Abstract
Epidemiological studies suggest that timing of obesity onset - and underlying metabolic dysfunction - is important in determining pancreatic cancer rates: early and young adult abdominal overweight/obesity is more strongly associated with this cancer than obesity that develops later in life. Parental obesity and overweight are associated with metabolic dysfunction and obesity in their children. Here, we evaluated the impact of parental overweight on offspring's susceptibility of pancreatic cancer using the P48Cre/+/KrasG12D/+ mouse model. Male mice were fed an obesity-inducing diet (OID) before conception and mated with females raised on a control diet (CO) to generate the offspring. In a separate experiment, pregnant dams were fed CO or OID throughout gestation. The resulting OID offspring from the maternal (OID-m) or paternal lineage (OID-p) were used to study body weight, metabolic parameters and pancreatic cancer development and for molecular analysis. Parental obesity increased offspring's body weight at birth, weaning and in adulthood compared to CO, with gender- and genotype-specific differences. OID-p and OID-m offspring showed metabolic disorder and accelerated development of high-grade PanIN/PDAC. OID offspring also had higher rates of acinar-to-ductal reprogramming assessed by CPA1+/SOX9+-positive pancreatic cells. Levels of Tenascin C (TNC), an ECM glycoprotein shown to suppress apoptosis, were elevated in OID offspring, particularly females. In line with that, OID offspring displayed increased collagen content and decreased apoptosis in pancreatic lesions compared to CO. An ancestral history of obesity through either the paternal or maternal lineages increases offspring's susceptibility to pancreatic cancer development.
Original language | English (US) |
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Pages (from-to) | 511-523 |
Number of pages | 13 |
Journal | Endocrine-related cancer |
Volume | 26 |
Issue number | 5 |
DOIs | |
State | Published - 2019 |
Externally published | Yes |
Bibliographical note
Funding Information:This research was supported by the National Institutes of Health (CA178309) and pilot funding from the National Center For Advancing Translational Sciences of the National Institutes of Health (UL1TR001409) to Sonia de Assis. This research was also supported by the National Institutes of Health Lombardi Comprehensive Cancer Center Support Grant (P30-CA51008).
Funding Information:
This research was supported by the ?ational 阀nstitutes of Health (CA178309) and pilot funding from the ?ational Center For Advancing Translational Sciences of the ?ational 阀nstitutes of Health (UL1TR001409) to Sonia de Assis. This research was also supported by the ?ational 阀nstitutes of Health Lombardi Comprehensive Cancer Center Support Grant (P30-CA51008).
Publisher Copyright:
© 2019 Society for Endocrinology Published by Bioscientifica Ltd. Printed in Great Britain
Keywords
- Developmental programming
- Obesity
- Pancreatic cancer