Pancreatic Ductal Epithelium Research Articles

CXCL12 Chemokine Expression Suppresses Human Pancreatic Cancer Growth and Metastasis

Pancreatic ductal adenocarcinoma is an unsolved health problem with nearly 75% of patients diagnosed with advanced disease and an overall 5-year survival rate near 5%. Despite the strong link between mortality and malignancy, the mechanisms behind pancreatic cancer dissemination and metastasis are poorly understood. Correlative pathological and cell culture analyses suggest the chemokine receptor CXCR4 plays a biological role in pancreatic cancer progression. In vivo roles for the CXCR4 ligand CXCL12 in pancreatic cancer malignancy were investigated. CXCR4 and CXCR7 were consistently expressed in normal and cancerous pancreatic ductal epithelium, established cell lines, and patient-derived primary cancer cells. Relative to healthy exocrine ducts, CXCL12 expression was pathologically repressed in pancreatic cancer tissue specimens and patient-derived cell lines. To test the functional consequences of CXCL12 silencing, pancreatic cancer cell lines stably expressingthe chemokine were engineered. Consistent with a role for CXCL12 as a tumor suppressor, cells producing the chemokine wereincreasingly adherent and migration deficient in vitro and poorly metastatic in vivo, compared to control cells. Further, CXCL12 reintroduction significantly reduced tumor growth in vitro, with significantly smaller tumors in vivo, leading to a pronounced survival advantage in a preclinical model. Together, these data demonstrate a functional tumor suppressive role for the normal expression of CXCL12 in pancreatic ducts, regulating both tumor growth andcellulardissemination to metastatic sites.

Immunohistochemical distribution of glucagon -, insulin -, somatostatin -, gastrin-, and serotonin-containing cells in the pancreas of the Van cat

The regional distribution, relative frequency, and appearance of glucagon (A-cell)-, insulin (B-cell)-, somatostatin (D-cell)-, gastrin (G-cell)-, and serotonin (EC-cell)-secreting cells in the endocrine and exocrine pancreas of Van cats were examined using the immunohistochemistry method. Glucagon immunopositive A-cells were principally found in the central region of the islets of Langerhans, while insulin immunopositive B-cells were located in the periphery of the pancreatic islets. Moreover, several A- and B-cells were observed as only single cells or clusters of 2 to 3 immunopositive cells in the exocrine parenchyma and the pancreatic duct epithelium. Somatostatin and gastrin immunopositive reactivities were negligible in the peripheral regions of the pancreatic islets of Langerhans and in the exocrine parenchyma. However, serotonin-immunopositive EC-cells were observed in neither the endocrine islets nor any other sites of the tissue. The existence, regional distribution, and relative frequency of A-, B-, D-, G- and EC-cells in the pancreas of Van cats have been analyzed in this study for the first time. The immunopositivity and distribution of endocrine cells in the Van cat pancreas were determined to be partially different from those of other carnivorous species such as dogs and other cats.

Characterization of Store-Operated Calcium Channels in Pancreatic Duct Epithelia

Store-operated Ca2+ channels (SOCs) are activated by depletion of intracellular Ca2+ stores following agonist-mediated Ca2+ release. In pancreatic duct epithelial cells (PDEC), the activation of GPCR coupled to phospholipase C stimulated SOC-mediated Ca2+ influx. Direct measurement of [Ca2+] in the ER showed that SOCs slowed ER depletion. SOC-mediated currents were inwardly rectifying and greatly increased in the absence of divalent cations, as typical for SOCs in other cell types. Pharmacology of epithelial SOCs was consistent with that of some types of SOCs. In polarized PDEC, SOCs were localized specifically to the basolateral membrane. Both STIM and Orai proteins were expressed in PDEC and were colocalized after store depletion. Furthermore, knockdown of Orai3 expression, the most abundant Orai subtype, reduced SOC-mediated Ca2+ influx significantly. In conclusion, basolateral Ca2+ entry through SOCs fills internal Ca2+ stores depleted by external stimuli and facilitates Ca2+-dependent cellular processes such as salt and mucin secretion from the exocrine pancreatic ducts.

