Abstract
A high energy balance, or caloric excess, accounts as a tumor promoting factor, while a negative energy balance via caloric restriction, has been shown to delay cancer progression. The effect of energy balance on ovarian cancer progression was investigated in an isogeneic immunocompetent mouse model of epithelial ovarian cancer kept on a regimen of regular diet, high energy diet (HED) and calorie restricted diet (CRD), prior to inoculating the animals intraperitoneally with the mouse ovarian surface epithelial ID8 cancer cells. Tumor evaluation revealed that mice group on HED displayed the most extensive tumor formation with the highest tumor score at all organ sites (diaphragm, peritoneum, bowel, liver, kidney, spleen), accompanied with increased levels of insulin, leptin, insulin growth factor-1 (IGF-1), monocyte chemoattractant protein-1 (MCP-1), VEGF and interleukin 6 (IL-6). On the other hand, the mice group on CRD exhibited the least tumor burden associated with a significant reduction in levels of insulin, IGF-1, leptin, MCP-1, VEGF and IL-6. Immunohistochemistry analysis of tumors from HED mice showed higher activation of Akt and mTOR with decreased adenosine monophosphate activated kinase (AMPK) and SIRT1 activation, while tumors from the CRD group exhibited the reverse profile. In conclusion, ovarian cancer growth and metastasis occurred more aggressively under HED conditions and was significantly curtailed under CRD. The suggested mechanism involves modulated secretion of growth factors, cytokines and altered regulation of AMPK and SIRT1 that converges on mTOR inhibition. While the role of a high energy state in ovarian cancer has not been confirnmed in the literature, the current findings support investigating the potential impact of diet modulation as adjunct to other anticancer therapies and as possible individualized treatment strategy of epithelial ovarian cancer.
Highlights
Ovarian cancer is the fifth leading cause of cancer death in women, making it the most lethal gynecologic cancer [1]
One of the pathways shown to be significantly elevated by high energy diet and reduced by calorie restriction (CR) is the insulin-insulin growth factor (IGF-1) pathway and its downstream signaling leading to the activation of the phosphatidylinositol-3 kinase (PI3K)/Akt- mTOR pathways [14]
We present a comprehensive investigation of how positive and negative energy balance attained by providing high energy diet (HED) and calorie restricted diet (CRD), respectively, modulates ovarian cancer progression in an immunocompetent animal model of ovarian cancer
Summary
Ovarian cancer is the fifth leading cause of cancer death in women, making it the most lethal gynecologic cancer [1]. One of the pathways shown to be significantly elevated by high energy diet and reduced by calorie restriction (CR) is the insulin-insulin growth factor (IGF-1) pathway and its downstream signaling leading to the activation of the phosphatidylinositol-3 kinase (PI3K)/Akt- mTOR pathways [14]. The PI3K/Akt pathway, apart from being activated by insulin/IGF-1, integrates signaling from other stimuli and environmental cues to regulate cell survival and proliferation [18]. It is one of the most commonly activated pathways in all cancers [19]. Hormones like adiponectin and leptin have been widely shown to undergo alterations under energy modulations [20,21,22]
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