Abstract 1402: A xenograft pancreatic cancer mouse model to study the function of extracellular DNA in metastasis
Authors: Fushi Wen, Alex Shen, Andrew Choi, Jiaqi Shi
Journal: Cancer Research (2012)

Abstract Pancreatic cancer is one of the most lethal cancers with the lowest survival rate of all solid cancers. This is largely due to its highly aggressive metastasis, which almost always leads to death. Understanding the mechanisms and the process of pancreatic cancer metastasis is critical towards its prevention and treatments. Although the etiology of pancreatic cancer is not well understood, the relationship between inflammation and the development of this cancer has been well recognized. Extracellular DNA (exDNA) is a newly discovered component associated with inflammation. exDNA production can be induced by interleukin 8 (IL-8), one of the major inflammatory and angiogenic cytokine. IL-8 exhibits a significantly elevated level in pancreatic cancer cell lines MiaPaCa-2 and BxPC3 and has been shown to play a role in stimulating pancreatic tumorigenesis and metastasis. With this background, we initiated a study to examine the presence of exDNA associated with pancreatic cancer cells. We have discovered a large amount of extracellular DNA associated with cultured pancreatic cancer cells but not with the normal pancreatic cells. Here, we tested the hypothesis that pancreatic cancer cells produce extracellular DNA to promote their metastasis. Our in vitro study showed that removal of the exDNA by DNase I inhibited metastasis-associated characteristics of cancer cells including cell migration, invasion, and adhesion. To test our hypothesis in vivo, we generated the orthotopic xenograft pancreatic cancer mouse model. We used the pancreatic cancer cell line MiaPaCa-2/LucE expressing luciferase to induce tumors. We assessed the effect of DNase I treatment on pancreatic cancer metastasis from pancreases, the primary tumor site, to different organs. Tumors were examined directly in size and weight, and indirectly by the bioluminescent signal intensity that corresponds to the tumor size. Our preliminary data showed that continuous applications of a low dosage of DNase I reduced the tumor incidences and the tumor size measured by the chemiluminescence in all the organs examined. When mouse tumor tissues were stained with DAPI, a DNA-specific fluorescent dye and examined through immunohistochemistry (IHC) with DNA-specific antibody, high level of exDNA was found in the tumor tissues. More exDNA was found to be associated with the inflammatory area in the tumor tissues. We conclude that extracellular DNA play a novel role in metastatic behaviors of pancreatic cancer cells in vitro and facilitate metastasis in vivo. To our knowledge, this is the first report on the presence of exDNA associated with pancreatic cancer tissues and the first report on the inhibition of DNase I treatment on pancreatic cancer metastasis. Our results open new avenues for understanding the metastasis of pancreatic cancer, and facilitate the identification of new drug targets and development of new treatments. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1402. doi:1538-7445.AM2012-1402