Squamous Cell Carcinoma of the Pancreas with Liver Metastasis: Report of A Case and Review of Literature

Context: Squamous cell carcinoma of the pancreas is a rare entity. The incidence has been estimated at approximately 1% of all pancreatic malignancies. The histogenesis is uncertain, but it has been proposed to originate from areas of squamous metaplasia of pancreatic ductal epithelium. Aims: We report a case of 68 years old patient with a liver metastatic squamous cell carcinoma of the pancreas. Histological diagnosis was established by CT guided biopsy of the liver. Two types of chemotherapy have been performed with an association of Gemcitabine and cisplatinum. An objective response was obtained and the patient’s health improved. Conclusion: Pure squamous cell carcinoma of the pancreas is a very rare malignancy. In most cases, it is not possible to make a preoperative histological diagnosis and curative resection is unlikely because of dissemination at the time of initial diagnosis or laparotomy.

Trisomy of the Dscr1 gene suppresses early progression of pancreatic intraepithelial neoplasia driven by oncogenic Kras

Individuals with Down syndrome exhibit remarkably reduced incidence of most solid tumors including pancreatic cancer. Multiple mechanisms arising from the genetic complexity underlying Down syndrome has been suggested to contribute to such a broad cancer protection. In this study, utilizing a genetically engineered mouse model of pancreatic cancer, we demonstrate that trisomy of the Down syndrome critical region-1 (Dscr1), an endogenous calcineurin inhibitor localized on chromosome 21, suppresses the progression of pancreatic intraepithelial neoplasia-1A (PanIN-1A) to PanIN-1B lesions without affecting the initiation of PanIN lesions mediated by oncogenic KrasG12D. In addition, we show that Dscr1 trisomy attenuates nuclear localization of nuclear factor of activated T-cells (NFAT) accompanied by upregulation of the p15Ink4b tumor suppressor and reduction of cell proliferation in early PanIN lesions. Our data suggest that attenuation of calcineurin–NFAT signaling in neoplastic pancreatic ductal epithelium by a single extra copy of Dscr1 is sufficient to inhibit the progression of early PanIN lesions driven by oncogenic Kras, and thus may be a potential mechanism underlying reduced incidence of pancreatic cancer in Down syndrome individuals.

NPTX2 Hypermethylation in Pure Pancreatic Juice Predicts Pancreatic Neoplasms

The neuronal pentraxin II (NPTX2) gene is methylated in over 90% primary pancreatic cancer tissues but rarely in normal pancreatic ductal epithelia. Here, the authors investigated the utility of methylated NPTX2 as a diagnostic marker for pancreatic cancer in pure pancreatic juice samples of patients with benign and malignant pancreatic diseases, including pancreatic cancer, intraductal papillary mucinous neoplasm or chronic pancreatitis using methylation-specific polymerase chain reaction (MSP) and quantitative MSP. MSP assays revealed that the incidence of aberrant NPTX methylation in pure pancreatic juice samples was 64.5% (20 of 31) in patients with pancreatic cancer, 70.0% (7 of 10) in patients with malignant intraductal papillary mucinous neoplasm, 33.3% (2 of 6) in patients with benign intraductal papillary mucinous neoplasm and 21.7% (5 of 23) in patients with chronic pancreatitis. NPTX2 hypermethylation in patients with chronic pancreatitis was significantly lower than that of pancreatic cancer (P<0.01) or patients with intraductal papillary mucinous neoplasm (P<0.05). At a cutoff value of 1.39 for quantitative MSP, the incidence of aberrant NPTX2 methylation was 61.3% (19 of 31) in patients with pancreatic cancer, 50.0% (5 of 10) in patients with malignant intraductal papillary mucinous neoplasm, 0% in patients with benign intraductal papillary mucinous neoplasm and 8.7% (2 of 23) in patients with chronic pancreatitis. There was a significant difference in NPTX2 methylation between pancreatic cancer and chronic pancreatitis (P<0.01). Our findings indicate that detection of aberrant methylation of NPTX2 in pure pancreatic juice samples could be useful as a molecular marker to discriminate between patients with malignant and benign disease of the pancreas.

