Pancreatic intraepithelial neoplasia and ductal adenocarcinoma induced by DMBA in mice: effects of alcohol and caffeine

Wendt, Luiz Roberto Rigo; Osvaldt, Alessandro Bersch; Bersch, Vivian Pierri; Schumacher, Rita de Cássia Alves; Edelweiss, Maria Isabel Albano; Rohde, Luis Augusto

doi:10.1590/s0102-86502007000300008

Cited by 24 publications

(13 citation statements)

References 35 publications

(26 reference statements)

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“…Interestingly, even though ethanol has been shown in a carcinogen-induced model of pancreatic cancer to enhance the development of pancreatic ductal adenocarcinomas [Wendt et al, 2007], it is still debated whether ethanol increases the risk of pancreatic cancer in humans [Gapstur et al, 2011; Michaud et al, 2010]. Since we demonstrate the differential effect of ethanol on premalignant and malignant pancreatic cells, it is possible that the varying effects of ethanol may negate the tumor promotion and inhibition effects of ethanol.…”

Section: Discussionmentioning

confidence: 71%

Ethanol differentially regulates snail family of transcription factors and invasion of premalignant and malignant pancreatic ductal cells

et al. 2011

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Pancreatic cancer is one of the deadliest of cancers with a dismal 5-year survival rate. Epidemiological studies have identified chronic pancreatitis as a risk factor for pancreatic cancer. Pancreatic cancer cells also demonstrate increased expression of the transcription factor Snail, a key regulator of epithelial-mesenchymal transition. As ethanol is one of the major causes of pancreatitis, we examined the effect of ethanol on Snail family members in immortalized human pancreatic ductal epithelial (HPDE) cells and in pancreatic cancer cells. Ethanol induced Snail mRNA levels 2.5-fold in HPDE cells, with only 1.5-fold mRNA induction of the Snail-related protein Slug. In contrast, ethanol increased Slug mRNA levels 1.5-2-fold in pancreatic cancer cells, with minimal effect on Snail. Because Snail increases invasion of cancer cells, we examined the effect of ethanol on invasion of HPDE and pancreatic cancer cells. Surprisingly, ethanol decreased invasion of HPDE cells, but had no effect on invasion of pancreatic cancer cells. Mechanistically, ethanol increased adhesion of HPDE cells to collagen and increased expression of the collagen binding α2- and β1-integrins. In contrast, ethanol did not affect collagen adhesion or integrin expression in pancreatic cancer cells. Also in contrast to HPDE cells, ethanol did not attenuate ERK1/2 phosphorylation in pancreatic cancer cells; however, inhibiting ERK1/2 decreased pancreatic cancer cell invasion. Overall, our results identify the differential effects of ethanol on premalignant and malignant pancreatic cells, and demonstrate the pleiotropic effects of ethanol on pancreatic cancer progression.

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Section: Discussionmentioning

confidence: 71%

Ethanol differentially regulates snail family of transcription factors and invasion of premalignant and malignant pancreatic ductal cells

et al. 2011

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“…Current animal models of pancreatic cancer include xenograft models [7][8][9] , carcinogen-induced models [10][11][12][13] , and genetically engineered models [14][15][16][17][18] . In the carcinogeninduced model, when pancreatic cancer is induced, hepatocellular carcinoma and other tumors occur simultaneously due to poor specificity of the carcinogen; thereby, the accuracy of using such animal models is limited.…”

Section: Discussionmentioning

confidence: 99%

Establishment of an orthotopic pancreatic cancer mouse model: Cells suspended and injected in Matrigel

