Molecular Targets of CNS Tumors

Molecular Targets of CNS Tumors is a selected review of Central Nervous System (CNS) tumors with particular emphasis on signaling pathway of the most common CNS tumor types. To develop drugs which specifically attack the cancer cells requires an understanding of the distinct characteristics of those cells. Additional detailed information is provided on selected signal pathways in CNS tumors

The Roles of MIST1 and RAB26 in Zymogenic (Chief) Cell Differentiation and Subcellular Organization

Little is known about how differentiating cells reorganize their cellular structure to perform specialized physiological functions. Specifically, exocrine cells like pancreatic acinar and zymogenic chief cells have a highly developed secretory architecture that is rapidly established upon differentiation. What is known in these cells is that the evolutionarily conserved transcription factor MIST1 is required for final maturation. We hypothesized that MIST1 directly regulates specific subcellular components that facilitate functional maturation of secretory cells. We show that MIST1 binds to conserved CATATG E-boxes to activate transcription of 6 genes, including the small GTPases RAB26 and RAB3D. We next demonstrate that RAB26 and RAB3D expression is significantly downregulated in Mist1-/- ZCs and upregulated in gastric cancer cell lines stably expressing MIST1 and induced to form secretory granules. Moreover, granule formation in these MIST1-expressing cells requires Rab activity because treatment with a Rab prenylation inhibitor or transfection of dominant negative RAB26 abrogates granule formation. We next sought to elucidate how a scaling factor like MIST1 rearranges cellular architecture through transcriptional targets, specifically RAB26. We confirm that RAB26 expression was tissue specific and confined to acinar secretory cells. Functional studies in gastric cell lines showed RAB26 association with lysosomes but not with secretory granules. In addition, increasing RAB26 expression caused lysosomes to coalesce in a central, perinuclear region, causing redistribution of other organelles including mitochondria into distinct subcellular neighborhoods. In mouse exocrine cells that are null for Mist1 and lack RAB26, we found lysosomes to be similarly abnormally distributed. Normally, lysosomes cluster centrally and basally away from secretory granules, whereas in Mist1-/- cells, they rapidly accumulate apically and degrade secretory vesicles. We confirmed active granule degradation when much of the vesicle phenotype in Mist1-/- mice was rescued upon crossing with mice deficient in the lysosome acid hydrolase processing enzyme, GlcNAc-1-phosphotransferase, alpha and beta subunits (Gntpab-/-). Taken together, we propose that MIST1 promotes normal maturation of secretory granules through blocking their targeting by the cellular degradation/recycling machinery. These results illustrate how a transcription factor can regulate cell architecture and have implications for disease processes like acute pancreatitis where MIST1 is lost, and secretory vesicles are targeted to lysosomes

A biomaterials approach for therapeutic angiogenesis

Peripheral arterial disease (PAD) affects over 200 million people worldwide and can lead to limb ischaemia, amputation and death. Therapeutic angiogenesis aims to promote the formation of new blood vessels in order to treat ischaemia. The programming inherent within cells can be utilised to treat diseases at the cellular level. Adipose derived mesenchymal stem cells (ADMSCs) have been shown to secrete pro-angiogenic proteins, thus could have great potential as a therapy for ischemic disease. In addition, biomaterials can effectively deliver therapeutics to a target site and utilise physical characteristics to influence cell behaviour. Surface topography is known to influence cell alignment, morphology and affect cellular expression of growth factors. This work investigated the effect of surface topography on the secretion of angiogenic growth factors from ADMSCs. Hierarchically structured substrate materials were prepared from poly-DL-lactide-co-glycolide (PLGA) using a thermally induced phase separation (TIPS) process. TIPS materials were characterised using atomic force microscopy to quantify roughness and stiffness, as well as scanning electron microscopy techniques where PLGA processed with TIPS were shown to have higher surface roughness and porosity values. ADMSC proliferation increased on the TIPS-processed substrates compared with the control substrates and the effect of surface topography on the angiogenic secretome of ADMSCs was measured using an in vitro model of angiogenesis, proteomic analysis and measurement of vascular endothelial growth factor (VEGF165). VEGF165 was significantly increased in the supernatants collected from ADMSCs cultured on the TIPS substrate compared with control substrates when normalised for the number of cells. The collected supernatants resulted in increased capillary tubule length, number of capillary junctions and capillary branches in the in vitro angiogenesis assay compared with supernatants collected from control substrates. 5 This work also investigated the effects of TIPS-processed materials implanted in a pre-clinical model of PAD. Laser Doppler imaging revealed an increase in revascularisation in the ischeamic limbs treated TIPS processed materials compared with control materials. Histology and von Willebrand factor staining revealed evidence of blood vessel formation around the implanted TIPS processed materials. This study has shown that ADMSCs seeded onto 2D and 3D TIPS-processed PLGA secreted increased quantities of pro-angiogenic factors in vitro, and when implanted in vivo, TIPS-processed biomaterials improved reperfusion in a pre-clinical model of PAD. These findings open up the opportunity for utilising a unique biomaterial for the treatment of ischemic disease through the promotion of angiogenesis

The HBP1 tumor suppressor is a negative epigenetic regulator of MYCN driven neuroblastoma through interaction with the PRC2 complex

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The senescent cell induced bystander effect

PhD ThesisThe induction of senescence in response to persistent stress induces major phenotypic changes in senescent cells, including the secretion of a host of inflammatory factors and reactive oxygen species. Recent evidence has implicated senescent cells in the diseases of ageing and cancer; however, the mechanism by which this occurs is still unknown. This thesis uses a reporter cell line with cells expressing a fluorescent conjugate that allows real time live cell imaging of a sub set of cells within a co-culture, to provide the first evidence that senescent cells can induce a DNA damage response in healthy cells, and thus implicates a potential mechanism by which senescent cells could non-autonomously contribute to the ageing process. The use of specific inhibitors, stimulation, and targeted repression indicate that gap junctions, reactive oxygen species, p38, mTOR and NF-κB all play a key role in this observed bystander effect of senescent cells, and offer potential targets for therapies designed to reduce the damaging effects of senescent cells.Proctor & Gamble: BBSRC