TNF-Like Weak Inducer of Apoptosis (TWEAK) Promotes Beta Cell Neogenesis from Pancreatic Ductal Epithelium in Adult Mice

Aim/HypothesisThe adult mammalian pancreas has limited ability to regenerate in order to restore adequate insulin production from multipotent progenitors, the identity and function of which remain poorly understood. Here we test whether the TNF family member TWEAK (TNF-like weak inducer of apoptosis) promotes β-cell neogenesis from proliferating pancreatic ductal epithelium in adult mice.MethodsC57Bl/6J mice were treated with Fc-TWEAK and pancreas harvested at different time points for analysis by histology and immunohistochemistry. For lineage tracing, 4 week old double transgenic mice CAII-CreERTM: R26R-eYFP were implanted with tamoxifen pellet, injected with Fc-TWEAK or control Ig twice weekly and analyzed at day 18 for TWEAK-induced duct cell progeny by costaining for insulin and YFP. The effect of TWEAK on pancreatic regeneration was determined by pancytokeratin immunostaining of paraffin embedded sections from wildtype and TWEAK receptor (Fn14) deficient mice after Px.ResultsTWEAK stimulates proliferation of ductal epithelial cells through its receptor Fn14, while it has no mitogenic effect on pancreatic α- or β-cells or acinar cells. Importantly, TWEAK induces transient expression of endogenous Ngn3, a master regulator of endocrine cell development, and induces focal ductal structures with characteristics of regeneration foci. In addition, we identify by lineage tracing TWEAK-induced pancreatic β-cells derived from pancreatic duct epithelial cells. Conversely, we show that Fn14 deficiency delays formation of regenerating foci after Px and limits their expansion.Conclusions/InterpretationWe conclude that TWEAK is a novel factor mediating pancreatic β-cell neogenesis from ductal epithelium in normal adult mice.

Characterization of store-operated Ca2+ channels in pancreatic duct epithelia

Store-operated Ca2+ channels (SOCs) are activated by depletion of intracellular Ca2+ stores following agonist-mediated Ca2+ release. Previously we demonstrated that Ca2+ influx through SOCs elicits exocytosis efficiently in pancreatic duct epithelial cells (PDEC). Here we describe the biophysical, pharmacological, and molecular properties of the duct epithelial SOCs using Ca2+ imaging, whole-cell patch-clamp, and molecular biology. In PDEC, agonists of purinergic, muscarinic, and adrenergic receptors coupled to phospholipase C activated SOC-mediated Ca2+ influx as Ca2+ was released from intracellular stores. Direct measurement of [Ca2+] in the ER showed that SOCs greatly slowed depletion of the ER. Using IP3 or thapsigargin in the patch pipette elicited inwardly rectifying SOC currents. The currents increased ∼8-fold after removal of extracellular divalent cations, suggesting competitive permeation between mono- and divalent cations. The current was completely blocked by high doses of La3+ and 2-aminoethoxydiphenyl borate (2-APB) but only partially depressed by SKF-96365. In polarized PDEC, SOCs were localized specifically to the basolateral membrane. RT-PCR screening revealed the expression of both STIM and Orai proteins for the formation of SOCs in PDEC. By expression of fluorescent STIM1 and Orai1 proteins in PDEC, we confirmed that colocalization of the two proteins increases after store depletion. In conclusion, basolateral Ca2+ entry through SOCs fills internal Ca2+ stores depleted by external stimuli and will facilitate cellular processes dependent on cytoplasmic Ca2+ such as salt and mucin secretion from the exocrine pancreatic ducts.

