Thompson Massey (queenoffice19)

Wnt, a family of secreted signal proteins, serves diverse functions in animal development, stem cell systems, and carcinogenesis. Although Wnt is generally considered a morphogen, the mechanism by which Wnt ligands disperse is still debated. Heparan sulfate proteoglycans (HSPGs) are extracellular regulators involved in Wnt ligand dispersal. Drosophila genetics have revealed that HSPGs participate in accumulation and transport of Wnt ligands. Based on these findings, a "restricted diffusion" model, in which Wnt ligands are gradually transferred by repetitive binding and dissociation to HSPGs, has been proposed. WH-4-023 mouse Nonetheless, we recently found that HSPGs are not uniformly distributed, but are locally clustered on cell surfaces in Xenopus embryos. HSPGs with N-sulfo-rich HS chains and those with N-acetyl-rich unmodified HS chains form different clusters. Furthermore, endogenous Wnt8 ligands are discretely accumulated in a punctate fashion, colocalized with the N-sulfo-rich clusters. Based on these lines of evidence, here we reconsider the classical view of morphogen spreading controlled by HSPGs.Gastrointestinal cancers are a significant cause of cancer mortality worldwide and have been strongly linked with chronic inflammation. Current therapies focus on epithelial/cancer cells; however, the importance of the tumor microenvironment in the development and treatment of the disease is also now well established. Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment, and are actively participating in tumor initiation, promotion and metastasis. They structurally and functionally affect cancer cell proliferation, tumor immunity, angiogenesis, extracellular matrix remodeling and metastasis through a variety of signaling pathways. CAFs originate predominantly from resident mesenchymal cells, which are activated and reprogrammed in response to cues from cancer cells. In recent years, chronic inflammation of the gastrointestinal tract has also proven an important driver of mesenchymal cell activation and subsequent CAF development, which in turn are capable of regulating the transition from acute to chronic inflammation and cancer. In this review, we will provide a concise overview of the mechanisms that drive fibroblast reprogramming in cancer and the recent advances on the downstream signaling pathways that regulate the functional properties of the activated mesenchyme. This new mechanistic insight could pave the way for new therapeutic strategies and better prognosis for cancer patients.Hepatocellular carcinoma (HCC) has a dismal long-term outcome. We aimed to construct a multi-gene model for prognosis prediction to inform HCC management. The cancer-specific differentially expressed genes (DEGs) were identified using RNA-seq data of paired tumor and normal tissue. A prognostic signature was built by LASSO regression analysis. Gene set enrichment analysis (GSEA) was performed to further understand the underlying molecular mechanisms. A 10-gene signature was constructed to stratify the TCGA and ICGC cohorts into high- and low-risk groups where prognosis was significantly worse in the high-risk group across cohorts (P less then 0.001 for all). The 10-gene signature outperformed all previously reported models for both C-index and the AUCs for 1-, 3-, 5-year survival prediction (C-index, 0.84 vs 0.67 to 0.73; AUCs for 1-, 3- and 5-year OS, 0.84 vs 0.68 to 0.79, 0.81 to 0.68 to 0.80, and 0.85 vs 0.67 to 0.78, respectively). Multivariate Cox regression analysis revealed risk group and tumor stage to be independent predictors of survival in HCC. A nomogram incorporating tumor stage and signature-based risk group showed better performance for 1- and 3-year survival than for 5-year survival. GSEA revealed enrichment of pathways related to cell cycle regulation among high-risk samples and metabolic processes in the low-risk group. Our 10-gene model is robust for prognosis prediction and may help