Abstract
BackgroundPancreatic cancer (PDAC) is characterized by an abundant fibrous tissue rich in Tenascin-C (TNC), a large ECM glycoprotein mainly synthesized by pancreatic stellate cells (PSCs). In human pancreatic tissues, TNC expression increases in the progression from low-grade precursor lesions to invasive cancer. Aim of this study was the functional characterization of the effects of TNC on biologic relevant properties of pancreatic cancer cells.MethodsProliferation, migration and adhesion assays were performed on pancreatic cancer cell lines treated with TNC or grown on a TNC-rich matrix. Stable transfectants expressing the large TNC splice variant were generated to test the effects of endogenous TNC. TNC-dependent integrin signaling was investigated by immunoblotting, immunofluorescence and pharmacological inhibition.ResultsEndogenous TNC promoted pancreatic cancer cell growth and migration. A TNC-rich matrix also enhanced migration as well as the adhesion to the uncoated growth surface of poorly differentiated cell lines. In contrast, adhesion to fibronectin was significantly decreased in the presence of TNC. The effects of TNC on cell adhesion were paralleled by changes in the activation state of paxillin and Akt.ConclusionTNC affects proliferation, migration and adhesion of poorly differentiated pancreatic cancer cell lines and might therefore play a role in PDAC spreading and metastasis in vivo.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) represents 85–90% of all pancreatic neoplasms
PDAC survival rates improved only marginally in the last 30 years and PDAC patients still have a very poor prognosis, with an overall 5-year survival rate below 5% and a median survival rate that ranges from 2 months in patients with metastatic disease to 8 months in patients with non-metastatic disease at the time of diagnosis [2]
We performed an extensive analysis of the effects of exogenous TNC on pancreatic cancer cell functions and we investigated the effect of endogenous TNC overexpression in the pancreatic cancer cell line PANC-1
Summary
Pancreatic ductal adenocarcinoma (PDAC) represents 85–90% of all pancreatic neoplasms. In 2010 43,140 people in the US were estimated to be diagnosed with pancreatic cancer and 36,800 to die of this lethal disease, making PDAC the fourth most common cause of tumor-related mortality in spite of an incidence of only 3% of total cases [1]. PDAC outcomes did not change much in the last several years mainly because of late diagnosis. PDAC as localized and regional disease is mainly asymptomatic and tools for an early detection are still missing. Pancreatic cancer is often refractory to any chemotherapy and radiotherapy treatment, and many clinical trials have failed to demonstrate a significant improvement in overall survival during the last decade [3]. Pancreatic cancer (PDAC) is characterized by an abundant fibrous tissue rich in Tenascin-C (TNC), a large ECM glycoprotein mainly synthesized by pancreatic stellate cells (PSCs). Aim of this study was the functional characterization of the effects of TNC on biologic relevant properties of pancreatic cancer cells
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