Abstract
Preclinical evaluation of new therapies using a novel mouse model of pancreatic cancer which recapitulates the tumor stromal and immune microenvironment
Journal of the American College of Surgeons, Vol.221(4), pp.e21-e22
10/2015
DOI: 10.1016/j.jamcollsurg.2015.08.354
Abstract
Introduction
A valid animal tumor-model should recapitulate tumorigenic properties as well as the immune-stromal microenvironment. Cell-line based orthotopic-models for pancreatic cancer are established in immunodeficient mice and lack immune and stromal components. These components are present in the genetically-engineered KrasG12D-Trp53-PdxCre (KPC) tumor-model but its immense variability in time-to-invasive disease (47-355 days) makes it unsuitable for evaluating novel therapies. To address these shortcomings, we have developed and characterized a novel tumor-model where tumors from KPC-mice were implanted in WT-mice (wild type).
Methods
3 mm3 pieces of pancreatic tumors harvested from KPC-mice were implanted into the pancreas of WT C57BL/6 mice at laparotomy. After 4-8 weeks, tumors were harvested and stromal and immune-components were characterized by immunohistochemistry and flow-cytometry respectively. In another model the effect of Minnelide, a novel molecule which was developed in our laboratory and is currently in Phase I clinical trials against GI malignancies, on tumor growth and microenvironment was evaluated.
Results
Consistent tumor growth was observed with time [Volume (mm3, Mean±SD); 4wks: 1101±347, 8wks: 1958 ±590]. At 8 weeks, 30% of mice had succumbed to tumor growth suggesting utility of this model to assess disease specific survival. Staining for stromal components (collagen and αSMA) and immune markers (CD45) showed intense desmoplasia and immune infiltration. Minnelide treatment resulted in significant decrease in tumor volumes, tumor weight, stromal collagen content and CD3 infiltration.
Conclusions
Our model demonstrates consistent growth rate, tumor-associated mortality, recapitulates tumor microenvironment and circumvents the variability seen in previous models. This model can be a valuable tool to evaluate novel therapies.
Details
- Title: Subtitle
- Preclinical evaluation of new therapies using a novel mouse model of pancreatic cancer which recapitulates the tumor stromal and immune microenvironment
- Creators
- Kaustav Majumder - University of MinnesotaShrey Modi - University of MinnesotaRohit K. Chugh - University of MinnesotaSulagna Banerjee - University of MinnesotaAshok Saluja - University of MinnesotaVikas Dudeja - University of Minnesota
- Resource Type
- Abstract
- Publication Details
- Journal of the American College of Surgeons, Vol.221(4), pp.e21-e22
- DOI
- 10.1016/j.jamcollsurg.2015.08.354
- ISSN
- 1072-7515
- eISSN
- 1879-1190
- Publisher
- ELSEVIER SCIENCE INC
- Language
- English
- Date published
- 10/2015
- Academic Unit
- Anatomy and Cell Biology; Surgery
- Record Identifier
- 9985244570502771
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