Jiang¹,

Lee²,

Wang³

et al. 2014

WJG

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AIM:To establish an orthotopic mouse model of pancreatic cancer that mimics the pathological features of exocrine pancreatic adenocarcinoma. METHODS:Pan02 cells were suspended in low-temperature Matrigel and injected into the parenchyma of pancreatic tails of C57BL/6 mice, with cells suspended in phosphate buffered saline (PBS) serving as a control. Primary and implanted tumors were confirmed pathologically. The rate of tumor formation and intraperitoneal implantation in the two groups were compared at different time points after injection. Leakage and intraabdominal dispersion of Matrigel and PBS, both dyed with methylene blue, were compared after injection into the parenchyma of the pancreas. We observed adherence and proliferation in Pan02 cells suspended in Matrigel in vitro . We also compared the pathological manifestation of this orthotopic pancreatic cancer model in the head and tails of the pancreas. The characteristics of the origin of epithelial cells and exocrine markers of established orthotopic pancreatic tumors were confirmed using immunohistochemistry. RESULTS:Diluted Matrigel could form a gel drip in the pancreatic parenchyma, effectively preventing leakage from the injection site and avoiding dispersion in the abdominal cavity. Pan02 cells were able to adhere to a dish, proliferate, and migrate in the gel drip. The tumor formation rate in the Matrigel group was 100% at both 2 and 3 wk after injection, whereas it was 25.0% and 37.5% in the PBS group at 2 and 3 wk, respectively (P < 0.05). The intraperitoneal tumor implantation rate was 75.0% in the PBS group after 3 wk of injection, while it was 12.5% in the Matrigel group (P < 0.05). Hepatoduodenal ligament and duodenal invasions with obstructive jaundice and upper digestive obstruction with mesenteric lymph node metastasis were observed in the pancreatic head group. In the pancreatic tail group, spleen and gastric invasion were dominant, leading to retroperitoneal lymph nodes metastasis. Positive immunohistochemical staining of cytokeratin and negative staining of vimentin and chromogranin A confirmed that the orthotopic pancreatic tumor injected with Pan02 cells suspended in Matrigel was of epithelial origin and expressed exocrine markers of cancer. CONCLUSION:This method of low-temperature Matrigel suspension and injection is effective for establishing an orthotopic mouse model of pancreatic cancer. model in immunocompetent mice. The orthotopic pancreatic cancer models in the pancreatic head and tail both effectively mimic the relative pathological features of exocrine adenocarcinoma of the human pancreas. This model system will provide a platform for exploring new research outcomes for the effective treatment and management of pancreatic cancer.

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“…However, in a transplacental induction model of pancreatic ductal cancer featuring NNK and EtOH treatment in the Syrian golden hamster, EtOH alone caused pancreatitis and hyperplasia, while NNK alone did not induce either [8], indicating a strong enhancing effect of pancreatitis on pancreatic carcinogenesis. It has also been reported that EtOH and nicotine promote pancreatic carcinogenesis in the DMBA-implanted mouse model [85,86]. …”

Section: Modifying Factors In the Experimental Pancreatic Carcinogenementioning

confidence: 99%

Experimental Animal Models of Pancreatic Carcinogenesis for Prevention Studies and Their Relevance to Human Disease

Takahashi

Hori

Mutoh

et al. 2011

Cancers

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Pancreatic cancer is difficult to cure, so its prevention is very important. For this purpose, animal model studies are necessary to develop effective methods. Injection of N-nitrosobis(2-oxopropyl)amine (BOP) into Syrian golden hamsters is known to induce pancreatic ductal adenocarcinomas, the histology of which is similar to human tumors. Moreover, K-ras activation by point mutations and p16 inactivation by aberrant methylation of 5′ CpG islands or by homozygous deletions have been frequently observed in common in both the hamster and humans. Thus, this chemical carcinogenesis model has an advantage of histopathological and genetic similarity to human pancreatic cancer, and it is useful to study promotive and suppressive factors. Syrian golden hamsters are in a hyperlipidemic state even under normal dietary conditions, and a ligand of peroxizome proliferator-activated receptor gamma was found to improve the hyperlipidemia and suppress pancreatic carcinogenesis. Chronic inflammation is a known important risk factor, and selective inhibitors of inducible nitric oxide synthase and cyclooxygenase-2 also have protective effects against pancreatic cancer development. Anti-inflammatory and anti-hyperlipidemic agents can thus be considered candidate chemopreventive agents deserving more attention.

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Pancreatic intraepithelial neoplasia and ductal adenocarcinoma induced by DMBA in mice: effects of alcohol and caffeine

Cited by 24 publications

References 35 publications

Ethanol differentially regulates snail family of transcription factors and invasion of premalignant and malignant pancreatic ductal cells

Ethanol differentially regulates snail family of transcription factors and invasion of premalignant and malignant pancreatic ductal cells

Establishment of an orthotopic pancreatic cancer mouse model: Cells suspended and injected in Matrigel

Experimental Animal Models of Pancreatic Carcinogenesis for Prevention Studies and Their Relevance to Human Disease

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