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Mol Cancer Res. 2018 Feb;16(2):309-321. doi: 10.1158/1541-7786.MCR-17-0466. Epub 2017 Nov 13.

Adipose-Derived VEGF-mTOR Signaling Promotes Endometrial Hyperplasia and Cancer: Implications for Obese Women.

Author information

1
Gynaecology Oncology Group, University of Newcastle, Newcastle, New South Wales, Australia.
2
School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.
3
Department of Medical Oncology, Calvary Mater Newcastle, Newcastle, New South Wales, Australia.
4
Department of Gynecological Oncology, John Hunter Hospital, Newcastle, New South Wales, Australia.
5
Department of Maternity and Gynecology, John Hunter Hospital, Newcastle, New South Wales, Australia.
6
Gynaecology Oncology Group, University of Newcastle, Newcastle, New South Wales, Australia. pradeep.tanwar@newcastle.edu.au.
7
Priority Research Centre for Reproductive Science, University of Newcastle, Newcastle, New South Wales, Australia.
8
Cancer Research Program, Hunter Medical Research Institute, Newcastle, New South Wales, Australia.

Abstract

Obesity is responsible for increased morbidity and mortality in endometrial cancer. Despite the positive correlation of body mass index (BMI) or obesity in endometrial carcinogenesis, the contribution of adipose tissue to the pathogenesis of endometrial hyperplasia and cancer is unclear. This study clarifies the role of adipocytes in the pathogenesis of endometrial cancer by demonstrating that adipocyte-conditioned medium (ACM) increases proliferation, migration, and survival of endometrial cancer cells compared with preadipocyte-conditioned medium (PACM). Comparative cytokine array analysis of ACM and PACM reveal upregulation of a group of cytokines belonging to the VEGF signaling pathway in ACM. VEGF protein expression is upregulated in visceral adipose tissue (VAT) in obese patients, which is correlated with increased tumor growth in an in vivo xenograft model. The increased tumor size is mechanistically associated with the activation of the PI3K/AKT/mTOR pathway, a downstream target of VEGF signaling, and its suppression decreased the growth-promoting effects of VAT on endometrial cancer cells. Similar to the human model systems, pathologic changes in endometrial cells in a hyperphagic obese mouse model are associated with increased body weight and hyperactive mTOR signaling. Analysis of human tissue specimens depicts increased in tumor vasculature and VEGF-mTOR activity in obese endometrial cancer patients compared with nonobese patients. Collectively, these results provide evidence that VEGF-mTOR signaling drives endometrial cell growth leading to hyperplasia and cancer.Implications: Adipocyte-derived VEGF-mTOR signaling may be an attractive therapeutic target against endometrial cancer in obese women. Mol Cancer Res; 16(2); 309-21. ©2017 AACR.

PMID:
29133593
DOI:
10.1158/1541-7786.MCR-17-0466
[Indexed for MEDLINE]
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