Physical Activity Decreases Inflammation and Delays Development of Obesity-Associated Pancreatic Ductal Adenocarcinoma.
Valentina Pita-GrisantiEricka Vélez-BonetKaylin M ChasserZachary HurstAlexus LietteGrace VulicKelly DubayAli LahootiNiharika BadiOlivia UeltschiKristyn Gumpper-FedusHsiang-Yin HsuehIla LahootiMyrriah ChavezSamantha TerhorstSue E KnoblaughLei CaoWei HuangChristopher C CossThomas A MaceFouad ChoueiryAlice HintonStacey CulpJennifer M MitchellRosemarie SchmandtMichaela Onstad GrinsfelderKaren M Basen-EngquistZobeida Cruz-MonserratePublished in: Cancer research (2024)
Obesity is a risk factor for pancreatic ductal adenocarcinoma (PDAC), a deadly disease with limited preventive strategies. Lifestyle interventions to decrease obesity represent a potential approach to prevent obesity-associated PDAC. Here, we examined whether decreasing obesity through physical activity (PA) and/or dietary changes could decrease inflammation in humans and prevent obesity-associated PDAC in mice. Comparison of circulating inflammatory-associated cytokines in subjects (overweight and obese) before and after a PA intervention revealed PA lowered systemic inflammatory cytokines. Mice with pancreatic-specific inducible KrasG12D expression were exposed to PA and/or dietary interventions during and after obesity-associated cancer initiation. In mice with concurrent diet-induced obesity (DIO) and KrasG12D expression, the PA intervention led to lower weight gain, suppressed systemic inflammation, delayed tumor progression, and decreased pro-inflammatory signals in the adipose tissue. However, these benefits were not as evident when obesity preceded pancreatic KrasG12D expression. Combining PA with diet-induced weight loss (DI-WL) delayed obesity-associated PDAC progression in the genetically engineered mouse model, but neither PA alone nor combined with DI-WL or chemotherapy prevented PDAC tumor growth in orthotopic PDAC models regardless of obesity status. PA led to upregulation of IL-15ra in adipose tissue. Adipose-specific overexpression of IL-15 slowed PDAC growth but only in non-obese mice. Overall, our study suggests that PA alone or combined with DI-WL can reduce inflammation and delay obesity-associated PDAC development or progression. Lifestyle interventions that prevent or manage obesity or therapies that target weight loss-related molecular pathways could prevent progression of PDAC.
Keyphrases
- weight loss
- insulin resistance
- weight gain
- high fat diet induced
- metabolic syndrome
- physical activity
- bariatric surgery
- adipose tissue
- type diabetes
- roux en y gastric bypass
- gastric bypass
- body mass index
- poor prognosis
- mouse model
- oxidative stress
- randomized controlled trial
- high fat diet
- skeletal muscle
- cardiovascular disease
- systemic lupus erythematosus
- pseudomonas aeruginosa
- glycemic control
- squamous cell carcinoma
- radiation therapy
- obese patients
- biofilm formation
- rectal cancer
- ankylosing spondylitis
- signaling pathway
- papillary thyroid
- preterm birth
- candida albicans