In vitro models 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.

Figure 1

(top) Non-transformed hTERT-immortalized HPNE cells grow as a monolayer in tissue culture. (middle and bottom) Examples of transformed HPNE cells with multi-layering (“focus” formation). In this example, the gene(s) responsible for this neoplastic phenotype are not known, as transformation was induced by transient activation of a Sleeping Beauty transposon, leading to disruption and/or activation of cancer-associated genes in the HPNE genome. In vitro models of pancreatic epithelial cells can be used for such “forward” genetics experiments, as well as for more traditional reverse genetics using known combination of oncogenes or tumor suppressor genes, as discussed in the text.

Figure 2

Pancreatic cancer does not occur ‘de novo’ but via development of clearly defined tangible precursor lesions that correlate with step-wise accumulation of genetic alterations. In order to develop systemic metastases, an invasive clone must overcome several additional selection barriers, including invasion into surrounding tissue, anchorage-independent survival in the blood stream, active migration and invasion at a distant organ site and establishment of a metastatic tumor lesion. While a variety of in vitro methods exist trying to mimic single aspects of this complex process, it is nevertheless impossible to faithfully mimic in its entirety by means of cell line-based in vitro models alone as of to date.