Prevention of Inflammation-Driven Colon Carcinogenesis in Human MUC1 Transgenic Mice by Vaccination with MUC1 DNA and Dendritic Cells

SIMPLE SUMMARY: Colorectal cancer is one of the most common cancers worldwide and improved treatments are needed. The present research focused on the use of a DNA vaccine targeted at one of the commonly found tumor-associated antigens, human MUC1. MUC1 transgenic mice were vaccinated with MUC1 DNA mixed with bone-marrow-derived dendritic cells (BMDCs). Then, inflammation-driven colon cancer was induced by injection of a carcinogen, azoxymethane, and administration of dextran-sulfate-sodium-containing drinking water. This mouse model of colon cancer resembles the colon cancer found in humans. The number and size of colonic tumors were compared to mice vaccinated with MUC1 DNA alone or BMDCs alone. The combination of MUC1 DNA and BMDCs reduced the tumor burden more than in the controls, showing an additive preventive effect. These findings demonstrate that in this human MUC1 transgenic mouse model, MUC1-expressing colonic tumors can be partially prevented by a vaccine containing MUC1 DNA and BMDCs. ABSTRACT: The preventive efficacy of MUC1-specific DNA immunization on inflammation-driven colon carcinogenesis in human MUC1 transgenic (MUC1.Tg) mice was investigated. Mice were vaccinated with MUC1 DNA mixed with autologous bone-marrow-derived dendritic cells (BMDCs), and then colonic tumors were induced by azoxymethane (AOM) injection and oral administration of dextran sulfate sodium (DSS). Two types of tumors, squamous metaplasia and tubular adenoma, were observed. Both expressed high levels of MUC1 as indicated by the binding of anti-MUC1 antibodies with different specificities, whereas MUC1 expression was not detected in normal colonic mucosa. When mice were immunized with MUC1 DNA + BMDCs, tumor incidence, tumor number, and tumor size were significantly reduced. In contrast, vaccination with MUC1 DNA alone or BMDCs alone was ineffective in reducing tumor burden. Inflammation caused by DSS was not suppressed by the MUC1 DNA + BMDCs vaccination. Furthermore, MUC1 protein expression levels, as judged by anti-MUC1 antibody binding in tumors grown after vaccination, did not significantly differ from the control. In conclusion, an inflammation-driven carcinogenesis model was established in MUC1.Tg mice, closely resembling human colon carcinogenesis. In this model, vaccination with MUC1 DNA + BMDCs was effective in overriding MUC1 tolerance and reducing the tumor burden by a mechanism not affecting the level of colonic inflammation.