Animal Models and Cell Lines of Pancreatic Neuroendocrine Tumors

Pancreatic neuroendocrine tumors (PNETs), also known as islet cell tumors, are mostly indolent neoplasms that probably arise from a network of endocrine cells that includes islet cells and pluripotent precursors in the pancreatic ductal epithelium. The incidence and prevalence of PNETs continue to rise in recent years because of more sensitive detection. The molecular pathogenesis, early detection, molecular predictors of tumor behavior, and targeted drug therapy of PNETs are not well understood and require additional basic and translational research. The rarity and indolent nature of these tumors, difficulty of access to appropriate patient tissue samples, and varying histopathology and secreted hormones pose particular challenges to PNET researchers. Animal models and cell lines are indispensable tools for investigating the pathogenesis, pathophysiology, mechanisms for tumor invasion and metastasis, and therapeutics of PNETs. This review summarizes currently available animal models and cell lines of PNETs, which have provided valuable insights into the pathogenesis and natural history of human PNETs. In the future, animal models and cell lines of PNETs should also be used to study early tumor detection and molecular predictors of tumor behavior and to test the responses to, and mechanisms for, novel targeted drug therapies.

The Expression of S100A4 in Human Pancreatic Cancer Is Associated With Invasion

Pancreatic cancer is one of the most lethal malignancies; its poor prognosis is strongly associated with invasion and metastasis. Expression of S100A4 has been reported to correlate with poor prognosis in various cancers. We have investigated the role of S100A4 in pancreatic cancer tumorigenesis and its clinicopathologic significance. Protein expression of S100A4 was examined by Western blot in pancreatic cancer cell lines and a human pancreatic ductal epithelium cell line, HPDE-6. Then the expressions of S100A4, TP53, and CD133 were examined immunohistochemically in resected specimens from 83 patients with pancreatic cancer to clarify their clinicopathologic significance. Survival analyses were performed using the Kaplan-Meier method and the Mantel-Cox method. Forty-eight (58%) of 83 patients with pancreatic cancer positively expressed S100A4, and 50 (60%) and 29 (36%) patients positively expressed TP53 and CD133, respectively. S100A4 expression was significantly correlated with perineural invasion (P = 0.029) and invasion pattern (P = 0.001). Neither TP53 nor CD133 expression showed significant correlations with any other parameters. Our present results suggest that S100A4 plays an important role in the invasiveness, particularly with perineural invasion and invasion pattern, of pancreatic cancer. Development of new strategies targeting S100A4 or its downstream effectors is warranted.

Immature squamous metaplasia (focal atypical epithelial hyperplasia) of the pancreatic duct—immunohistochemical distinction from intraductal carcinoma

Immature squamous metaplasia of the pancreatic duct (ISMPD) can be difficult to differentiate from an intraductal carcinoma of the pancreas (ICP), and little is known about the pathological nature of ISMPD. The aim of this study was to analyse 20 ISMPD and 10 ICP tissue samples. ISMPD shares some characteristics with ICP. Seven of 20 ISMPD samples were covered by a layer of pancreatic duct epithelium, whereas this was not seen in the ICP samples. Immunohistochemistry of ISMPD revealed positivity for p63 (100%), cytokeratin 5/6 (95%), cytokeratin 7 (95%), cytokeratin 20 (10%), and MUC-1 (95%), and the samples were negative for p53, carcinoembryonic antigen (CEA), and bcl-2. In contrast, ICP was positive for p63 (40%), p53 (10%), cytokeratin 7 (90%), cytokeratin 20 (20%), CEA (30%), and MUC-1 (80%), and negative for cytokeratin 5/6. However, in 84% (16) of the ISMPD samples, cytokeratin 7 was expressed only by an epithelial layer at the apical surface; this expression pattern was not found in any of the 10 ICP samples. The mean Ki67 labelling index was 1.0% in ISMPD and 18.5% in ICP. Our study suggests that immunohistochemical staining for cytokeratin 5/6 and Ki67 constitutes the best combination for differentiating ISMPD from ICP.

