hymecromone and Colorectal-Neoplasms

We have previously demonstrated that a low dose of cyclophosphamide (Cy) combined with gene therapy of interleukin-12 (AdIL-12) has a synergistic, although limited, antitumoral effect in mice with colorectal carcinoma. The main mechanism involved in the efficacy of Cy+AdIL-12 was the induction of a specific immune response mediated by cytotoxic T lymphocytes. Our current aims were to evaluate the effects of 4-methylumbelliferone (4Mu), a selective inhibitor of hyaluronan (HA) synthesis, on tumor microenvironment (TME) and to investigate how 4Mu affects the therapeutic efficacy of Cy+AdIL-12. The results showed that 4Mu significantly reduced the amount of tumoral HA leading to a significant decrease in tumor interstitial pressure (TIP). As a consequence, tumor perfusion was improved allowing an increased adenoviral transgene expression. In addition, treatment with 4Mu boosted the number of cytotoxic T lymphocytes that reach the tumor after adoptive transfer resulting in a potent inhibition of tumor growth. Importantly, we observed complete tumor regression in 75% of mice when 4Mu was administrated in combination with Cy+AdIL-12. The triple combination 4Mu+Cy+AdIL-12 also induced a shift toward antiangiogenic factors production in tumor milieu. Our results showed that TME remodeling is an interesting strategy to increase the efficacy of anticancer immunotherapies based on gene and/or cell therapy.

Topics: Adenoviridae; Adoptive Transfer; Animals; Antineoplastic Agents, Alkylating; Cell Line, Tumor; Colorectal Neoplasms; Combined Modality Therapy; Cyclophosphamide; Cytotoxicity, Immunologic; Disease Models, Animal; Gene Expression; Genes, Reporter; Genetic Therapy; Genetic Vectors; Hymecromone; Immunotherapy; Interleukin-12; Liver Neoplasms; Lymphocytes, Tumor-Infiltrating; Male; Mice; Neovascularization, Pathologic; T-Lymphocyte Subsets; Transduction, Genetic; Transgenes; Tumor Burden; Tumor Microenvironment

Human colorectal cancer cells were incubated with medium containing 4-methylumbelliferyl-beta-D-xyloside (Xyl-MU). The cells synthesized Xyl-MU-derivatives which were detected in the culture medium by gel-filtration high-performance liquid chromatography. These included a Xyl-MU-induced glycosaminoglycan and its biosynthetic intermediates, Galbeta1-4Xylbeta1-MU and Galbeta1-3Galbeta1-4Xylbeta1-MU, and other Xyl-MU-induced oligosaccharides, not related to Xyl-MU-induced glycosaminoglycan, were also synthesized. One of these oligosaccharides, sulfate-O-3GlcAbeta1-4Xylbeta1-MU, reacted with HNK-1, a mouse monoclonal antibody raised against human natural killer cells. Human neural cells and skin fibroblasts have also been reported to synthesize HNK-1-reactive sugar chains. Since HNK-1-reactive sugar chains are known to be involved in cell adhesion in the nervous system, the present results suggest that epithelium-derived colorectal cancer cells might also be able to utilize them in cell adhesion.

Topics: Animals; Antibodies, Monoclonal; Carbohydrate Sequence; CD57 Antigens; Chromatography, Gel; Chromatography, High Pressure Liquid; Colorectal Neoplasms; Culture Media; Disaccharides; Glucuronidase; Glycosaminoglycans; Humans; Hydrolysis; Hymecromone; Mice; Molecular Sequence Data; Oligosaccharides; Tumor Cells, Cultured