancer Association Consortium
Summary
Epithelial ovarian cancer is the deadliest gynecologic malignancy [1]. Despite extensive efforts to improve the detection and treatment of ovarian cancer, the majority of affected women still succumb to the disease. Accumulating evidence has begun to support the role of obesity in ovarian carcinogenesis In this respect, two epidemiological studies have established an association between ovarian cancer and body mass index (BMI), a strong marker for obesity [4, 5]. Two epidemiological studies have established an association between ovarian cancer and body mass index (BMI), a strong marker for obesity [4, 5] Consistent with these findings, our group has shown a 20% increase in the ovarian cancer age-adjusted mortality rate among Chilean women, a population where the obesity prevalence has strikingly risen above 30% in recent decades [6]. This increase in mortality is not related to changes in life expectancy or difficulties in accessing adequate treatment in a developing country
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