Possible involvement of CCL1-CCR8 interaction in lymphocytic recruitment in IgG4-related sclerosing cholangitis

IgG4-related sclerosing cholangitis and type 1 autoimmune pancreatitis (IgG4-SC/AIP) are characterized by massive lymphoplasmacytic infiltration including Th2 and regulatory T cells (Tregs). This study was conducted to address which chemotactic factors are involved in this condition. Chemokine expression profiles in tissue were examined in IgG4-SC/AIP (n=17), classical primary sclerosing cholangitis (IgG4(low) PSC, n=17), PSC with elevated serum/tissue IgG4 levels (IgG4(high) PSC, n=5), and primary biliary cirrhosis (n=7). We focused on five chemotactic factors/receptors (CCL1-CCR8, CCL17/CCL22-CCR4), given that CCR4 and CCR8 are predominantly expressed in both Th2 and Tregs. In conjunction with higher expression levels of IL-4 and IL-10, expression values of CCL1 and CCR8 transcripts were significantly higher in IgG4-SC/AIP than in IgG4(low) PSC (p=0.002) and IgG4(high) PSC (p=0.023). CCL1 and CCR8 were also overexpressed in IgG4(high) PSC than in IgG4(low) PSC (p=0.023). No difference was seen for CCL17, CCL22, and CCR4. In situ hybridization revealed CCL1 to be predominantly expressed in the pancreatic duct epithelium, peribiliary glands, and vascular endothelial cells including the ones involved in obliterative phlebitis in IgG4-SC/AIP, in contrast to IgG4(high) PSC where this chemotactic factor was positive in several infiltrating lymphocytes. These CCL1-expressing sites were infiltrated by CCR8(+) lymphocytes. On immunohistochemistry, GATA3(+) Th2 lymphocytes and FOXP3(+) Tregs were significantly larger in number in IgG4-SC/AIP, with the GATA3(+)/T-bet(+) cell ratio to be shifted in favour of Th2 in periductal and perivascular areas. CCL1-CCR8 interaction may play a critical role in lymphocytic recruitment in IgG4-SC/AIP, leading to duct-centred inflammation and obliterative phlebitis.

Adenovirus vector-mediated Gli1 siRNA induces growth inhibition and apoptosis in human pancreatic cancer with Smo-dependent or Smo-independent Hh pathway activation in vitro and in vivo

Activation of Hedgehog (Hh) signaling pathway is a core molecular mechanism in pancreatic carcinogenesis. However, the inhibition of upstream Hh signals does not inhibit the growth of a subset of pancreatic cancer (PC). This study was to examine the effect of siRNA targeting Gli1, the downstream component of Hh pathway, on PC cells and to provide some insight into the underlying mechanisms. A Gli1siRNA-expressing adenovirus (Ad-U6-Gli1siRNA) was constructed, and its effect on PC cells was investigated in vitro and in vivo. Gli1 was expressed in 83.3% (20/24) PC tissues, whereas no expression was found in normal pancreatic ductal epithelium. Gli1 was expressed in SW1990 and CFPAC cells in which Smo was completely absent, as well as in PaTu8988, Panc-1 and BxPC-3 cells in which Smo was concomitantly present. Ad-U6-Gli1siRNA induced cell growth inhibition, strong G0/G1 cell cycle arrest and apoptosis in all five human PC cell lines. Meanwhile, Ad-U6-Gli1siRNA significantly suppressed the expression of Gli1, Ptch1 and two target genes, Cyclin D2 and Bcl-2, in all five lines. Furthermore, two tumor xenograft nude mice models were established by subcutaneously injecting Smo-positive Panc-1 cells or Smo-negative SW1990 cells. The in vivo experimental results demonstrated that Ad-U6-Gli1siRNA inhibited the growth of both Panc1-derived and SW1990-derived tumors and induced cell apoptosis. Our study indicates that Gli1-targeting siRNA could induce growth inhibition and apoptosis in PC through knockdown of Gli1 and its target genes; and this method may represent a more effective therapeutic strategy for PC with Smo-dependent or Smo-independent Hh pathway activation.

