Abstract
Simple SummaryObesity is a recognized epidemic worldwide. Ovarian cancer (OvCa), the most lethal gynecologic malignancy, is characterized by widely disseminated metastatic implants in the peritoneal cavity. Metastatic lesions infiltrate the omentum, as well as perigonadal adipose and other visceral adipose depots. Meta-analyses support a link between obesity and OvCa progression, metastasis and survival. Recent studies demonstrated a crucial role of lipid regulatory proteins in OvCa growth and metastasis. The aim of this review is to summarize current understanding of the relationship between lipid regulatory proteins, obesity and OvCa progression, as well as the potential therapeutic targets for antitumor therapy in obese OvCa patients, with an emphasis on the role of sterol regulatory element binding protein 1 (SREBP1). Obesity has become a recognized global epidemic that is associated with numerous comorbidities including type II diabetes, cardiovascular disease, hypertension, and cancer incidence and progression. Ovarian cancer (OvCa) has a unique mechanism of intra-peritoneal metastasis, already present in 80% of women at the time of diagnosis, making it the fifth leading cause of death from gynecological malignancy. Meta-analyses showed that obesity increases the risk of OvCa progression, leads to enhanced overall and organ-specific tumor burden, and adversely effects survival of women with OvCa. Recent data discovered that tumors grown in mice fed on a western diet (40% fat) have elevated lipid levels and a highly increased expression level of sterol regulatory element binding protein 1 (SREBP1). SREBP1 is a master transcription factor that regulates de novo lipogenesis and lipid homeostasis, and induces lipogenic reprogramming of tumor cells. Elevated SREBP1 levels are linked to cancer cell proliferation and metastasis. This review will summarize recent findings to provide a current understanding of lipid regulatory proteins in the ovarian tumor microenvironment with emphasis on SREBP1 expression in the obese host, the role of SREBP1 in cancer progression and metastasis, and potential therapeutic targeting of SREBPs and SREBP-pathway genes in treating cancers, particularly in the context of host obesity.
Highlights
The prevalence of overweight and obesity has increased substantially and become a major health issue worldwide [1]
Strong epidemiologic evidence shows that obesity and excess accumulation of adipose tissue is associated with increased risk of numerous solid and hematologic cancer incidence and progression [6,7], and a high Body mass index (BMI) has been considered as a negative prognostic factor for oncological outcomes, cancer recurrence and mortality [8]
The released nSREBP is transported into the nucleus as a dimer and activates transcription by binding to the sterol regulatorysynthesis elementsmainly (SREs) sequence in the promoters of target genes involved in lipogenesis, such as low-density lipoprotein receptor (LDLR), ATP-citrate lyase (ACLY), acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN), and SCD1 [32,107,108,109]
Summary
The prevalence of overweight and obesity has increased substantially and become a major health issue worldwide [1]. Recent epidemiological studies show that the age-adjusted prevalence of combined overweight and obesity (BMI ≥ 25 kg/m2 ) was 68.8% overall, 73.9% among men and 63.7% among women [2,3]. Strong epidemiologic evidence shows that obesity and excess accumulation of adipose tissue is associated with increased risk of numerous solid and hematologic cancer incidence and progression [6,7], and a high BMI has been considered as a negative prognostic factor for oncological outcomes, cancer recurrence and mortality [8]. Recent murine in vivo studies demonstrated that genetic and diet-induced obesity leads to enhanced OvCa tumor burden, increased intracellular lipid content, and elevated expression of sterol regulatory element binding protein 1 (SREBP1) [28]. Enhanced expression of SREBP1 induces lipogenic reprogramming of tumor cells and promotes cancer cell proliferation and metastasis [36,37,38]. We discuss the current understanding of ovarian cancer metastasis mechanisms, summarize recent findings that obesity contributes to cancer progression with a focus on the role of lipid regulatory protein SREBP1 in regulating cancer progression and metastasis, and discuss potential therapeutic targets in obese cancer patients
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