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

Autor: Janine M. Lombard, Yvette Ius, Pravin Nahar, Kenneth Jaaback, Rachel O'Sullivan, Lisa Wood, Subhransu S. Sahoo, Pradeep S. Tanwar
Rok vydání: 2017
Předmět:
0301 basic medicine
Vascular Endothelial Growth Factor A
Cancer Research
medicine.medical_specialty
medicine.medical_treatment
Adipose tissue
03 medical and health sciences
Mice
0302 clinical medicine
Cell Movement
Internal medicine
Cell Line
Tumor
VEGF Signaling Pathway
medicine
Animals
Humans
Obesity
Molecular Biology
PI3K/AKT/mTOR pathway
Cells
Cultured
Cell Proliferation
2. Zero hunger
business.industry
Endometrial cancer
TOR Serine-Threonine Kinases
Cancer
3T3 Cells
Hyperplasia
medicine.disease
3. Good health
Endometrial hyperplasia
Endometrial Neoplasms
Tumor Burden
Up-Regulation
Disease Models
Animal
030104 developmental biology
Endocrinology
Cytokine
Oncology
Adipose Tissue
030220 oncology & carcinogenesis
Culture Media
Conditioned
Endometrial Hyperplasia
Cancer research
Cytokines
Female
business
Signal Transduction
Zdroj: Molecular cancer research : MCR. 16(2)
ISSN: 1557-3125
Popis: 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.
Databáze: OpenAIRE
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