Parental obesity programs pancreatic cancer development in offspring
| Autor: | Aseel Al-Yawar, Sonia de Assis, M. Idalia Cruz, Ana Cristina P Curi, Ali Baird, Raquel Santana da Cruz, Johan Clarke, Lu Jin, Bhaskar Kallakury |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Cancer Research medicine.medical_specialty Offspring Endocrinology Diabetes and Metabolism Overweight Biology Diet High-Fat Weight Gain Article Proto-Oncogene Proteins p21(ras) 03 medical and health sciences Mice 0302 clinical medicine Endocrinology Internal medicine Pancreatic cancer medicine Animals Obesity Young adult Parental obesity Metabolic disorder Cancer Maternal Nutritional Physiological Phenomena medicine.disease Pancreatic Neoplasms 030104 developmental biology Oncology Animals Newborn 030220 oncology & carcinogenesis Mutation Female medicine.symptom |
| Zdroj: | Endocr Relat Cancer |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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