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Abstract
BackgroundRelevant preclinical models that recapitulate the key features of human pancreatic ductal adenocarcinoma (PDAC) are needed in order to provide biologically tractable models to probe disease progression and therapeutic responses and ultimately improve patient outcomes for this disease. Here, we describe the establishment and clinical, pathological, molecular and genetic validation of a murine, orthotopic xenograft model of PDAC.MethodsHuman PDACs were resected and orthotopically implanted and propagated in immunocompromised mice. Patient survival was correlated with xenograft growth and metastatic rate in mice. Human and mouse tumor pathology were compared. Tumors were analyzed for genetic mutations, gene expression, receptor tyrosine kinase activation, and cytokine expression.ResultsFifteen human PDACs were propagated orthotopically in mice. Xenograft-bearing mice developed peritoneal and liver metastases. Time to tumor growth and metastatic efficiency in mice each correlated with patient survival. Tumor architecture, nuclear grade and stromal content were similar in patient and xenografted tumors. Propagated tumors closely exhibited the genetic and molecular features known to characterize pancreatic cancer (e.g. high rate of KRAS, P53, SMAD4 mutation and EGFR activation). The correlation coefficient of gene expression between patient tumors and xenografts propagated through multiple generations was 93 to 99%. Analysis of gene expression demonstrated distinct differences between xenografts from fresh patient tumors versus commercially available PDAC cell lines.ConclusionsThe orthotopic xenograft model derived from fresh human PDACs closely recapitulates the clinical, pathologic, genetic and molecular aspects of human disease. This model has resulted in the identification of rational therapeutic strategies to be tested in clinical trials and will permit additional therapeutic approaches and identification of biomarkers of response to therapy.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is an insidious disease, with the shortest survival of any solid malignancy [1]
We have demonstrated in our laboratory that in vitro assays do not correlate with response in the orthotopic xenograft model for targeted therapies to focal adhesion kinase (FAK) [4], urokinase plasminogen activator receptor [5], and epidermal growth factor receptor (EGFR)/Her2 and MEK [6]
To achieve more efficient engraftment during initial establishment of the human pancreatic ductal adenocarcinoma (PDAC) tumor line, NOD SCID mice were used for F1 and F2 generations
Summary
Pancreatic ductal adenocarcinoma (PDAC) is an insidious disease, with the shortest survival of any solid malignancy [1]. Surgical resection offers some patients a possibility of cure, but the vast majority of patients have unresectable, locoregionally advanced or metastatic disease at diagnosis. For these patients, medical therapy only marginally prolongs survival [2]. In order to improve outcomes, more effective therapies are needed, as well as better appreciation of therapeutic resistance mechanisms Integral to this is the development and utilization of well validated preclinical models that reflect the pathological, molecular and cellular properties of human tumors. Relevant preclinical models that recapitulate the key features of human pancreatic ductal adenocarcinoma (PDAC) are needed in order to provide biologically tractable models to probe disease progression and therapeutic responses and improve patient outcomes for this disease. We describe the establishment and clinical, pathological, molecular and genetic validation of a murine, orthotopic xenograft model of PDAC
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