ABSTRACT
BACKGROUND & AIMS Obesity is a risk factor for pancreatic ductal adenocarcinoma (PDAC), a deadly disease with limited preventive strategies. Lifestyle interventions to decrease obesity might prevent obesity-associated PDAC. Here, we examined whether decreasing obesity by increased physical activity (PA) and/or dietary changes would decrease inflammation in humans and prevent PDAC in mice.
METHODS Circulating inflammatory-associated cytokines of overweight and obese subjects before and after a PA intervention were compared. PDAC pre-clinical models were exposed to PA and/or dietary interventions after obesity-associated cancer initiation. Body composition, tumor progression, growth, fibrosis, inflammation, and transcriptomic changes in the adipose tissue were evaluated.
RESULTS PA decreased the levels of systemic inflammatory cytokines in overweight and obese subjects. PDAC mice on a diet-induced obesity (DIO) and PA intervention, had delayed weight gain, decreased systemic inflammation, lower grade pancreatic intraepithelial neoplasia lesions, reduced PDAC incidence, and increased anti-inflammatory signals in the adipose tissue compared to controls. PA had additional cancer prevention benefits when combined with a non-obesogenic diet after DIO. However, weight loss through PA alone or combined with a dietary intervention did not prevent tumor growth in an orthotopic PDAC model. Adipose-specific targeting of interleukin (IL)-15, an anti-inflammatory cytokine induced by PA in the adipose tissue, slowed PDAC growth.
CONCLUSIONS PA alone or combined with diet-induced weight loss delayed the progression of PDAC and reduced systemic and adipose inflammatory signals. Therefore, obesity management via dietary interventions and/or PA, or modulating weight loss related pathways could prevent obesity-associated PDAC in high-risk obese individuals.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Grant Support: Research reported in this publication was supported by Knowledge GAP MDACC (ZC-M), Start-up funds from The Ohio State University Comprehensive Cancer Center (OSUCCC) (ZC-M). The intramural research program Pelotonia Idea Award from the OSUCCC (ZC-M), Pelotonia Scholarship Program (MC-T, KD, AL, OU, and VP-G). The National Center for Advancing Translational Sciences TL1TR002735 (KG-F), and in part by the MD Anderson Cancer Center Support Grant CA016672 and the OSUCCC P30 CA16058 National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Any opinions, findings, and conclusions expressed in this material are those of the author(s) and do not necessarily reflect those of the Pelotonia Scholarship Program, The Ohio State University, and the National Institutes of Health.
Abbreviations
- CD
- control diet
- DIO
- diet-induced obesity
- ELISA
- enzyme-linked immunosorbent assay
- GEMM
- genetically engineered mouse model
- HFD
- high fat diet
- IL
- interleukin
- LCN2
- lipocalin-2
- MDSC
- myeloid derived stem cells
- NK
- natural killer
- PA
- physical activity
- PanIN
- pancreatic intraepithelial neoplasia
- PDAC
- pancreatic ductal adenocarcinoma
