|dc.description.abstract||A link between obesity and risk of colorectal cancer development is strongly supported by epidemiological studies. Several obesity-related factors are implicated in this relationship. Among them, insulin resistance, a direct consequence of excess body weight, is considered as one of the most important. However, the role of obesity and related conditions in disease progression and outcome in colorectal cancer patients is not completely clear. This study investigated the contribution of obesity, insulin resistance and inflammation in colorectal cancer progression and patient survival. As a potential mechanism that could mediate the effect of obesity on colorectal cancer outcome, this study focused on tumour angiogenesis and on tumour resistance to chemotherapy.
Patient body mass index (BMI), body surface area, as well as circulating markers of obesity, insulin resistance, inflammation (insulin, C-peptide, insulin-like growth factor-1 (IGF-1), C-reactive protein (CRP) and adiponectin) and angiogenesis (angiopoietin-2 (Ang-2), VEGF-A) were analysed in a New Zealand cohort of 344 colorectal cancer patients in relation to each other, to markers of disease progression and to patient survival. The effect of obesity-related and inflammatory factors on one of the main regulators of angiogenesis, hypoxia-inducible factor-1 (HIF-1), in colon cancer and stromal cells was analysed in vitro. Tumour angiogenesis was compared in two groups of colorectal cancer patients with distinct metabolic characteristics using immunohistochemical staining of tumour samples and analysis of angiogenic proteins levels. The effect of insulin and IGF-1 on cellular responses to chemotherapy drugs (5-fluorouracil, oxaliplatin and irinotecan) in colon cancer and endothelial cells was analysed in vitro.
In the colorectal cancer patient cohort, serum CRP and Ang-2, but not other markers, were associated with more advanced tumour characteristics and with worse patient survival. The immunohistochemical analysis of tumour samples showed no difference in tumour angiogenesis between colorectal cancer patients with different metabolic profiles. However, the results suggested that obesity-related factors may contribute to regulation of angiogenic pathways, and this was confirmed in vitro and in tumour tissue protein extracts. Finally, insulin and IGF-1 were shown to modulate the in vitro cellular response to chemotherapy drugs in colon cancer and endothelial cells.||