CpG ODN, Toll Like Receptor (TLR)-9 Agonist, Inhibits Metastatic Colon Adenocarcinoma in a Murine Hepatic Tumor Model

• Published in: The Journal of surgical research Vol. 174; no. 2; pp. 284 - 290
• Main Authors: Kim, Ik Yong, M.D, Yan, Xiaohong, Ph.D, Tohme, Samer, M.D, Ahmed, Aqeel, M.D, Cordon-Cardo, Carlos, M.D, Shantha Kumara, H.M.C., Ph.D, Kim, Soo-Ki, M.D, Whelan, Richard L., M.D
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.05.2012
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - secondary; Animals; colon cancer; Colonic Neoplasms - drug therapy; Colonic Neoplasms - pathology; CpG Islands; CpG oligodeoxynucleotide (CpG); Female; Liver - pathology; liver metastasis; Liver Neoplasms, Experimental - drug therapy; Liver Neoplasms, Experimental - pathology; Liver Neoplasms, Experimental - secondary; Mice; Mice, Inbred BALB C; Oligodeoxyribonucleotides - therapeutic use; Organ Size; Portal Vein; Surgery; toll like receptor (TLR)-9; Toll-Like Receptor 9 - agonists; CpG oligodeoxynucleotide (CpG); toll like receptor (TLR)-9; liver metastasis; colon cancer
• ISSN: 0022-4804; 1095-8673
• DOI: 10.1016/j.jss.2010.12.021

Background Colorectal liver metastases (mets) are often refractory to conventional therapies. CpG oligodeoxynucleotide 1826 (CpG), a Toll like receptor (TLR)-9 agonist, inhibits murine tumor growth by augmenting Th1 immunity. The impact of CpG on metastatic colon tumors is unknown. The purpose of this study was to determine the effect of CpG on the growth of hepatic colon cancer mets. Methods Two studies with separate control groups were performed using 40 Balb/C mice (study A, CpG 50 μg/dose; study B, 100 μg/dose; n = 9–11/subgroup). Tumors were induced via portal vein injection of 2 × 104 CT26 colon tumor cells. After surgery, the mice were randomized; test groups were given 14 daily intraperitoneal (i.p.) CpG injections (50 or 100 μg/dose) while the control group received i.p. saline. On d 21 mice were sacrificed, the livers and spleens excised and weighed and the mets counted (reported as median ± 95% confidence interval [CI]) and histologically assessed. Results The CpG mice had significantly fewer hepatic mets/mouse (study A, median two nodules, 95% CI, 0–3; study B, 0 nodules, 95% CI 0–0) than the control mice (study A, 6 nodules, 95% CI, 3–9, P = 0.002; Study B, 6 nodules, 95% CI, 3–9, P < 0.001). In study B, there were no mets in 9/11 CpG mice ( versus 2/10 for CpG 50 μg and 0/19 for control mice). The mean liver/spleen weights of the CpG mice in both studies were significantly greater than in control mice. Histologically, high mitotic rates were noted in control mets while fewer tumor cells and histiocytic and lymphocytic infiltrates were found in CpG livers. Conclusions CpG inhibited liver tumor growth in this model (100 μg/dose more than 50 μg/dose). CpG was associated with increased liver and spleen weights not related to tumor burden. Increased lymphocytic and histiocytic infiltrates were noted in CpG-treated tumor nodules.