Surgery (Austin & Northern Health) - Theses
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ItemThe renin angiotensin system and macrophages in regulation of colorectal liver metastases( 2012)Metastasis to the liver is the leading cause of death for colorectal cancer (CRC) patients. The systemic treatment of CRC liver metastases is suboptimal and with limited response rates. Targeting of the renin angiotensin system (RAS) may be a potential adjunct therapeutic strategy in this disease. Blockade of the RAS can inhibit tumour growth in a mouse model of CRC liver metastases. However, the underlying mechanisms remain unclear. Participation of the RAS in inflammatory diseases and in malignancy suggests that macrophages may be a novel mediator of RAS-induced effects. This thesis addressed the role of the RAS in regulating macrophage biology and its consequent impact on the growth of CRC liver metastases. Macrophage depletion studies using an orthotopic murine model of CRC liver metastases demonstrated the bimodal role of macrophages in determining tumour growth. They exhibit an early inhibitory and a later stimulatory effect. Alterations in iNOS- and VEGF- expressing cells, and T-cell responses may be responsible for the observed reduction in tumour burden following depletion of pro-tumour macrophages at the late stage of metastatic growth. Using combined in-vitro with in-vivo experiments the potential of the RAS to alter macrophage function was demonstrated. In-vivo, the anti-tumour affects of ACE inhibition (captopril) on CRC liver metastases was mediated by changes in macrophage biology that inhibited initial tumour seeding and proliferation, as well as promoting macrophage migration. In-vitro, both key RAS peptides, Ang II and Ang-(1–7) were capable of altering tumour-regulatory factors, including iNOS, MMP-9, VEGF and TNF-α in murine macrophages. These factors are equally important in directing macrophage polarisation (M1 or M2 macrophages). Conditioned media from macrophages stimulated with Ang-(1–7) reduced the proliferation and viability of both human and mouse CRC cells, but increased cell migration in-vitro. Supernatant of Ang II-treated macrophages also altered the kinetics of mouse, but not human CRC cells. Interestingly, Ang II and its receptor inhibition did not induce distinct macrophage polarisation. It is clear the RAS has important immunomodulatory roles that can regulate tumour progression and its metastasis. Further understanding of these physiological mechanisms will enable agents targeting the RAS to reach their full therapeutic potential in the treatment of CRC liver metastasis.