In vitromodels of pancreatic cancer for translational oncology research

Abstract

Background-Pancreatic cancer is a disease of near uniform fatality and the overwhelming majority of patients succumb to their advanced malignancy within a few months of diagnosis. Despite considerable advances in our understanding of molecular mechanisms underlying pancreatic carcinogenesis, this knowledge has not yet been fully translated into clinically available treatment strategies that yield significant improvements in disease free or overall survival.Objective-Cell line-based in vitro model systems provide powerful tools to identify potential molecular targets for therapeutic intervention as well as for initial pre-clinical evaluation of novel drug candidates. Here we provide a brief overview of recent literature on cell line-based model systems of pancreatic cancer and their application in the search for novel therapeutics against this vicious disease.Conclusion-While in vitro models of pancreatic cancer are of tremendous value for genetic studies and initial functional screenings in drug discovery, they carry several imanent drawbacks and are often poor in predicting therapeutic response in humans. Therefore, in most instances they are successfully exploited to generate hypothesis and identify molecular targets for novel therapeutics, which are subsequently subject to further in-depth characterization using more advanced in vivo model systems and clinical trials.

The Matricellular Protein CCN1/Cyr61 Is a Critical Regulator of Sonic Hedgehog in Pancreatic Carcinogenesis

“…Additionally, the viability of pancreatic cancer stem cells is also dependant on sustained expression of SHh signaling. Thus, blockading the SHh signaling pathway with an inhibitor reduces pancreatic cancer growth and improves outcomes (19,48). Recently, we found that CCN1 functions in a similar pathobiological role in pancreatic carcinogenesis, indicating that CCN1 signaling is critical for epithelial-mesenchymal transition and stemness and is required to promote tumor growth by the side population (cancer stem cells) of pancreatic cancer cells in a xenograft model (7).…”

“…The importance of SHh signaling in the development of pancreatic cancer and chemoresistance has fueled intensive study on this signaling molecule (48). Ample evidence indicates that SHh signaling is one of the "underpinning" signaling pathways which is aberrantly overexpressed in virtually all PDAC and is associated with tumor growth, metastasis and less survival in a genetically engineered mouse model of pancreatic cancer and an orthotropic xenograft model.…”

“…Next, we tested if active Notch-1 is requisite for CCN1-mediated activation of SHh in pancreatic cancer cells. To do so, Panc-1 cells were treated with a pharmacological inhibitor of ICD-releasing proteolytic enzyme ␥-secretase (DAPT, 5 M) (42) or vehicle for different times (24,48, and 72 h), and the levels of CCN1 and SHh were determined in the supernatants of tissue extracts using Western blotting. Studies showed that the expression of SHh was markedly diminished by DAPT at 48 h of treatment (Fig.…”

A synthetic lethal screen identifies the Vitamin D receptor as a novel gemcitabine sensitizer in pancreatic cancer cells

“…Gemcitabine, a nucleoside analog that blocks DNA replication, remains the first line therapy for patients with advanced PCa. 7,8 The efficacy of gemcitabine over 5-fluorouracil, which had previously been the drug of choice, was based on a very modest increase in medium survival of less than 2 months. 9 Although erlotinib (EGFR inhibitor) has been approved by the FDA for PCa, it only increased survival by less than a month, when used in combination with gemcitabine.…”

Oncolytic Activity of Avian Influenza Virus in Human Pancreatic Ductal Adenocarcinoma Cell Lines

“…The disease generally causes few or no symptoms, and diagnoses are typically made at an advanced stage, when only 1 in 5 patients is eligible for surgical resection (3). The average 5-year survival rates for this disease are less than 5%, and even in cases where surgery is possible, the rates rise to only 15% (2,4). In addition to surgical intervention, combination chemotherapy and radiation treatments are employed, but the highly aggressive and invasive nature of PDA leads to poor responses, and new innovative therapeutic approaches are in high demand.…”