Molecular profiling of direct xenograft tumors established from human pancreatic adenocarcinoma after neoadjuvant therapy.

ABSTRACT

BACKGROUND: Pancreatic adenocarcinoma is among the most resistant of human cancers, yet specific mechanisms of treatment resistance remain poorly understood. Models to study pancreatic cancer resistance remain limited and should reflect in vivo changes that occur within patient tumors. We sought to identify consistent, differentially expressed genes between treatment of naive pancreatic tumors and those exposed to neoadjuvant therapy using a strict, in vivo direct xenograft model system. METHODS: Over a 42-week period, 12 untreated and treated patient tumors were successfully engrafted into NOD/SCID mice. RNA from each treatment group (5 untreated and 4 treated) was isolated in triplicate and subjected to global gene expression analysis. Consistent gene expression changes with treatment were identified and confirmed using RT-PCR and immunohistochemistry. RESULTS: Engraftment of untreated patient tumors was more frequent than treated tumors (17 of 21 versus 16 of 49, P = .0002) but without differences in observed time until tumor formation. The histology of patient tumors was recapitulated in direct xenograft tumors. Relative to untreated tumors, treated tumors consistently demonstrated more than a 2-fold reduction in TGFß-R2 mRNA expression and more than a 5-fold increase in IGFBP3 expression (P < .0218) and were confirmed by immunohistochemistry. CONCLUSION: Engraftment of human pancreatic tumors into immunodeficient mice prior to and following neoadjuvant therapy is possible and provides an in vivo platform for comparison of global gene expression patterns. The decreased TGFß-R2 expression and increased IGFBP3 expression among direct xenograft tumors derived from treated tumors relative to untreated tumors suggests a role in therapy resistance and warrants further study.