Moderate alcohol intake promotes pancreatic ductal adenocarcinoma development in mice expressing oncogenic Kras

Kras mutations are associated with pancreatic ductal adenocarcinoma (PDAC). Although tobacco smoking, pancreatitis, and obesity are known environmental risk factors for PDAC, the contribution of moderate alcohol intake to PDAC remains elusive. In the present study, we tested whether a combination of risk factors or moderate alcohol intake induces PDAC development in mice. Control Pdx1Cre and Pdx1Cre;LSL-KrasG12D mutant mice were fed a Western alcohol diet containing high levels of cholesterol and saturated fat, 3.5% alcohol, and lipopolysaccharide for 5 mo. In addition, mice were treated with cerulein, for induction of pancreatitis, and nicotine every month. Treatment with all of these risk factors promoted development of advanced pancreatic neoplasia and PDAC in the Pdx1Cre;LSL-KrasG12D mice but not in the control Pdx1Cre mice. Moderate alcohol intake or Western diet feeding also significantly promoted advanced neoplasia and PDAC development in Pdx1Cre;LSL-KrasG12D mice compared with mice fed a regular chow. Alcohol, but not Western diet, increased tumor development in the liver in the Pdx1Cre;LSL-KrasG12D mice, but its origin remained elusive due to leakiness of Pdx1Cre in hepatocytes. RNA-seq analysis revealed that alcohol feeding increases expression of markers for tumors (Epcam, Krt19, Prom1, Wt1, and Wwtr1), stroma (Dcn, Fn1, and Tnc), and cytokines (Tgfb1 and Tnf) and decreases expression of Fgf21 and Il6 in the pancreatic tumor tissues. Immunostaining showed heterogeneous expression of nephronectin, S100 calcium-binding protein A6, and vascular cell adhesion molecule 1 in pancreatic tumors surrounded by podoplanin-positive stromal cells. Our data indicate that moderate alcohol drinking is a risk factor for development of PDAC.NEW & NOTEWORTHY Heavy alcohol intake has been suspected to be a risk factor of pancreatic ductal adenocarcinoma (PDAC) in humans. However, the contribution of moderate alcohol intake to PDAC development remains elusive. In the present study, we experimentally show that moderate alcohol feeding significantly induces advanced stages of pancreatic intraepithelial neoplasia development and invasive PDAC in Pdx1Cre;LSL-KrasG12D mutant mice. Our data indicate that moderate alcohol drinking is a risk factor for PDAC.

Medienart:

E-Artikel

Erscheinungsjahr:

2020

Erschienen:

2020

Enthalten in:

Zur Gesamtaufnahme - volume:318

Enthalten in:

American journal of physiology. Gastrointestinal and liver physiology - 318(2020), 2 vom: 01. Feb., Seite G265-G276

Sprache:

Englisch

Beteiligte Personen:

Asahina, Kinji [VerfasserIn]
Balog, Steven [VerfasserIn]
Hwang, Edward [VerfasserIn]
Moon, Eugene [VerfasserIn]
Wan, Emily [VerfasserIn]
Skrypek, Kaitlin [VerfasserIn]
Chen, Yibu [VerfasserIn]
Fernandez, Jay [VerfasserIn]
Romo, Janet [VerfasserIn]
Yang, Qihong [VerfasserIn]
Lai, Keane [VerfasserIn]
French, Samuel W [VerfasserIn]
Tsukamoto, Hidekazu [VerfasserIn]

Links:

Volltext

Themen:

3K9958V90M
6M3C89ZY6R
888Y08971B
Acinar-ductal metaplasia
Carcinogens
Central Nervous System Depressants
Ceruletide
Cytokines
EC 3.6.5.2
Ethanol
Homeodomain Proteins
Hras protein, mouse
Journal Article
Metastasis
Nephronectin
Nicotine
Pancreatic and duodenal homeobox 1 protein
Pancreatic intraepithelial neoplasia
Proto-Oncogene Proteins p21(ras)
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Trans-Activators

Anmerkungen:

Date Completed 11.05.2020

Date Revised 01.07.2023

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1152/ajpgi.00218.2019

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM303632933