Insights from engraftable immunodeficient mouse models of hyperinsulinaemia

Hyperinsulinemia, obesity and dyslipidemia are independent and collective risk factors for many cancers, however, there is a lack of suitable mouse models available to study this association.We examined the long-term effects of a “Western style” 23% high fat diet (HFD, 46% of total calculated energy from lipids) in two immunodeficient mouse strains (NOD/SCID and Rag1 -/-) suitable for engraftment with human-derived cell lines and tissue xenografts. HFD-fed mice of both strains exhibited diet-induced impairments in glucose tolerance at 16 and 23 weeks post initiation of HFD feeding. Only Rag1 -/- mice developed higher fasting insulin levels (2.16 ± 1.01ng/ml versus 0.71 ± 0.12ng/ml, P = 0.01) and increased insulin resistance (6.70 ± 1.68 HOMA-IR, versus 2.91 ± 0.42, P = 0.01) when fed a HFD. Similarly, hepatic steatosis was more extensive, and intramyocellular lipid storage was increased in HFD-fed Rag1 -/- mice. Conversely, NOD/SCID mice exhibited relatively low levels of steatosis and no intramyocellular lipid was observed. These data suggest that Rag1 -/- mice are a more suitable pre-clinical model for examining the interactions between hyperinsulinemia, obesity and hyperlipidemia and cancer than the more commonly used NOD/SCID mouse model.We next investigated the growth of human prostate cancer cell lines (PC3 and LNCaP) subcutaneously injected into hyperinsulinemic Rag1 -/- mice. Compared to normal chow-fed mice, tumor growth velocity was greater in HFD-fed mice with PC3 and LNCaP xenografts, and mice reached humane endpoints (cancer-associated cachexia and tumor burden) significantly earlier (P = 0.0078 and P = 0.031). Strikingly, HFD-fed mice bearing PC3 xenografts presented with significantly greater normalized wet tumor weight (485.16 ± 143.80% vs. 1562.69 ± 338.20%, P = 0.032), tumor volume (485.16 ± 143.80% vs.1562.69 ± 338.20%, P = 0.032) and number of Ki67 positive (proliferating) tumor cells (36.08 ± 2.53% vs. 66.14 ± 8.514, P = 0.032), compared to mice fed a normal chow diet.In summary, this is the first study of the metabolic effects of a long-term “Western style” HFD in two immunodeficient mouse strains suitable for xenograft studies. We demonstrate that the Rag1 -/- mouse is an appropriate and novel model for studying the interactions between hyperinsulinaemia and cancer.Citation Format: Michelle L. Maugham, Patrick B. Thomas, Gabrielle J. Crisp, Lisa K. Philp, Esha T. Shah, Adrian C. Herington, Chen Chen, Laura S. Gregory, Colleen C. Nelson, Inge Seim, Penny L. Jeffery, Lisa K. Chopin. Insights from engraftable immunodeficient mouse models of hyperinsulinaemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4819. doi:10.1158/1538-7445.AM2017-481