Expression of urocortin in pancreatic ductal adenocarcinoma and pancreatic intraepithelial neoplasia

Urocortin (UCN) is a 40-amino acid neuropeptide that regulates angiogenesis and inhibits cell proliferation. Our aim was to examine the relationship of UCN expression to the clinicopathological parameters of pancreatic ductal adenocarcinoma (PDAC) and histological grade of pancreatic intraepithelial neoplasia (PanIN). Tissue microarray was used to analyze UCN protein expression in 89 surgical specimens including 21 PanIN, 3 PDAC arising from PanIN, and 65 PDAC without PanIN. UCN immunoscores ranging from 0 to 12 were obtained by multiplying intensity (scored on a 3-point scale) by the percentage of stained cells (scored on a 4-point scale). Strong expression of UCN was detected in 5 specimens of non-neoplastic pancreatic ductal epithelia. UCN immunoscore was significantly higher in PanIN-1 than in PanIN-2 and PanIN-3 (p = 0.038) and significantly higher in well-differentiated PDAC or early American Joint Committee on Cancer (AJCC) stage PDAC than in poorly differentiated or advanced stage PDAC (p = 0.025, p = 0.018). Higher expression of UCN correlates with PDAC tumor grade and AJCC pathologic stage as well as PanIN grade. Immunohistochemical assessment of UCN may help clinicians predict tumor recurrence rate and help pathologists make a proper diagnosis.

Wireless Telemetry and Cystic Fibrosis: Just the pHacts

Wireless Telemetry and Cystic Fibrosis: Just the pHacts

A case of focal autoimmune pancreatitis (AIP) mimicking an intraductal papillary mucinous neoplasm (IPMN).

The present case involved a 76-year-old man with a cystic mass in the head of his pancreas. The cystic lesion, which measured 17.7×9.8mm, was first detected by ultrasonography (US) at the age of 72 years. Follow-up endoscopic ultrasonography (EUS) performed at 4years after the lesion had first been detected revealed a mural nodule measuring 14.0×8.4mm in the cyst. Endoscopic retrograde pancreatography (ERP) imaging revealed that the main pancreatic duct was in communication with the cyst and that there was no irregular narrowing of the main pancreatic duct. On the basis of these results, the patient was diagnosed with an intraductal papillary mucinous neoplasm (IPMN), and stomach-preserving pancreaticoduodenectomy was performed. A histopathological examination revealed that the interior of the cystic part of the lesion was lined by a pancreatic ductal epithelium. A pathological examination of the nodular lesion detected storiform fibrosis, severe lymphoplasmacytic infiltration, and hyperplasia in the pancreatic duct epithelium together with a small amount of mucus. On immunohistological staining, the infiltrating lymphoplasmacytes were found to be positive for IgG4. Accordingly, the patient was diagnosed with focal autoimmune pancreatitis (AIP). In conclusion, we reported a case of focal AIP mimicking IPMN. This case showed neither enlargement of the pancreas nor irregular narrowing of the main pancreatic duct.

Ameliorating effect of ursodeoxycholate on the toxic effect of chenodeoxycholate on pancreatic ductal epithelia

Ameliorating effect of ursodeoxycholate on the toxic effect of chenodeoxycholate on pancreatic ductal epithelia

The Cystic Fibrosis of Exocrine Pancreas

The cystic fibrosis transmembrane conductance regulator (CFTR) protein is highly expressed in the pancreatic duct epithelia and permits anions and water to enter the ductal lumen. This results in an increased volume of alkaline fluid allowing the highly concentrated proteins secreted by the acinar cells to remain in a soluble state. This work will expound on the pathophysiology and pathology caused by the malfunctioning CFTR protein with special reference to ion transport and acid-base abnormalities both in humans and animal models. We will also discuss the relationship between cystic fibrosis (CF) and pancreatitis, and outline present and potential therapeutic approaches in CF treatment relevant to the pancreas.

