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Cancer Res. 2015 Dec 1;75(23):5046-57. doi: 10.1158/0008-5472.CAN-15-0706. Epub 2015 Nov 16.

Obesity Contributes to Ovarian Cancer Metastatic Success through Increased Lipogenesis, Enhanced Vascularity, and Decreased Infiltration of M1 Macrophages.

Author information

1
Department of Chemistry and Biochemistry, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana. Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana.
2
Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana.
3
University of Toledo College of Medicine and Life Sciences, Toledo, Ohio.
4
Earlham College, Richmond, Indiana.
5
Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana. Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana.
6
Department of Pathology and Anatomical Sciences, University of Missouri School of Medicine, Columbia, Missouri. Department of Medical Physiology and Pharmacology, University of Missouri School of Medicine, Columbia, Missouri.
7
Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana. Department of Medical Physiology and Pharmacology, University of Missouri School of Medicine, Columbia, Missouri.
8
Zen-Bio Inc., Research Triangle Park, North Carolina.
9
Department of Chemistry and Biochemistry, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana. Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana. sstack@nd.edu.

Abstract

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancy, with high mortality attributable to widespread intraperitoneal metastases. Recent meta-analyses report an association between obesity, ovarian cancer incidence, and ovarian cancer survival, but the effect of obesity on metastasis has not been evaluated. The objective of this study was to use an integrative approach combining in vitro, ex vivo, and in vivo studies to test the hypothesis that obesity contributes to ovarian cancer metastatic success. Initial in vitro studies using three-dimensional mesomimetic cultures showed enhanced cell-cell adhesion to the lipid-loaded mesothelium. Furthermore, in an ex vivo colonization assay, ovarian cancer cells exhibited increased adhesion to mesothelial explants excised from mice modeling diet-induced obesity (DIO), in which they were fed a "Western" diet. Examination of mesothelial ultrastructure revealed a substantial increase in the density of microvilli in DIO mice. Moreover, enhanced intraperitoneal tumor burden was observed in overweight or obese animals in three distinct in vivo models. Further histologic analyses suggested that alterations in lipid regulatory factors, enhanced vascularity, and decreased M1/M2 macrophage ratios may account for the enhanced tumorigenicity. Together, these findings show that obesity potently affects ovarian cancer metastatic success, which likely contributes to the negative correlation between obesity and ovarian cancer survival.

PMID:
26573796
PMCID:
PMC4668203
DOI:
10.1158/0008-5472.CAN-15-0706
[Indexed for MEDLINE]
Free PMC Article

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