Pancreatic ductal adenocarcinoma (PDAC) is unique among solid tumors because of the extremely dense desmoplasfic reaction that surrounds the cancer cell glands of this tumor. The cancer desmoplasia is produced by the myofibroblasfic activated pancreatic stellate cell (PaSC) The PaSCs when acfivated produce large amounts of extracellular matrix (ECM) proteins and modulate the growth of PDAC by providing a scaffold for the cancer cells to grow as well as growth factors, angiogenesis factors and immune modulators. Evidence is mounting that interplay between the cancer cells and activated PaSCs are responsible for the growth, metastasis and chemoresistance of PDAC. We propose that various systemic factors occurring in alcohol abuse and high fat/high calorie diet (HFCD) stimulate conversion of the endogenous quiescent PaSCs to their activated, myofibroblasfic and pancreafic cancer promoting state. In this state the stellate cell is a key participant in pancreafic carcinogenesis. Our hypothesis states that alcohol abuse and HFCD promote desmoplasia and, in turn, promote the development of pancreafic cancer through the effects of alcohol metabolites, lepfin, insulin-like growth factor-1 (IGF-1), lipopolysaccharide (LPS), tumor necrosis factor-a (TNF-a) and oxidized low density lipoprotein (oxLDL) on PaSCs. These mediators act on PaSCs resulting in their activation, proliferation, production of extracellular matrix proteins and chemical signals that are essential for promotion of pancreatic cancer. These effects are mediated in large part through the PI 3kinase/Akt and mTOR signaling systems of PaSCs. Also, these systemic factors interact with cancer precursors PanIN cells regulafing their PI3kinase/Akt and mTOR signaling systems resulfing in the secretion of factors that additionally promote the procarcinogenic effects of the PaSCs. To test our hypothesis the following Specific Aims are proposed: 1) to characterize the effects of ethanol (and its metabolites), lepfin, IGF-1, LPS, TNF-a, oxLDL on PaSC pro-carcinogenic responses;2) to determine the role of the PI 3kinase/ Akt and mTOR signaling system in PaSC procarcinogenic responses;3) to examine the effects of ethanol feeding on PaSC responses and PanlNs progression in the conditional KrasG12D model subjected to standard or high caloric diets;and 4) to determine PaSC responses in vivo in the animal models of the program.

Public Health Relevance

Our investigations will demonstrate how alcohol and dietary factors infiuence pancreatic carcinogenesis through their effects on the pancreatic stellate cell which represents the source of cancer desmoplasia. Because of emerging information showing the important role of the stellate cell and desmoplasia in pancreatic carcinogenesis, our results will lead to novel and likely unexpected insights about the mechanism of promotion of pancreatic cancer leading to important preventative and therapeutic clinical strategies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA163200-03
Application #
8712203
Study Section
Special Emphasis Panel (ZCA1-RPRB-B)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
3
Fiscal Year
2014
Total Cost
$203,218
Indirect Cost
$72,345
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Yang, Zemin; Liu, Yu; Qin, Lan et al. (2017) Cathepsin H-Mediated Degradation of HDAC4 for Matrix Metalloproteinase Expression in Hepatic Stellate Cells: Implications of Epigenetic Suppression of Matrix Metalloproteinases in Fibrosis through Stabilization of Class IIa Histone Deacetylases. Am J Pathol 187:781-797
Eibl, Guido; Cruz-Monserrate, Zobeida; Korc, Murray et al. (2017) Diabetes Mellitus and Obesity as Risk Factors for Pancreatic Cancer. J Acad Nutr Diet :
Birtolo, Chiara; Pham, Hung; Morvaridi, Susan et al. (2017) Cadherin-11 Is a Cell Surface Marker Up-Regulated in Activated Pancreatic Stellate Cells and Is Involved in Pancreatic Cancer Cell Migration. Am J Pathol 187:146-155
Lew, Daniel; Afghani, Elham; Pandol, Stephen (2017) Chronic Pancreatitis: Current Status and Challenges for Prevention and Treatment. Dig Dis Sci 62:1702-1712
Schmidt, Andrea; Sinnett-Smith, James; Young, Steven et al. (2017) Direct growth-inhibitory effects of prostaglandin E2 in pancreatic cancer cells in vitro through an EP4/PKA-mediated mechanism. Surgery 161:1570-1578
Lugea, Aurelia; Waldron, Richard T (2017) Exosome-Mediated Intercellular Communication Between Stellate Cells and Cancer Cells in Pancreatic Ductal Adenocarcinoma. Pancreas 46:1-4
Yu, Juehua; Liu, Shi-He; Sanchez, Robbi et al. (2017) Pancreatic cancer actionable genes in precision medicine and personalized surgery. Surgeon 15:24-29
Chang, Jen-Kuan; Ni, Yang; Han, Liang et al. (2017) Protein kinase D1 (PKD1) phosphorylation on Ser203 by type I p21-activated kinase (PAK) regulates PKD1 localization. J Biol Chem 292:9523-9539
Andersen, Dana K; Korc, Murray; Petersen, Gloria M et al. (2017) Diabetes, Pancreatogenic Diabetes, and Pancreatic Cancer. Diabetes 66:1103-1110
Eibl, Guido; Rozengurt, Enrique (2017) KRAS, YAP, and obesity in pancreatic cancer: A signaling network with multiple loops. Semin Cancer Biol :

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