Dual roles of hemidesmosomal proteins in the pancreatic epithelium: the phosphoinositide 3-kinase decides

Given the failure of chemo- and biotherapies to fight advanced pancreatic cancer, one major challenge is to identify critical events that initiate invasion. One priming step in epithelia carcinogenesis is the disruption of epithelial cell anchorage to the basement membrane which can be provided by hemidesmosomes (HDs). However, the existence of HDs in pancreatic ductal epithelium and their role in carcinogenesis remain unexplored. HDs have been explored in normal and cancer pancreatic cells, and patient samples. Unique cancer cell models where HD assembly can be pharmacologically manipulated by somatostatin/sst2 signaling have been then used to investigate the role and molecular mechanisms of dynamic HD during pancreatic carcinogenesis. We surprisingly report the presence of mature type-1 HDs comprising the integrin α6β4 and bullous pemphigoid antigen BP180 in the human pancreatic ductal epithelium. Importantly, HDs are shown to disassemble during pancreatic carcinogenesis. HD breakdown requires phosphoinositide 3-kinase (PI3K)-dependent induction of the matrix-metalloprotease MMP-9, which cleaves BP180. Consequently, integrin α6β4 delocalizes to the cell-leading edges where it paradoxically promotes cell migration and invasion through S100A4 activation. As S100A4 in turn stimulates MMP-9 expression, a vicious cycle maintains BP180 cleavage. Inactivation of this PI3K-MMP-9-S100A4 signaling loop conversely blocks BP180 cleavage, induces HD reassembly and inhibits cell invasion. We conclude that mature type-1 HDs are critical anchoring structures for the pancreatic ductal epithelium whose disruption, upon PI3K activation during carcinogenesis, provokes pancreatic cancer cell migration and invasion.

Abstract 3593: GABA counteracts ethanol induced stimulation of pancreatic cancer cells and normal pancreatic duct epithelia .

Abstract Pancreatic cancer has a high mortality rate and alcoholism is a risk factor independent of smoking. We have shown that nicotinic acetylcholine receptors (nAChRs) regulate pancreatic ductal epithelia and pancreatic ductal adenocarcinoma (PDAC) cells in an autocrine fashion by stimulating their production of the stress neurotransmitters noradrenaline and adrenaline that signal through beta-adrenergic receptors (β-ARs). Our current study has investigated the modulation of this autocrine regulatory loop by chronic ethanol and explored the potential prevention of these effects by γ-amino butyric acid (GABA). Treatment for seven days with ethanol at a concentration equivalent to the legal blood alcohol limit in the United States induced protein expression and sensitivity of nAChRs α3, α5 and α7 resulting in increased production of noradrenaline and adrenaline which drive proliferation and migration via cAMP-dependent signaling downstream of β-ARs. Treatment with GABA prevented all of these responses to chronic ethanol, reducing cell proliferation and migration below base levels in untreated cells. Our findings suggest that alcoholism induces multiple cAMP-dependent PDAC stimulating signaling pathways by up-regulating the protein expression and sensitivity of nAChRs that regulate stress neurotransmitters production. Moreover, our data identify GABA as a promising agent for the prevention of PDAC in individuals at risk due to chronic alcohol consumption. Supported by R01CA042829 and R01CA130888 with the National Cancer Institute Citation Format: Mohammed H. Al-Wadei, Hussein A.N. Al-Wadei, Hildegard M. Schuller. GABA counteracts ethanol induced stimulation of pancreatic cancer cells and normal pancreatic duct epithelia . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3593. doi:10.1158/1538-7445.AM2013-3593