A Novel Immunocompetent Mouse Model of Pancreatic Cancer with Robust Stroma: a Valuable Tool for Preclinical Evaluation of New Therapies.

Abstract

A valid preclinical tumor model should recapitulate the tumor microenvironment. Immune and stromal components are absent in immunodeficient models of pancreatic cancer. While these components are present in genetically engineered models such as Kras(G12D); Trp53(R172H); Pdx-1Cre (KPC), immense variability in development of invasive disease makes them unsuitable for evaluation of novel therapies. We have generated a novel mouse model of pancreatic cancer by implanting tumor fragments from KPC mice into the pancreas of wild type mice. Three-millimeter tumor pieces from KPC mice were implanted into the pancreas of C57BL/6J mice. Four to eight weeks later, tumors were harvested, and stromal and immune components were evaluated. The efficacy of Minnelide, a novel compound which has been shown to be effective against pancreatic cancer in a number of preclinical murine models, was evaluated. In our model, consistent tumor growth and metastases were observed. Tumors demonstrated intense desmoplasia and leukocytic infiltration which was comparable to that in the genetically engineered KPC model and significantly more than that observed in KPC tumor-derived cell line implantation model. Minnelide treatment resulted in a significant decrease in the tumor weight and volume. This novel model demonstrates a consistent growth rate and tumor-associated mortality and recapitulates the tumor microenvironment. This convenient model is a valuable tool to evaluate novel therapies.

• Authors: Kaustav Majumder, Nivedita Arora, Shrey Modi, Rohit Chugh, Alice Nomura, Bhuwan Giri, Rajinder Dawra, Sundaram Ramakrishnan, Sulagna Banerjee, Ashok Saluja, Vikas Dudeja
• Journal: Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract (J Gastrointest Surg) Vol. 20 Issue 1 Pg. 53-65; discussion 65 (Jan 2016) ISSN: 1873-4626 [Electronic] United States
• PMID: 26582596 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Diterpenes
• Epoxy Compounds
• Organophosphates
• Phenanthrenes
• 14-O-phosphonooxymethyltriptolide disodium salt

Topics

• Adenocarcinoma (drug therapy, pathology)
• Animals
• Antineoplastic Agents (therapeutic use)
• Diterpenes
• Epoxy Compounds
• Female
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Neoplasms, Experimental (drug therapy, pathology)
• Organophosphates (therapeutic use)
• Pancreatic Neoplasms (drug therapy, pathology)
• Phenanthrenes (therapeutic use)
• Random Allocation
• Tumor Microenvironment