Regulation of TRAIL receptor expression by ß-catenin in colorectal tumours.

Tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL) is being investigated as a targeted cancer therapeutic and the expression of its pro-apoptotic receptors, DR4 and DR5, increases during colorectal carcinogenesis. This study investigated the role of ß-catenin in the regulation of these receptors. In human colorectal adenoma and carcinoma cell lines, downregulation of ß-catenin resulted in lower total DR4 and DR5 protein levels. Similarly, cell membrane expression of DR4 and DR5 was reduced after downregulation of ß-catenin in colon carcinoma cells, whereas induction of ß-catenin in HeLa cells led to increased cell membrane expression of DR4 and DR5. Downregulation of ß-catenin decreased the recombinant human TRAIL sensitivity of human colon carcinoma cells. Activation of the transcription factor T-cell factor-4 (TCF-4) is an important function of ß-catenin. Dominant-negative TCF-4 overexpression, however, did not significantly affect TRAIL receptor expression or recombinant human TRAIL sensitivity. Human colorectal adenomas (N = 158) with aberrant (cytoplasmic and nuclear) ß-catenin expression had a higher percentage of immunohistochemical DR4 and DR5 staining per tumour (mean: 73 and 88%, respectively) than those with membranous ß-catenin staining only (mean: 50 and 70%, respectively, P < 0.01 for both). Furthermore, aberrant ß-catenin staining co-localized with DR4 and DR5 expression in 92% of adenomas. In 53 human colorectal carcinomas, aberrant ß-catenin expression was present in most cases and DR4/5 expression was largely homogenous. Similarly, in adenomas from APC(min) mice, cytoplasmic ß-catenin staining co-localized with staining for the murine TRAIL death receptor. In conclusion, the gradual increase in TRAIL receptor expression during colorectal carcinogenesis is at least partially mediated through increased ß-catenin expression, independently of TCF-4-signalling.

[A woman with gingival enlargement]. / Een vrouw met gezwollen tandvlees.

A 65-year-old female complained of diffuse and rapidly progressive gingival enlargement. Gingival overgrowth can be caused by medication, infections or systemic diseases. In case of generalized, quickly progressive gingival enlargement, acute myeloid leukemia should be considered. Blood results showed an acute myelomonocytic leukemia. Treating the leukemia resolved the symptoms.

Independent induction of caspase-8 and cFLIP expression during colorectal carcinogenesis in sporadic and HNPCC adenomas and carcinomas.

BACKGROUND: TNF-Related Apoptosis Inducing Ligand (TRAIL) is a promising agent for the induction of apoptosis in neoplastic tissues. Important determinants of TRAIL sensitivity are two intracellular proteins of the TRAIL pathway, caspase-8 and its anti-apoptotic competitor cellular Flice-Like Inhibitory Protein (cFLIP). METHODS: The aim of this study was to investigate basic expression of caspase-8 and cFLIP in normal colorectal epithelium (n=20), colorectal adenomas (n=66) and colorectal carcinomas (n=44) using immunohistochemistry performed on both sporadic and Hereditary Non-Polyposis Colorectal Cancer (HNPCC or Lynch syndrome)-associated adenomas and carcinomas. RESULTS: Expression of both caspase-8 and cFLIP was similar in cases with sporadic and hereditary origin. Expression of caspase-8 in colorectal adenomas and carcinomas was increased when compared to normal colon tissue (P=0.02). Nuclear, paranuclear as well as cytoplasmic localizations of caspase-8 were detected. Immunohistochemistry revealed an upregulation of cFLIP in colorectal carcinomas in comparison to normal epithelium and colorectal adenomas (P<0.001). A large variation in the caspase-8/cFLIP ratio was observed between the individual adenomas and carcinomas. CONCLUSION: Caspase-8 and cFLIP are upregulated during colorectal carcinogenesis. Upregulation of caspase-8 and/or downregulation of cFLIP may be interesting approaches to maximize TRAIL sensitivity in colorectal neoplasms.

T-cells fighting B-cell lymphoproliferative malignancies: the emerging field of CD19 CAR T-cell therapy.

CAR T-cells are autologous T-cells transduced with a chimeric antigen receptor (CAR). The CAR contains an antigen recognition part (originating from an antibody), a T-cell receptor transmembrane and cytoplasmic signalling part, and one or more co-stimulatory domains. While CAR T-cells can be directed against any tumour target, most experience thus far has been obtained with targeting of the B-cell antigen CD19 that is expressed by B-cell acute lymphocytic leukaemia, chronic lymphocytic leukaemia and other B-cell lymphomas. The first clinical results are promising, although there are profound differences in response between patients with different haematological malignancies. Treatment-related side effects have been observed that require specific management. This review will explain the mechanism of action, summarise the experience to date and point out future directions for this hopeful new addition to the therapeutic armamentarium in the treatment of lymphoproliferative B-cell malignancies.

A bioinformatical and functional approach to identify novel strategies for chemoprevention of colorectal cancer.

Comparing normal colorectal mucosa and adenomas focusing on deregulated pathways obtains insight into the biological processes of early colorectal carcinogenesis. Publicly available microarray expression data from 26 normal mucosa and 47 adenoma samples were analyzed. Biological pathways enriched in adenomas were identified with Gene Set Enrichment Analysis (GSEA). The analysis revealed 10, 11 and 16 gene sets distinguishing adenomas from normal mucosa according to Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Map Annotator and Pathway Profiler (GenMAPP) and Biocarta databases, respectively. Biological pathways known to be involved in colon carcinogenesis such as cell cycle (P=0.002) and Wnt signaling (P=0.007) were enriched in adenomas. In addition, we found enrichment of novel pathways such as retinoblastoma (Rb) pathway (P=0.002), Src pathway (P=0.004), folate biosynthesis (P=0.019) and Hedgehog signaling (P=0.037) in adenomas. Microarray results for Rb and Src pathway genes were validated by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) on mRNA isolated from an independent set of adenoma and normal colon samples. A high correlation between microarray data and qRT-PCR expression data was found. The relevance of targeting of identified pathways was shown using the Rb pathway inhibitors roscovitine and PD-0332991 and the Src pathway inhibitor dasatinib. All inhibitors used induced cell growth reduction in adenoma cells. This study shows a bioinformatical and functional approach leading to potentially new options for chemoprevention of colorectal cancer.