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Title: Investigation into the role of HMGb1 in relation to myofibroblasts and cancer cells exposed to various conditions
Author: Sharma, Sikander
ISNI:       0000 0004 5369 7438
Awarding Body: Liverpool John Moores University
Current Institution: Liverpool John Moores University
Date of Award: 2015
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A dynamic stroma that changes with alterations occurring in the epithelium is fundamental for the maintenance of epithelial tissue. Glucose starvation, anoxia 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 they are known to be involved in all stages of tumour progression. HMGb1 is a nuclear protein that plays an important role in nucleosome stabilisation and gene transcription. Whilst HMGb1 is a nuclear protein, it has been reported to takes part in the immune system when passively released by necrotic cells or actively secreted by inflammatory cells such as dendritic cells in the extracellular milieu. The data presented in this thesis suggests that the microenvironmental condition of glucose starvation is responsible for the active release of HMGb1 from different types of cancer cell lines (HT29, MCF-7 and A549) under normoxic conditions. Recombinant HMGb1 (10ng/ml) was shown to trigger proliferation in myofibroblasts cells via activation of PI3K and MEK1/2. Conditioned medium collected from glucose deprived HT29 cells was shown to stimulate migration and invasion of colonic myofibroblasts, and these processes were significantly inhibited by immunoneutralising antibodies to HMGb1, RAGE and TLR-4, along with specific inhibitors of PI3K and MEK1/2. In addition, MMP-2 and MMP-9 two major degraders of basement membrane were investigated for their involvement in CCD18 myofibroblasts migration and invasion in matrigel membrane invasion assay setup. The data suggested that these proteases are not upregulated in this set up and thought not to play any major role in the migration and invasion of myofibroblast cells. There remains a possibility for other proteases being released from myofibroblasts and subsequent digestion of matrigel matrix in this set up. Together these data suggest that HMGb1 released from the cancer cells under glucose starvation is involved in stimulating the CCD18 myofibroblasts migration and invasion and that this was through activation of RAGE and TLR-4, resulting in activation of the MAPK and PI3K signalling pathways. Thus, this study suggests that HMGb1 may be released by cancer cells in areas of low glucose in solid tumours with the resulting activation of myofibroblasts. Therefore, HMGb1 may be considered as potential therapeutic target to inhibit solid tumour growth.
Supervisor: Evans, Andrew ; Hemers, Elaine ; Hobbs, Glyn Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral