H. L. Beal1, J. Shea1, M. Firpo1, S. Mulvihill1,2, C. Scaife1,2 1University Of Utah,Department Of Surgery Research,Salt Lake City, UTAH, USA 2Huntsman Cancer Institute,Salt Lake City, UTAH, USA
Introduction:
Pancreatic adenocarcinoma (PDA) is an exceptionally lethal disease. The development of new efficacious therapies could be improved through the development of animal models that more faithfully replicate disease biology. One such approach is to utilize patient-derived primary mouse xenograft tumors. Here we describe the results of our xenograft tumor banking program from 2011-2013 and compare the xenograft phenotype to the patients, as well as patient prognosis, and compare characteristics of the xenograft tumor with the patient tumor. We tested the hypothesis that a more aggressive tumor phenotype will grow more frequently in mice.
Methods:
With IRB and IACUC approval, tumor samples from suspected PDA cases were obtained within an hour of resection, placed in media, cut into approximately 1mm3 pieces, mixed with Matrigel, and implanted subcutaneously into SCID hairless female mice. Upon reaching 2cm in diameter, the tumor was processed for histology and re-implanted in a new mouse. Tumors for histology were fixed in formalin, embedded in paraffin and then stained with hematoxylin and eosin or immunohistochemically stained with epithelial markers (E-cadherin and β-catenin). Each patient’s chart was reviewed for patient demographics, diagnosis, recurrence, and overall and disease-free survival.
Results:
In the three year study period, 54 patients with periampullary adenocarcinoma were enrolled. Twenty-two patients were female (age 68 +/- 7 years) and 32 were male (age 63 +/- 9 years). We implanted 47 PDA tumors, 4 cholangiocarcinoma tumors, and 3 ampullary tumors. The overall xenograft take rate was 44%. Take rates for PDA (13/39; 9 under observation), cholangiocarcinoma (4/4), and ampullary (3/3) tumors were 33%, 100%, and 100%, respectively. Once established, 84% of tumors successfully grew in a second mouse.
Histologically, mouse PDA xenograft tumors were remarkably similar to the original patient tumor with all samples demonstrating extensive desmoplastic tissue surrounding tumor cells. The histological characteristics of the tumor appear to be stable over several passages. The xenograft tumors cells were positive for both E-cadherin and β -catenin. Mean survival in patients with succefully engrafted PDA tumors was 10 +/- 6 months, while patients whose tumor did not engraft had mean survival of 21 +/- 10 months (p=0.005).
Conclusion:
We have successfully established 13 patient derived PDA, 3 ampullary and 4 cholangiocarcimonas. The PDA xenograft tumors maintain histological similarities with the patient tumor and preliminary survival analysis suggests that more aggressive tumors are more likely to establish in the mouse model. The tumors established in our xenograft banking program, are an important resource that can be utilized to evaluate new therapeutics treatments.