Antitumor effect induced by dendritic cell (DC)-based immunotherapy against peritoneal dissemination of the hamster pancreatic cancer
Introduction
In almost all cases of pancreatic cancer patients, because of liver metastasis, peritoneal dissemination and local recurrence in the early postoperative stage, even macroscopically radical operations have not been successful in improving the prognosis of pancreatic cancer. Peritoneal dissemination is the most important factor in the prognosis of pancreatic cancer patients. Therefore, a therapeutical approach to control peritoneal dissemination is urgently required in clinical oncology.
Recently, using several DC-based immunotherapeutic approaches against intractable cancers, some positive results were reported for melanoma [1], kidney [2] and prostate cancers [3], lymphoma [4] and colorectal cancers [5]. However, few clinical approaches to the treatment of peritoneal dissemination have been successful, because control of it is very difficult in the devastating conditions of terminal cancer and the poor self-immune response of such patients. Previously, our group already demonstrated that hamster bone marrow (BM)-derived DCs loaded with tumor lysate could induce tumor-specific cytotoxic T lymphocyte (CTL) activity and a significant anti-tumor response in subcutaneously pancreatic cancer-bearing hamsters [6].
In the present study, based on the promising therapeutical effect on a subcutaneous tumor, we have focused on peritoneal dissemination, the worst of the local progressions or recurrences after surgery in pancreatic cancer resulting in death, and investigated the therapeutical effect of DC treatment on pancreatic cancer-induced peritoneal disseminations in hamsters in terms of tumor weight and survival time.
Section snippets
Hamsters and cell lines
Specific pathogen-free 3 to 4-week-old female Syrian hamsters were purchased from Japan SLC, Inc. (Shizuoka, Japan) and housed under pathogen-free conditions. All animal used in this study were cared for and used humanely according to the principles of laboratory animal care (NIH publication No. 85-23, revised 1985) and the Guidelines for animal experiments of the National Cancer Center, Tokyo. The PGHAM-1 hamster pancreatic cancer cell line was kindly provided by Dr Uchida (Nippon Medical
Tracking of GFP-labeled BM-derived DCs in vivo
Almost all (more than 85%) GFP cDNA-transduced hamster DCs were GFP-positive and the MFI was very high, 5147 (data not shown). In vivo, the frequency of fluorescence-positive cells in the lymph node cell suspension was highest in omental lymph node tissue (6.8%, Fig. 1). No significant number of positive cells was seen in other lymph node tissues.
Inhibition of tumor growth and peritoneal dissemination
On day 24, 7 days after the last DC injection, 3 hamsters from each group were harvested and the remaining tumors were investigated. Tumor weight and
Discussion
To date, several therapeutic attempts to control peritoneal disseminations of pancreatic cancers have been reported [9], [10], [11], [12], [13], [14]. One group of therapeutic modalities is based on gene therapy. Aoki et al. [9] demonstrated that the herpes simplex virus thymidine kinase (HSV-TK) gene could be transduced intraperitoneally into tumor cells by way of an injection of DNA-lipopolyamine complex, but the feasibility of the gene-delivery system is not clear. Another group uses
Acknowledgements
We thank Ms Ohtsubo, Ms Hasegawa, Ms Kajimura and Ms Ebinuma for their excellent technical assistance. This work was supported by Grants in Aid from the Ministry of Health and Welfare for Cancer Research (9–32 and 10–28) and the Second-Term Comprehensive 10-year Strategy of Cancer Control from the Ministry of Health and Welfare in Japan.
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