Mesenchymal-epithelial signalling in tumour microenvironment: role of high-mobility group Box 1.

Glucose deprivation, hypoxia and acidosis are characteristic features of the central core of most solid tumours. Myofibroblasts are stromal cells present in many such solid tumours, including those of the colon, and are known to be involved in all stages of tumour progression. HMGB1 is a nuclear protein with an important role in nucleosome stabilisation and gene transcription; it is also released from immune cells and is involved in the inflammatory process. We report that the microenvironmental condition of glucose deprivation is responsible for the active release of HMGB1 from various types of cancer cell lines (HT-29, MCF-7 and A549) under normoxic conditions. Recombinant HMGB1 (10 ng/ml) triggered proliferation in myofibroblast cells via activation of PI3K and MEK1/2. Conditioned medium collected from glucose-deprived HT-29 colon cancer cells stimulated the migration and invasion of colonic myofibroblasts, and these processes were significantly inhibited by immunoneutralising antibodies to HMGB1, RAGE and TLR4, together with specific inhibitors of PI3K and MEK1/2. Our data suggest that HMGB1 released from cancer cells under glucose deprivation is involved in stimulating colonic myofibroblast migration and invasion and that this occurs through the activation of RAGE and TLR4, resulting in the activation of the MAPK and PI3K signalling pathways. Thus, HMGB1 might be released by cancer cells in areas of low glucose in solid tumours with the resulting activation of myofibroblasts and is a potential therapeutic target to inhibit solid tumour growth

Attendance and attainment are they linked: a study in the first-year of a bioscience degree

There is much evidence in the literature that suggests that student attendance rate is linked with both attainment and retention. Levels of attendance have been shown to be influenced by many factors, such as part-time work and day and time of learning opportunity. The aims of this current study were to investigate the links between a) attendance and attainment b) attendance and day/time of the module in two first-year modules of a bioscience degree. The results confirm the link between attendance and module attainment, but did not find a relationship between attendance and timetabling of the module. Therefore, for any university aiming to increase their overall student attainment the key recommendation would be the introduction of a robust and visible attendance monitoring system

Epithelial-mesenchymal signalling : role of matrix metalloproteinase-7

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

The role of matrix metalloproteinase-7 in redefining the gastric microenvironment in response to Helicobacter pylori

BACKGROUND & AIMS: Interactions between epithelial and stromal cells are important determinants of mucosal organization, but the signaling mechanisms are understood incompletely. Matrix metalloproteinase (MMP)-7 is produced uniquely in epithelia, may act on growth factors and matrix proteins, and in the stomach is increased with Helicobacter pylori infection. We have studied the role of MMP-7 in signaling between epithelial cells and a key stromal cell type, the myofibroblast. METHODS: Immunohistochemistry and Western blotting were applied to gastric corpus biopsy specimens; primary cultures of human gastric glands and myofibroblasts were used to study the role of MMP-7 in regulating proliferation and migration of the latter, and MMP-7 substrates were identified by proteomic methods. RESULTS: Increased abundance of the myofibroblast marker alpha-smooth muscle actin was identified in H. pylori-positive biopsy specimens. Media from H pylori-infected gastric epithelial cultures stimulated proliferation and migration of primary human gastric myofibroblasts and antisense oligonucleotide treatment indicated a role for MMP-7. Proteomic methods identified insulin-like growth factor binding protein (IGFBP)-5 as a substrate for MMP-7 in medium from gastric myofibroblasts. Knockdown of IGFBP-5 by small interfering RNA or immunoneutralization of IGF-II, abolished myofibroblast responses to MMP-7. Proliferation of gastric epithelial cells also was stimulated by MMP-7-treated myofibroblasts via IGF-II. CONCLUSIONS: MMP-7 acts as an epithelial-derived signal increasing the bioavailability of IGF-II released from myofibroblasts. Because IGF-II acts on both stromal and epithelial cells, the findings suggest that increased MMP-7 expression contributes to redefining the niche occupied by dividing cells and leading to hyperproliferation in H pylori infection