Type

PhD Thesis

Authors

Graham Pidgeon

Subjects

Microbiology

Topics
cell biology biotechnology cancer therapeutic use tumor growth gram negative bacteria endotoxins tumor development

Effect of surgery and endotoxin on metastatic tumor growth and regulation of VEGF expression and angiogenesis by endotoxin (2001)

Abstract The surgical removal of primary tumours has been associated with the subsequent growth of previously dormant metastases. This accelerated growth has previously been ascribed to the removal of the primary tumour and the anti-angiogenic factors they produce, such as angiostatin and endostatin. Endotoxin or lipopolysaccharide (LPS) is a cell wall constituent of gram negative bacteria, ubiquitously present in air and endogenous gut bacteria, that may be introduced during surgery. LPS has been shown to be angiogenic and vascular endothelial growth factor (VEGF) is the most potent angiogenic cytokine identified to date. The role of endotoxin in surgically induced metastatic tumour growth, the therapeutic use of anti-endotoxin agents in the perioperative period, the regulation of VEGF expression by endotoxin and the effect of VEGF and endotoxin on tumour cell survival was examined. A murine model of experimental metastasis was established where no primary tumour was present. This allowed the effect of the surgical procedure on metastatic growth to be examined in the absence of any possible angiostatin / endostatin effect. Animals undergoing open surgery or laparoscopy with air sufflation of the peritoneum displayed increased metastatic tumour burden, reflected in higher proliferation and lower apoptosis within the metastases. Circulating levels of VEGF were also elevated in these groups and correlated with plasma levels of endotoxin. These changes were not observed in a group receiving laparoscopy with sterile C 0 2. Endotoxin injection resulted in similar effects, with increased metastatic burden and significantly higher serum VEGF levels than controls. The anti-endotoxin agent, rBPI21, reduced metastatic growth and serum VEGF levels in mice following LPS injection or open surgery, whereas the monoclonal antibody, E5, had no effect on tumour growth. LPS increased tumour cell proliferation and VEGF production. Endotoxin also increased proliferation, decreased apoptosis and enhanced the production of VEGF by endothelial cells and resulted in increased angiogenesis in vivo. LPS, through the induction of VEGF, or VEGF alone increased Bcl-2 expression in tumour cells resulting in a significant decrease in tumour cell apoptosis. These results demonstrate that endotoxin plays a role in the enhanced growth of metastases following surgical trauma by altering the critical balances governing tumour growth. Treatment with the antiendotoxin agent, rBPI2), blocked post-operative growth of metastases. Endotoxin regulates immune and tumour cell production of VEGF. Furthermore, endotoxin, through the induction of VEGF, or VEGF alone act as survival factors for tumour cells.
Collections Ireland -> Dublin City University -> Thesis Type = Doctoral Thesis
Ireland -> Dublin City University -> Subject = Biological Sciences: Cell biology
Ireland -> Dublin City University -> DCU Faculties and Centres = DCU Faculties and Schools: Faculty of Science and Health
Ireland -> Dublin City University -> Subject = Biological Sciences: Biotechnology
Ireland -> Dublin City University -> Publication Type = Thesis
Ireland -> Dublin City University -> Subject = Medical Sciences: Cancer
Ireland -> Dublin City University -> DCU Faculties and Centres = DCU Faculties and Schools
Ireland -> Dublin City University -> Subject = Biological Sciences
Ireland -> Dublin City University -> Status = Unpublished
Ireland -> Dublin City University -> Subject = Medical Sciences
Ireland -> Dublin City University -> DCU Faculties and Centres = DCU Faculties and Schools: Faculty of Science and Health: School of Biotechnology

Full list of authors on original publication

Graham Pidgeon

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Graham Pidgeon
Trinity College Dublin
Total Publications: 38