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Hypomethylating therapy in an aggressive stroma-rich model of pancreatic carcinoma.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that resists current treatments. To test epigenetic therapy against this cancer, we used the DNA demethylating drug 5-aza-2'-deoxycytidine (DAC) in an aggressive mouse model of stromal rich PDAC (KPC-Brca1 mice). In untreated tumors, we found globally decreased 5-methyl-cytosine (5-mC) in malignant epithelial cells and in cancer-associated myofibroblasts (CAF), along with increased amounts of 5-hydroxymethyl-cytosine (5-HmC) in CAFs, in progression from pancreatic intraepithelial neoplasia to PDAC. DAC further reduced DNA methylation and slowed PDAC progression, markedly extending survival in an early-treatment protocol and significantly though transiently inhibiting tumor growth when initiated later, without adverse side effects. Escaping tumors contained areas of sarcomatoid transformation with disappearance of CAFs. Mixing-allografting experiments and proliferation indices showed that DAC efficacy was due to inhibition of both the malignant epithelial cells and the CAFs. Expression profiling and immunohistochemistry highlighted DAC induction of STAT1 in the tumors, and DAC plus IFN-? produced an additive antiproliferative effect on PDAC cells. DAC induced strong expression of the testis antigen deleted in azoospermia-like (DAZL) in CAFs. These data show that DAC is effective against PDAC in vivo and provide a rationale for future studies combining hypomethylating agents with cytokines and immunotherapy.

SUBMITTER: Shakya R

PROVIDER: S-EPMC3548986 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Hypomethylating therapy in an aggressive stroma-rich model of pancreatic carcinoma.

Shakya Reena R Gonda Tamas T Quante Michael M Salas Martha M Kim Samuel S Brooks Jenna J Hirsch Steffen S Davies Justine J Cullo Angelica A Olive Kenneth K Wang Timothy C TC Szabolcs Matthias M Tycko Benjamin B Ludwig Thomas T

Cancer research 20121129 2

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that resists current treatments. To test epigenetic therapy against this cancer, we used the DNA demethylating drug 5-aza-2'-deoxycytidine (DAC) in an aggressive mouse model of stromal rich PDAC (KPC-Brca1 mice). In untreated tumors, we found globally decreased 5-methyl-cytosine (5-mC) in malignant epithelial cells and in cancer-associated myofibroblasts (CAF), along with increased amounts of 5-hydroxymethyl-cytosine (5-HmC) in CAFs, ...[more]

PMID: 23204224

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent desmoplastic/stromal reaction, which contributes to the poor clinical outcome of this disease. Therefore, greater understanding of the stroma development and tumor-stroma interactions is highly required. Pancreatic stellate cells (PSC) are myofibroblast-like cells located in exocrine areas of the pancreas, which as a result of inflammation produced by PDAC migrate and accumulate in the tumor mass, secreting extracellular matrix components and producing the dense PDAC stroma. Currently, only a few orthotopic or ectopic animal tumor models, where PDAC cells are injected into the pancreas or subcutaneous tissue layer, or genetically engineered animals offer tumors that encompass some stromal component. Herein, we report generation of a simple 3D PDAC in vitro micro-tumor model without an addition of external extracellular matrix, which encompasses a rich, dense and active stromal compartment. We have achieved this in vitro model by incorporating PSCs into 3D PDAC cell culture using a modified hanging drop method. It is now known that PSCs are the principal source of fibrosis in the stroma and interact closely with cancer cells to create a tumor facilitatory environment that stimulates local and distant tumor growth. The 3D micro-stroma models are highly reproducible with excellent uniformity, which can be used for PDAC-stroma interaction analysis and high throughput automated drug-screening assays. Additionally, the increased expression of collagenous regions means that molecular based perfusion and cytostaticity of gemcitabine is decreased in our Pancreatic adenocarcinoma stroma spheroids (PDAC-SS) model when compared to spheroids grown without PSCs. We believe this model will allow an improved knowledge of PDAC biology and has the potential to provide an insight into pathways that may be therapeutically targeted to inhibit PSC activation, thereby inhibiting the development of fibrosis in PDAC and interrupting PSC-PDAC cell interactions so as to inhibit cancer progression.

Dataset Information

Hypomethylating therapy in an aggressive stroma-rich model of pancreatic carcinoma.

Publications

Hypomethylating therapy in an aggressive stroma-rich model of pancreatic carcinoma.

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