Dataset Information

TGF-? and ?v?6 integrin act in a common pathway to suppress pancreatic cancer progression.

ABSTRACT: The TGF-? pathway is under active consideration as a cancer drug target based on its capacity to promote cancer cell invasion and to create a protumorigenic microenvironment. However, the clinical application of TGF-? inhibitors remains uncertain as genetic studies show a tumor suppressor function of TGF-? in pancreatic cancer and other epithelial malignancies. Here, we used genetically engineered mouse models to investigate the therapeutic impact of global TGF-? inhibition in pancreatic cancer in relation to tumor stage, genetic profile, and concurrent chemotherapy. We found that ?v?6 integrin acted as a key upstream activator of TGF-? in evolving pancreatic cancers. In addition, TGF-? or ?v?6 blockade increased tumor cell proliferation and accelerated both early and later disease stages. These effects were dependent on the presence of Smad4, a central mediator of TGF-? signaling. Therefore, our findings indicate that ?v?6 and TGF-? act in a common tumor suppressor pathway whose pharmacologic inactivation promotes pancreatic cancer progression.

SUBMITTER: Hezel AF

PROVIDER: S-EPMC3764481 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

TGF-β and αvβ6 integrin act in a common pathway to suppress pancreatic cancer progression.

Hezel Aram F AF Deshpande Vikram V Zimmerman Stephanie M SM Contino Gianmarco G Alagesan Brinda B O'Dell Michael R MR Rivera Lee B LB Harper Jay J Lonning Scott S Brekken Rolf A RA Bardeesy Nabeel N

Cancer research 20120711 18

The TGF-β pathway is under active consideration as a cancer drug target based on its capacity to promote cancer cell invasion and to create a protumorigenic microenvironment. However, the clinical application of TGF-β inhibitors remains uncertain as genetic studies show a tumor suppressor function of TGF-β in pancreatic cancer and other epithelial malignancies. Here, we used genetically engineered mouse models to investigate the therapeutic impact of global TGF-β inhibition in pancreatic cancer ...[more]

PMID: 22787119

Similar Datasets

Project description:BackgroundTransforming growth factor (TGF)-β signaling pathway, may act both as a tumor suppressor and as a tumor promoter in pancreatic cancer, depending on tumor stage and cellular context. TGF-β pathway has been under intensive investigation as a potential therapeutic target in the treatment of cancer. We hypothesized a correlation between TGF-βR2/SMAD4 expression in the tumor, plasma TGF-β1 ligand level, genetic variation in TGF-B pathway and prognosis of pancreatic cancer.MethodWe examined TGF-βR2 and SMAD4 protein expression in biopsy or surgical samples from 91 patients with pancreatic ductal adenocarcinoma (PDAC) using immunohistochemistry. Plasma level of TGF-β1 was measured in 644 patients with PDAC using ELISA. Twenty-eight single nucleotide polymorphisms (SNP) of the TGF-β1, TGF-β2, TGF-β3, TGF-βR1, TGF-βR2, and SMAD4 genes were determined in 1636 patients with PDAC using the Sequenom method. Correlation between protein expression in the tumor, plasma TGF-β1 level, and genotypes with overall survival (OS) was evaluated with Cox proportional regression models.ResultsThe expression level of TGF-βR2 and SMAD4 as an independent marker was not associated with OS. However, patients with both low nuclear staining of TGF-βR2 and high nuclear staining of SMAD4 may have better survival (P = 0.06). The mean and median level of TGF-β1 was 15.44 (SD: 10.99) and 12.61 (interquartile range: 8.31 to 19.04) ng/ml respectively. Patients with advanced disease and in the upper quartile range of TGF-β1 level had significantly reduced survival than those with low levels (P = 0.02). A significant association of SMAD4 SNP rs113545983 with overall survival was observed (P<0.0001).ConclusionOur data provides valuable baseline information regarding the TGF-β pathway in pancreatic cancer, which can be utilized in targeted therapy clinical trials. High TGF-β1 plasma level, SMAD4 SNP or TGF-βR2/SMAD4 tumor protein expression may suggest a dependence on this pathway in patients with advanced pancreatic cancer.

Dataset Information

TGF-? and ?v?6 integrin act in a common pathway to suppress pancreatic cancer progression.

Publications

TGF-β and αvβ6 integrin act in a common pathway to suppress pancreatic cancer progression.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets