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 Kras?^^? model subjected to standard or high caloric diets;and 4) to determine PaSC responses in vivo in the animal models ofthe program.

Public Health Relevance

Our invesfigations 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 #
5P01CA163200-02
Application #
8561433
Study Section
Special Emphasis Panel (ZCA1-RPRB-B)
Project Start
2013-08-01
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$200,855
Indirect Cost
$70,539
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Liou, Geou-Yarh; Döppler, Heike; Necela, Brian et al. (2015) Mutant KRAS-induced expression of ICAM-1 in pancreatic acinar cells causes attraction of macrophages to expedite the formation of precancerous lesions. Cancer Discov 5:52-63
Young, Steven H; Rey, Osvaldo; Sinnett-Smith, James et al. (2014) Intracellular Ca2+ oscillations generated via the Ca2+-sensing receptor are mediated by negative feedback by PKC? at Thr888. Am J Physiol Cell Physiol 306:C298-306
Sinnett-Smith, James; Ni, Yang; Wang, Jia et al. (2014) Protein kinase D1 mediates class IIa histone deacetylase phosphorylation and nuclear extrusion in intestinal epithelial cells: role in mitogenic signaling. Am J Physiol Cell Physiol 306:C961-71
Lu, Qing-Yi; Zhang, Lifeng; Eibl, Guido et al. (2014) Overestimation of flavonoid aglycones as a result of the ex vivo deconjugation of glucuronides by the tissue *-glucuronidase. J Pharm Biomed Anal 88:364-9
Arensman, Michael D; Telesca, Donatello; Lay, Anna R et al. (2014) The CREB-binding protein inhibitor ICG-001 suppresses pancreatic cancer growth. Mol Cancer Ther 13:2303-14
Kong, Ming; Zhu, Longdong; Bai, Li et al. (2014) Vitamin D deficiency promotes nonalcoholic steatohepatitis through impaired enterohepatic circulation in animal model. Am J Physiol Gastrointest Liver Physiol 307:G883-93
Rozengurt, Enrique; Soares, Heloisa P; Sinnet-Smith, James (2014) Suppression of feedback loops mediated by PI3K/mTOR induces multiple overactivation of compensatory pathways: an unintended consequence leading to drug resistance. Mol Cancer Ther 13:2477-88
Ming, Ming; Sinnett-Smith, James; Wang, Jia et al. (2014) Dose-Dependent AMPK-Dependent and Independent Mechanisms of Berberine and Metformin Inhibition of mTORC1, ERK, DNA Synthesis and Proliferation in Pancreatic Cancer Cells. PLoS One 9:e114573
Edderkaoui, Mouad; Eibl, Guido (2014) Risk factors for pancreatic cancer: underlying mechanisms and potential targets. Front Physiol 5:490
Soares, Heloisa P; Ni, Yang; Kisfalvi, Krisztina et al. (2013) Different patterns of Akt and ERK feedback activation in response to rapamycin, active-site mTOR inhibitors and metformin in pancreatic cancer cells. PLoS One 8:e57289

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