Objectives: Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are characterized by a prominent intraductal component, which has malignant potential. Adenocarcinoma arising in IPMN has a less aggressive biological behavior, and survival after surgery has been shown to be better than for pancreatic ductal adenocarcinoma (PDAC). Many authors suggest that IPMNs are distinct neoplasms with a unique genetic signature. In addition to chromosomal instability, PDAC carries characteristic mutation types such as K-ras and p53 mutations. For PDAC, cell culture and xenograft models have become a powerful tool to study tumor behavior and genetics. Our lab recently reported that the Sonic Hedgehog (Shh) pathway is over-expressed in >95% of PDAC. In this study we describe a novel xenograft model and cell culture deriving from malignant IPMN, created to biologically and genetically characterize IPMNs and compare them to PDAC.
Methods: From a fresh surgical specimen of invasive main duct IPMN a xenograft tumor line and cell culture were created and its histology, K-ras and P53 status determined. Members of Shh pathway signalling (Shh, Ptch1, Ptch2, Smo, and Gli2) were assessed by quantitative RT-PCR, and global genomic changes were evaluated by array Comparative Genomic Hybridization (CGH).
Results: IPMN tumors were successfully implanted and enriched in a xenograft model, and a cell line was established. Histology of the xenograft tumors revealed characteristics identical to those of the parent tumor. Cytogenetic analysis showed a tetraploid karyotype with multiple chromosomal aberrations reflecting genomic instability, K-ras mutation at codon 12 (GGT>GTT) and p53 mutation at codon 273 in exon 8 (CGT>TGT) as well as over expression of the Shh pathway. Thus, IPMNs do share certain genetic features that characterize PDAC. Array CGH reveals chromosomal gains at 3q, 5p, 9p, 12p, 18p, and 19q, and losses which involve chromosomes 4, 5q, 6q, distal 6p, 8p, 8q, 9q, 13q, 14q, 15q, 17p, 18q, 19p, and 21. These data are comparable to previously published chromosomal aberrations in IPMNs and show overlapping and distinct characteristics compared to PDAC.
Conclusion: This study describes a novel xenograft model and cell line deriving from adenocarcinoma arising in IPMN. Characterization of the model shows similarities to the parent tumor in accord with previously published data on IPMNs. Compared to PDAC, this model shows shared aberrations as well as evidence for distinct genomic changes. More importantly, the xenograft model may be useful for future preclinical chemotherapy studies in vivo.