Obesity as a modulator of tumour microenvironment and anti-tumour responses in a mouse model

Abstract

Considerable recent attention has focused on obesity as a major global health problem. Obese individuals are at increased risk not only for metabolic syndrome, but also for different types of cancer including melanoma. The consequences for melanoma tumour development was explored with a high fat diet (HFD) which induced obesity in a Low-density lipoprotein receptor deficient (C57BL6 LDLR-/-) mice. Additionally, the presence or absence of dietary Vitamin D3 supplementation (in HFD fed mice) on melanoma tumour growth was also examined. In vitro assays demonstrated the key role that fatty acids (FAs) (either purified or present in the serum of HFD fed animals) had on the properties of B16-F10 and macrophages. FAs and serum from HFD fed mice fuelled B16F10 melanoma growth and led to an increase in cell proliferation, migration, lipid inclusion and altered chemokine production. Furthermore, FAs enhance expression of pro-inflammatory mediators by macrophages.VitD3 affects B16-F10 in dose dependent manner. However, VitD3 supplemented HFD serum increased B16-F10 proliferation. In the in vivo part, LDLR-/- mice were subjected to different types of diet (HFD, VitD3plus supplemented HFD and control diet) for 2 or 10 weeks prior to syngeneic implantation of B16F10. After 2- weeks post-injection of B16-F10, HFD feeding increases tumour growth combined with increases in adipose tissues in LDLR-/- tumour bearing mice, induced inflammation; modulate expression of specific receptors implicated in obesity (GPR120 and Leptin receptors). Interestingly, VitD3 given to mice fed HFD was unable to reverse the effect of HFD, lead to heavier and bigger tumours and reduction in CD4+CD25+FOXP3+Tregs population. In conclusion, an obesogenic diet modulates melanoma tumour growth by establishing both chronic inflammation and potentially an immune suppressive microenvironment. Unexpectedly, VitD3 supplemented HFD promoted melanoma tumour progression in obese LDLR-/- mice, revealing the potential risk of vitamin D supplementation on a background of obesity mediated cancer.

Date of Award	9 Dec 2019
Original language	English
Awarding Institution	University of Leicester
Supervisor	Cordula Stover (Supervisor) & Lee Machado (Supervisor)