Obesity increases tumor aggressiveness in a genetically engineered mouse model of serous ovarian cancer

Abstract

Objectives Obesity is associated with increased risk and worse outcomes for ovarian cancer. Thus, we examined the effects of obesity on ovarian cancer progression in a genetically engineered mouse model of serous ovarian cancer. Methods We utilized a unique serous ovarian cancer mouse model that specifically deletes the tumor suppressor genes, Brca1 and p53, and inactivates the retinoblastoma (Rb) proteins in adult ovarian surface epithelial cells, via injection of an adenoviral vector expressing Cre (AdCre) into the ovarian bursa cavity of adult female mice (KpB mouse model). KpB mice were subjected to a 60% calories-derived from fat in a high fat diet (HFD) versus 10% calories from fat in a low fat diet (LFD) to mimic diet-induced obesity. Tumors were isolated at 6 months after AdCre injection and evaluated histologically. Untargeted metabolomic and gene expression profiling was performed to assess differences in the ovarian tumors from obese versus non-obese KpB mice. Results At sacrifice, mice on the HFD (obese) were twice the weight of mice on the LFD (non-obese) (51 g versus 31 g, p = 0.0003). Ovarian tumors were significantly larger in the obese versus non-obese mice (3.7 cm2 versus 1.2 cm2, p = 0.0065). Gene expression and metabolomic profiling indicated statistically significant differences between the ovarian tumors from the obese versus non-obese mice, including metabolically relevant pathways.

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

“…While Affymetrix-based gene expression profiling of tumors formed in the KpB murine model of ovarian cancer subjected to a high fat diet showed enhanced mRNA expression of LCN2 [37]; we did not observe expression of this adipokine at the protein level in our models [Fig. 7A–D].…”

“…Previous studies have implicated proteins involved in lipid regulation in the intra-peritoneal growth of metastatic ovarian cancer including the adipokine lipocalin-2 (LCN2) and the lipid transport protein fatty acid binding protein-4 (FABP4) [28, 37]. While Affymetrix-based gene expression profiling of tumors formed in the KpB murine model of ovarian cancer subjected to a high fat diet showed enhanced mRNA expression of LCN2 [37]; we did not observe expression of this adipokine at the protein level in our models [Fig.…”

The effect of celecoxib on tumor growth in ovarian cancer cells and a genetically engineered mouse model of serous ovarian cancer

“…Recombinant adenovirus Ad5-CMV-Cre (AdCre) was purchased from the University of Iowa Transfer Vector Core at a titer of 10 11 −10 12 infectious particles/ml. To maximize weight gain, mice were provided a high-fat diet (HFD, obese group) (60% kcal from fat, Research Diets, New Brunswick, NJ) and control mice (non-obese group) were provided a low-fat diet (LFD) (10% kcal from fat, Research Diets, New Brunswick, NJ) ad libitum , beginning at 3 weeks of age [59]. AdCre injection occurred at 6 weeks to induce OC [58].…”

Obesity Exposure Across the Lifespan on Ovarian Cancer Pathogenesis

“…Genomic and metabolic differences characterize ovarian tumors arising in obese and lean mice. Gene expression and metabolomic profiling indicated statistically significant differences between ovarian tumors arising in obese versus lean mice (Figure 2 & Table 2) (18). 417 genes were up-regulated and 22 genes down-regulated in ovarian tumors from obese KpB mice versus lean mice (FDR<0.2), including genes involved in glucose, fatty acid and lipid metabolism as well as regulators of metabolic signaling pathways such as 5' adenosine monophosphate-activated protein kinase (AMPK).…”