PMID- 30865925
OWN - NLM
STAT- MEDLINE
DCOM- 20200721
LR  - 20200901
IS  - 1479-6821 (Electronic)
IS  - 1351-0088 (Print)
IS  - 1351-0088 (Linking)
VI  - 26
IP  - 5
DP  - 2019 May
TI  - Parental obesity programs pancreatic cancer development in offspring.
PG  - 511-523
LID - 10.1530/ERC-19-0016 [doi]
LID - ERC-19-0016.R1
AB  - 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.
FAU - da Cruz, Raquel Santana
AU  - da Cruz RS
FAU - Clarke, Johan
AU  - Clarke J
FAU - Curi, Ana Cristina P
AU  - Curi ACP
FAU - Al-Yawar, Aseel
AU  - Al-Yawar A
FAU - Jin, Lu
AU  - Jin L
FAU - Baird, Ali
AU  - Baird A
FAU - Cruz, M Idalia
AU  - Cruz MI
FAU - Kallakury, Bhaskar
AU  - Kallakury B
FAU - de Assis, Sonia
AU  - de Assis S
LA  - eng
GR  - K22 CA178309/CA/NCI NIH HHS/United States
GR  - P30 CA051008/CA/NCI NIH HHS/United States
GR  - UL1 TR001409/TR/NCATS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - England
TA  - Endocr Relat Cancer
JT  - Endocrine-related cancer
JID - 9436481
RN  - EC 3.6.5.2 (Hras protein, mouse)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - Diet, High-Fat/adverse effects
MH  - Female
MH  - Male
MH  - *Maternal Nutritional Physiological Phenomena
MH  - Mice
MH  - Mutation
MH  - Obesity/*complications/pathology
MH  - Overweight/*complications/pathology
MH  - Pancreatic Neoplasms/etiology/*pathology
MH  - Proto-Oncogene Proteins p21(ras)/genetics
MH  - Weight Gain
PMC - PMC6717698
MID - NIHMS1524245
OTO - NOTNLM
OT  - developmental programming
OT  - obesity
OT  - pancreatic cancer
COIS- Declaration of interest: The authors have no conflicts of interest to declare.
EDAT- 2019/03/14 06:00
MHDA- 2020/07/22 06:00
PMCR- 2020/09/01
CRDT- 2019/03/14 06:00
PHST- 2019/03/06 00:00 [received]
PHST- 2019/03/13 00:00 [accepted]
PHST- 2019/03/14 06:00 [pubmed]
PHST- 2020/07/22 06:00 [medline]
PHST- 2019/03/14 06:00 [entrez]
PHST- 2020/09/01 00:00 [pmc-release]
AID - ERC-19-0016.R1 [pii]
AID - 10.1530/ERC-19-0016 [doi]
PST - ppublish
SO  - Endocr Relat Cancer. 2019 May;26(5):511-523. doi: 10.1530/ERC-19-0016.