ABSTRACT
Colorectal cancer (CRC) is one of the most prevalent fatal neoplasias worldwide. Despite efforts to improve the early diagnosis of CRC, the mortality rate of patients is still nearly 50%. The primary treatment strategy for CRC is surgery, which may be accompanied by chemotherapy and radiotherapy. The conventional and first-line chemotherapeutic agent utilized is 5-fluorouracil (5FU). However, it has low efficiency. Combination treatment with leucovorin and oxaliplatin or irinotecan improves the effectiveness of 5FU therapy. Unfortunately, most patients develop drug resistance, leading to disease progression. Here, we evaluated the effect of a potential alternative adjuvant treatment for 5FU, helminth-derived Taenia crassiceps (TcES) molecules, on treating advanced colitis-associated colon cancer. The use of TcES enhanced the effects of 5FU on established colonic tumors by downregulating the expression of the immunoregulatory cytokines, Il-10 and Tgf-ß, and proinflammatory cytokines, Tnf-α and Il-17a, and reducing the levels of molecular markers associated with malignancy, cyclin D1, and Ki67, both involved in apoptosis inhibition and the signaling pathway of ß-catenin. TcES+5FU therapy promoted NK cell recruitment and the release of Granzyme B1 at the tumor site, consequently inducing tumor cell death. Additionally, it restored P53 activity which relates to decreased Mdm2 expression. In vitro assays with human colon cancer cell lines showed that therapy with TcES+5FU significantly reduced cell proliferation and migration by modulating the P53 and P21 signaling pathways. Our findings demonstrate, for the first time in vivo, that helminth-derived excreted/secreted products may potentiate the effect of 5FU on established colon tumors.
Subject(s)
Fluorouracil , Animals , Fluorouracil/pharmacology , Fluorouracil/therapeutic use , Taenia/drug effects , Colonic Neoplasms/drug therapy , Colonic Neoplasms/pathology , Apoptosis/drug effects , Cytokines/metabolism , Mice , Humans , Cell Line, Tumor , Carcinogenesis/drug effects , Granzymes/metabolism , Cell Proliferation/drug effects , Mice, Inbred BALB CABSTRACT
AIMS: Cervical Cancer (CC) is one of the most important health problems in women. It frequently presents genetic changes at chromosome region 3q21. This region contains the Cellular Retinol Binding Protein 1 gene (CRBP1) which has been implicated as an important element in the development of other types of cancer. The main goal of the present work was to determine the molecular alterations of CRBP1 and its relationship to CC. METHODS: To determine the molecular alterations of CRBP1 gene in CC; twenty-six CC and twenty-six healthy cervix samples were evaluated for: 1) Copy number gain by real-time PCR analysis, 2) expression levels by an immunohistochemistry assay on tissue microarray, and 3) the methylation status of the CRBP1 promoter region. RESULTS: The increase in CRBP1 copy number was observed in 10 out of the 26 CC samples analyzed, while healthy cervices samples showed no changes in the copy number. In addition, there was a lack of expression of the CRBP1 gene in an important number of the CC samples (17/26), and the CRBP1 gene promoter was methylated in 15/26 of the CC samples. Interestingly, there was a significant association between the lack of expression of the CRBP1 gene and its methylation status. CONCLUSIONS: The data indicates that, both activating and inactivating changes in the CRBP1 gene could be significant events in the development and progression of CC, and the lack of expression of the CRBP1 protein could be related with to the development of CC. We believe that there is enough evidence to consider to CRBP1 gene as a tumor suppressor gene for CC.
Subject(s)
Biomarkers, Tumor/genetics , Carcinoma, Squamous Cell/genetics , Genes, Tumor Suppressor , Retinol-Binding Proteins, Cellular/genetics , Uterine Cervical Neoplasms/genetics , Biomarkers, Tumor/metabolism , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Case-Control Studies , DNA Copy Number Variations , DNA Methylation , Female , Gene Dosage , Gene Expression Regulation, Neoplastic , Genetic Predisposition to Disease , HeLa Cells , Humans , Middle Aged , Phenotype , Promoter Regions, Genetic , Retinol-Binding Proteins, Cellular/metabolism , Uterine Cervical Neoplasms/metabolism , Uterine Cervical Neoplasms/pathologyABSTRACT
Cultured glial cells from the cerebellum of 15-day-old taiep rats produced NO, increased iNOS levels, up-regulated iNOS expression and promoted TNF release when stimulated with LPS and IFNgamma. These responses were much greater than in control cells. In taiep glial cells, NO production and iNOS levels and expression induced by the co-stimulatory signal were resistant to the inhibitory effect of TGFbeta1. The glial cell priming might have been generated by oligodendrocyte alteration in taiep rats.
